The Promising Seesaw Relationship Between Activity and Stability of Ru-Based Electrocatalysts for Acid Oxygen Evolution and Proton Exchange Membrane Water Electrolysis.

The development of electrocatalysts that are not reliant on iridium for efficient acid-oxygen evolution is a critical step towards the proton exchange membrane water electrolysis (PEMWE) and green hydrogen industry. Ruthenium-based electrocatalysts have garnered widespread attention due to their remarkable catalytic activity and lower commercial price. However, the challenge lies in balancing the seesaw relationship between activity and stability of these electrocatalysts during the acid-oxygen evolution reaction (OER). This review delves into the progress made in Ru-based electrocatalysts with regards to acid OER and PEMWE applications. It highlights the significance of customizing the acidic OER mechanism of Ru-based electrocatalysts through the coordination of adsorption evolution mechanism (AEM) and lattice oxygen oxidation mechanism (LOM) to attain the ideal activity and stability relationship. The promising tradeoffs between the activity and stability of different Ru-based electrocatalysts, including Ru metals and alloys, Ru single-atomic materials, Ru oxides, and derived complexes, and Ru-based heterojunctions, as well as their applicability to PEMWE systems, are discussed in detail. Furthermore, this paper offers insights on in situ control of Ru active sites, dynamic catalytic mechanism, and commercial application of PEMWE. Based on three-way relationship between cost, activity, and stability, the perspectives and development are provided.

In Situ Electrochemical Rapid Induction of Highly Active γ-NiOOH Species for Industrial Anion Exchange Membrane Water Electrolyzer.

Limited by the strong oxidation environment and sluggish reconstruction process in oxygen evolution reaction (OER), designing rapid self-reconstruction with high activity and stability electrocatalysts is crucial to promoting anion exchange membrane (AEM) water electrolyzer. Herein, trace Fe/S-modified Ni oxyhydroxide (Fe/S-NiOOH/NF) nanowires are constructed via a simple in situ electrochemical oxidation strategy based on precipitation-dissolution equilibrium. In situ characterization techniques reveal that the successful introduction of Fe and S leads to lattice disorder and boosts favorable hydroxyl capture, accelerating the formation of highly active γ-NiOOH. The Density Functional Theory (DFT) calculations have also verified that the incorporation of Fe and S optimizes the electrons redistribution and the d-band center, decreasing the energy barrier of the rate-determining step (*O→*OOH). Benefited from the unique electronic structure and intermediate adsorption, the Fe/S-NiOOH/NF catalyst only requires the overpotential of 345 mV to reach the industrial current density of 1000 mA cm-2 for 120 h. Meanwhile, assembled AEM water electrolyzer (Fe/S-NiOOH//Pt/C-60 °C) can deliver 1000 mA cm-2 at a cell voltage of 2.24 V, operating at the average energy efficiency of 71% for 100 h. In summary, this work presents a rapid self-reconstruction strategy for high-performance AEM electrocatalysts for future hydrogen economy.

A distributed parameter model of the Janus-Helmholtz transducer.

The Janus-Helmholtz (JH) transducer is a low-frequency, high-power, broadband underwater transducer type. Numerous studies have shown the effectiveness of the finite element method (FEM) in designing JH transducers and predicting their electroacoustic performance. However, a precise theoretical model for JH transducers has not yet been proposed, and the modal identification problem of JH transducers remains unsolved. In this paper, a distributed parameter model (DPM) of the JH transducer is proposed, which consists of the DPM of a Janus transducer and the DPM of a cylindrical liquid cavity under elastic wall conditions. By comparing the DPM with FEM, it is confirmed that the DPM can accurately calculate the resonant frequencies, admittance, amplitude, and phase of vibration velocity of the JH transducer. Additionally, a physical analogy is introduced to reveal the relationships between the transducer's resonances. Two JH transducers with different liquid cavities are fabricated and tested, and the results from the DPM, FEM, and experiments exhibit good agreement. The DPM can not only provide valuable theoretical support but also significantly reduce much time in designing JH transducers. Furthermore, it may inspire further advancements in adjusting the resonant frequencies or expanding the working bandwidth of JH transducers.

Dynamically Stabilized Electronic Regulation and Electrochemical Reconstruction in Co and S Atomic Pair Doped Fe3 O4 for Water Oxidation.

The electronic regulation and surface reconstruction of earth-abundant electrocatalysts are essential to efficient oxygen evolution reaction (OER). Here, an inverse-spinel Co,S atomic pair codoped Fe3 O4 grown on iron foam (Co,S-Fe3 O4 /IF) is fabricated as a cost-effective electrocatalyst for OER. This strategy of Co and S atomic pair directional codoping features accelerates surface reconstruction and dynamically stabilizes electronic regulation. CoS atomic pairs doped in the Fe3 O4 crystal favor controllable surface reconstruction via sulfur leaching, forming oxygen vacancies and Co doping on the surface of reconstructed FeOOH (Co-FeOOH-Ov /IF). Before and after surface reconstruction via in situ electrochemical process, the Fe sites with octahedral field dynamically maintains an appropriate electronic structure for OER intermediates, thus exhibiting consistently excellent OER performance. The electrochemically tuned Fe-based electrodes exhibit a low overpotential of 349 mV at a current density of 1000 mA cm-2 , a slight Tafel slope of 43.3 mV dec-1 , and exceptional long-term electrolysis stability of 200 h in an alkaline medium. Density functional theory calculations illustrate the electronic regulation of Fe sites, changes in Gibbs free energies, and the breaking of the restrictive scaling relation between OER intermediates. This work provides a promising directional codoping strategy for developing precatalysts for large-scale water-splitting systems.

The effects of polyethylene microplastics on the growth, reproduction, metabolic enzymes, and metabolomics of earthworms Eisenia fetida.

The existing data regarding the effects of polyethylene (PE) microplastics (MPs) smaller than 5 mm in size on earthworms are insufficient to fully comprehend their toxicity. In this study, earthworms Eisenia fetida were exposed to artificially added PE at a concentration ranging from 0.05 to 20 g/kg soil (0.005%-2%) for 60 days to determine the concentration range causing negative effects on earthworms and to uncover the potential toxic mechanisms. The individual growth, reproduction, and metabolic enzyme activities, including phase I enzymes (cytochrome P450 [CYP] 1A2, 2B6, 2C9, and 3A4), and phase II metabolic enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione sulfotransferase (GST)), and metabolomics were measured. The observed variations in responses of multiple cross-scale endpoints indicated that individual indices are less responsive to PE MPs than metabolic enzymes or metabolomics. Despite the absence of significant alterations in growth inhibition based on body weight, PE MPs at concentrations equal to or exceeding 2.5 g/kg were found to exert a toxic effect on earthworms, which was evidenced by significant changes in metabolic enzyme activities (CYP1A2, 2B6, 2C9, and 3A4, SOD, CAT, and GST) and important small molecule metabolites screened based on metabolomics, likely due to the bioaccumulation of PE. The toxicity of PE MPs to earthworms is inferred to be associated with neurotoxicity, oxidative damage, decreased detoxification capacity, energy metabolism imbalance, and impaired amino acid and purine metabolism due to bioaccumulation. The findings of this study will enhance our understanding of the molecular toxicity mechanisms of PE MPs and contribute to a more accurate assessment of the ecological risks posed by PE MPs in soil.

Ligand Modulation of Active Sites to Promote Cobalt-Doped 1T-MoS2 Electrocatalytic Hydrogen Evolution in Alkaline Media.

Highly efficient hydrogen evolution reaction (HER) electrocatalyst will determine the mass distributions of hydrogen-powered clean technologies, while still faces grand challenges. In this work, a synergistic ligand modulation plus Co doping strategy is applied to 1T-MoS2 catalyst via CoMo-metal-organic frameworks precursors, boosting the HER catalytic activity and durability of 1T-MoS2 . Confirmed by Cs corrected transmission electron microscope and X-ray absorption spectroscopy, the polydentate 1,2-bis(4-pyridyl)ethane ligand can stably link with two-dimensional 1T-MoS2 layers through cobalt sites to expand interlayer spacing of MoS2 (Co-1T-MoS2 -bpe), which promotes active site exposure, accelerates water dissociation, and optimizes the adsorption and desorption of H in alkaline HER processes. Theoretical calculations indicate the promotions in the electronic structure of 1T-MoS2 originate in the formation of three-dimensional metal-organic constructs by linking π-conjugated ligand, which weakens the hybridization between Mo-3d and S-2p orbitals, and in turn makes S-2p orbital more suitable for hybridization with H-1s orbital. Therefore, Co-1T-MoS2 -bpe exhibits excellent stability and exceedingly low overpotential for alkaline HER (118 mV at 10 mA cm-2 ). In addition, integrated into an anion-exchange membrane water electrolyzer, Co-1T-MoS2 -bpe is much superior to the Pt/C catalyst at the large current densities. This study provides a feasible ligand modulation strategy for designs of two-dimensional catalysts.

Blockade of exosome generation by GW4869 inhibits the education of M2 macrophages in prostate cancer.

BACKGROUND: Tumor-associated macrophages are considered to be a major contributor affecting the development of tumors. Recently, numerous studies have shown that tumor cells were able to educate their microenvironment by delivering a significant amount of exosomes, however, the mechanism that exosomes from PCa cells work in macrophage polarization remains obscure. Therefore, we sought to determine whether blockade of exosome generation by GW4869, an inhibitor of exosome biogenesis, would impede macrophages from differentiating into M2 cells. RESULTS: In this study, we first obtained exosomes from the supernatant media of PCa cells cultured with exosome-free serum using the Magcapture™ Exosome Isolation Kit PS, and then investigated their effects on macrophages. Our data confirmed that exosomes released by prostate cancer cells can induce macrophages to differentiate into M2 cells. Mechanistically speaking, exosomes exert their effects on macrophages through activating the AKT and STAT3 signaling pathways. Importantly, treatment with GW4869 significantly inhibited the release of exosomes from PCa cells, and further impaired M2 differentiation of macrophages and their pro-tumor activity. We also demonstrated that GW4869 was able to inhibit the education of M2 macrophages, and then inhibit the progression of prostate cancer in vivo. CONCLUSIONS: In brief, our findings indicated that GW4869 impeded the PCa exosome-induced M2 differentiation of macrophages and the progression of prostate cancer, suggesting that GW4869 could play an important role in the treatment of prostate cancer metastasis as an inhibitor of tumor exosome secretion.

Electrocardiographic localization of peripherally inserted central catheter tip position in critically ill patients with advanced cancer: An application study.

BACKGROUND: We compared the methods of electrocardiogram (ECG) and X-ray localization of the peripherally inserted central catheter (PICC) tip position, in order to find a more convenient, practical, and safe method. OBJECTIVE: To investigate the value of applying electrocardiographic localization of the PICC tip position in critically ill patients with advanced cancer in Hebei Province, China. METHOD: Enrolled 137 advanced cancers requiring PICC placement. The position of the catheter tip was localized with the bedside electrocardiogram in real time. Then, the localization was performed using a chest X-ray (the gold standard). The accuracy of electrocardiographic location was checked. RESULTS: Specific P waves were observed in 130 patients. No change in the P waves was observed for the remaining seven patients. The age of the latter group of patients was more advanced (87.29 [5.15] years), a significant difference to that of the 130 patients with specific P waves (71.58 [14.84] years) (t = -6.704, p < .001). Specific P waves not only involve ascendance in P waves but also ascendance in QRS waves. CONCLUSIONS: The use of an ECG to localize the PICC tip in critically ill patients with advanced cancer may replace the unnecessary use of chest X-rays. Specific P waves not only involve an increase in P waves but also an increase in QRS waves. If there is no change in the P wave, a chest X-ray film must be obtained. In elderly patients, because there is a possibility of catheter tip malposition, a comprehensive evaluation should be performed before surgery.

Effects of multi-walled carbon nanotubes in soil on earthworm growth and reproduction, enzymatic activities, and metabolomics.

Increased production and environmental release of multi-walled carbon nanotubes (MWCNTs) increase soil exposure and potential risk to earthworms. However, MWCNT toxicity to earthworms remains unclear, with some studies identifying negative effects and others negligible effects. In this study, to determine whether exposure to MWCNTs negatively affects earthworms and to elucidate possible mechanisms of toxicity, earthworms were exposed to sublethal soil concentrations of MWCNTs (10, 50, and 100 mg/kg) for 28 days. Earthworm growth and reproduction, activities of cytochrome P450 (CYP) isoforms (1A2, 2C9, and 3A4) and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and glutathione-s-transferase (GST)), and metabolomics were determined. Effects of MWCNTs on earthworms depended on exposure concentration. Exposure to MWCNTs did not significantly affect growth and reproduction of individual earthworms. Exposure to 50 mg/kg MWCNTs significantly increased activities of CYP2C9, CYP3A4, SOD, CAT, and GST but clearly reduced levels of L-aspartate, L-asparagine, and glutamine. With exposure to 100 mg/kg MWCNTs, toxic effects on earthworms were observed, with significant inhibition in activities of CYP isoenzymes and SOD, significant reductions in L-aspartate, L-asparagine, glutamine, and tryptophan, and simultaneous accumulations of citrate, isocitrate, fumarate, 2-oxoglutarate, pyruvate, D-galactose, carbamoyl phosphate, formyl anthranilate, hypoxanthine, and xanthine. Results suggest that toxicity of MWCNTs to earthworms is associated with reduced detoxification capacity, excessive oxidative stress, and disturbance of multiple metabolic pathways, including amino acids metabolism, the tricarboxylic acid cycle, pyruvate metabolism, D-galactose metabolism, and purine metabolism. The study provides new insights to better understand and predict the toxicity of MWCNTs in soil.

Evaluation of the combined toxicity of multi-walled carbon nanotubes and cadmium on earthworms in soil using multi-level biomarkers.

The coexistence of multi-walled carbon nanotubes (MWCNTs) with cadmium (Cd) in soil may cause the combined biological effects, but few study reported about their joint toxic effects on earthworms. Therefore, this study investigated the effects of sub-lethal levels of MWCNTs (10, 50, 100 mg/kg) and Cd (2.0, 10 mg/kg) on earthworms Eisenia fetida for 14 days. The changes in multi-level biomarkers of growth inhibition rate, cytochrome P450 isoenzymes (CYP1A2, 2C9 and 3A4), and small molecular metabolites (metabolomics) were determined. The toxic interaction between MWCNTs and Cd was characterized by the combination of the biomarker integration index (BRI), joint effect index concentration addition index (CAI), and the effect concentration addition index (EAI). The results showed that the single MWCNTs exposure caused insignificant change in most biomarkers, while the combined exposure of MWCNTs (50-100 mg/kg) and 10 mg/kg Cd led to significant changes in ten most important metabolites identified by metabolomics and activities of CYP1A2, 2C9, and 3A4. Compared with the toxicity of Cd alone, the combined toxicity of the mixture was significantly reduced. According to the integration of BRI and CAI/EAI, a clearly antagonistic interaction at relatively low effects was observed between MWCNTs and Cd. The responses of multiple biomarkers suggest the toxic action mode of the mixture on earthworms was related to the oxidative injury, and the disruption of amino acid, purine, and pyrimidine metabolism, and the urea cycle.

The responses of the growth, cytochrome P450 isoenzymes activities and the metabolomics in earthworms to sublethal doses of dichlorvos in soil.

In this paper, earthworms (Eisenia fetida) were exposed to sublethal doses of dichlorvos (spiked concentration of 0.1, 1.0, 10 mg/kg) in soil for 14 days, the metabolomics and activities of cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9 and CYP3A4) of earthworms were analyzed aiming to identify sensitive biomarkers and reveal possible mode of toxic action. The results showed that CYP1A2 and CYP2C9 activity appeared to be more sensitive than CYP3A4 activity in response to dichlorvos, and that metabolic responses based on the metabolomics depended on both of the length of exposure and exposure dose. Malate, ornithine, glucose, inosine, myo-inositol and some amino acids (glutamine, tryptophan, phenylalanine, tyrosine, leucine, histidine, glutamate, lysine) and CYP isozenzymes may be biomarkers to reveal the toxic effect of dichlorvos on earthworms. Compared to controls, when dichlorvos dose reached 1.0 and 10 mg/kg on day 14, glucose and ornithine increased significantly, malate and some amino acids (glutamine, tryptophan, phenylalanine, tyrosine, leucine) decreased significantly, and activities of CYP1A2 and CYP2C9 were inhibited significantly. The current results suggested that 1.0 and 10 mg/kg dichlorvos for 14 days of exposure blocked energy metabolism, disordered Krebs cycle, interfered amino acids metabolism and evoked toxic effects on earthworms.

SIRT1 downregulated FGB expression to inhibit RCC tumorigenesis by destabilizing STAT3.

Renal cell carcinoma (RCC) is one of the common lethal urologic tumors. Recent studies revealed that SIRT1 might function as a tumor suppressor during the progression of RCC. In addition, studies showed that FGB expression was abnormally upregulated in RCC and related to the progress of RCC. This study aimed to define the function of SIRT1 and underlying mechanism in the RCC progression. The expression of SIRT1 and FGB in RCC specimens and cells were detected by immunoblotting and immunostaining. Luciferase reporter assay was performed to confirm FGB as the target gene of STAT3. Other methods including stable transfection, co-immunoprecipitation, Western blot, and in vitro and in vivo proliferation assays were also performed. Our results showed that SIRT1 expression was downregulated in RCC tissues compared to adjacent normal tissues and relatively high expression of SIRT1 conferred a better prognosis for patients. Next, we showed that SIRT1 overexpression inhibited RCC tumorigenesis both in vitro and in vivo. In addition, FGB expression was upregulated in RCC tissues and overexpressing SIRT1 reduced FGB expression levels. Furthermore, inhibition of RCC proliferation by SIRT1 overexpression was rescued by FGB overexpression, indicating that SIRT1 inhibited RCC proliferation by repressing FGB expression. Mechanistically, we confirmed that FGB was the target gene of STAT3, and SIRT1 repressed the expression of FGB by deacetylation of STAT3, leading to STAT3 destabilization and degradation. SIRT1 inhibited RCC tumorigenesis by downregulating FGB expression, and this novel SIRT1-STAT3-FGB axis provided a potential target for RCC therapy.

Real-world experience of first-line afatinib in patients with EGFR-mutant advanced NSCLC: a multicenter observational study.

BACKGROUND: This study aimed to evaluate the efficacy, side-effects and resistance mechanisms of first-line afatinib in a real-world setting. METHODS: This is a multicenter observational study of first-line afatinib in Malaysian patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Patients' demographic, clinical and treatment data, as well as resistance mechanisms to afatinib were retrospectively captured. The statistical methods included Chi-squared test and independent t-test for variables, Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis. RESULTS: Eighty-five patients on first-line afatinib from 1st October 2014 to 30th April 2018 were eligible for the study. EGFR mutations detected in tumors included exon 19 deletion in 80.0%, exon 21 L858R point mutation in 12.9%, and rare or complex EGFR mutations in 7.1% of patients. Among these patients, 18.8% had Eastern Cooperative Oncology Group performance status of 2-4, 29.4% had symptomatic brain metastases and 17.6% had abnormal organ function. Afatinib 40 mg or 30 mg once daily were the most common starting and maintenance doses. Only one-tenth of patients experienced severe side-effects with none having grade 4 toxicities. The objective response rate was 76.5% while the disease control rate was 95.3%. At the time of analysis, 56 (65.9%) patients had progression of disease (PD) with a median progression-free survival (mPFS) of 14.2 months (95% CI, 11.85-16.55 months). Only 12.5% of the progressed patients developed new symptomatic brain metastases. The overall survival (OS) data was not mature. Thirty-three (38.8%) patients had died with a median OS of 28.9 months (95% CI, 19.82-37.99 months). The median follow-up period for the survivors was 20.0 months (95% CI, 17.49-22.51 months). Of patients with PD while on afatinib, 55.3% were investigated for resistance mechanisms with exon 20 T790 M mutation detected in 42.0% of them. CONCLUSIONS: Afatinib is an effective first-line treatment for patients with EGFR-mutant advanced NSCLC with a good response rate and long survival, even in patients with unfavorable clinical characteristics. The side-effects of afatinib were manageable and T790 M mutation was the most common resistance mechanism causing treatment failure.

MicroRNA-485-5p reduces O-GlcNAcylation of Bmi-1 and inhibits colorectal cancer proliferation.

Emerging evidences showed that miRNAs are involved in the oncogenesis of many cancers. Here, miRNA microarray analysis was performed to screen the significant miRNAs involved in the progression of colorectal cancer (CRC), miR-485-5p was chosen for further study. We found that the expression of miR-485-5p was significantly lower in CRC specimens and cell lines. In addition, low expression level of miR-485-5p is correlated with tumor progression and poor survival in CRC patients. Based on in vitro and in vivo assays, we found that miR-485-5p significantly inhibits CRC proliferation. Moreover, our results showed that miR-485-5p inhibits cell proliferation by reducing Bmi-1 protein expression, which has been reported to control the proliferation of many cancers. Mechanistically, OGT is a direct target of miR-485-5p, and miR-485-5p could inhibit the O-GlcNAcylation level of Bmi-1 by OGT. Overall, these results suggested that as a tumor suppressor, miR-485-5p may regulate CRC cells proliferation, which could regulate the O-GlcNAcylation and the stability of Bmi-1 through targeting OGT. This may give insight into a novel mechanism and therapy of CRC growth.

A COL1A1 Promoter-Controlled Expression of TGF-ß Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses.

BACKGROUND: Soluble TGF-ß1 type II receptor (sTßRII) via TGF-ß1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses. AIM: To test whether the use of a TGF-ß1-responsive collagen I promoter COL1A1, via generating a feedback loop to TGF-ß1 level, could offer accurate control on sTßRII expression. METHODS: Recombinant adenoviruses with COL1A1 (Ad-COL-sTßRII/Luc) or CMV promoter (Ad-CMV-sTßRII/Luc) were constructed and characterized. Inhibition of TGF-ß activity was determined both in vitro and in vivo. Total and bioactive TGF-ß, hepatic fibrosis scale, α-SMA, collagen levels, and liver function were determined. RESULTS: COL1A1, but not CMV, responded to TGF-ß1 in vitro. Both in vitro and in vivo, Ad-COL-sTßRII could significantly, but not completely inhibit TGF-ß1 activity while Ad-CMV-sTßRII almost completely inhibited TGF-ß1 activity. As evidenced by fibrosis scale, α-SMA, and collagen levels in liver tissue, Ad-COL-sTßRII and Ad-CMV-sTßRII had comparable efficacies in treating hepatic fibrosis. Ad-COL-sTßRII was better than Ad-CMV-sTßRII in liver function restore. Ad-CMV-sTßRII, but not Ad-COL-sTßRII, induced high level of anti-dsDNA and anti-Sm antibodies in rats. CONCLUSIONS: COL1A1 can precisely control sTßRII expression to inhibit excessive bioactive TGF-ß level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.

Speckle-Type POZ Protein Down-Regulates Matrix Metalloproteinase 2 Expression via Sp1/PI3K/Akt Signaling Pathway in Colorectal Cancer.

BACKGROUND: Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM: In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS: The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS: SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS: SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.

Visual outcome after endoscopic third ventriculostomy for hydrocephalus.

PURPOSE: Hydrocephalus-related symptoms are mostly improved after successful endoscopic third ventriculostomy (ETV). However, visual symptoms can be different. This study was focused on visual symptoms. We analyzed the magnetic resonance images (MRI) of the orbit and visual outcomes. METHODS: From August 2006 to November 2016, 50 patients with hydrocephalus underwent ETV. The male-to-female ratio was 33:17, and the median age was 61 years (range, 5-74 years). There were 18 pediatric and 32 adult patients. Abnormal orbital MRI findings included prominent subarachnoid space around the optic nerves and vertical tortuosity of the optic nerves. We retrospectively analyzed clinical symptoms, causes of hydrocephalus, ETV success score (ETVSS), ETV success rate, ETV complications, orbital MRI findings, and visual impairment score (VIS). RESULTS: The median duration of follow-up was 59 months (range, 3-113 months). The most common symptoms were headache, vomiting, and gait disturbance. Visual symptoms were found in 6 patients (12%). The most common causes of hydrocephalus were posterior fossa tumor in 13 patients, pineal tumor in 12, aqueductal stenosis in 8, thalamic malignant glioma in 7, and tectal glioma in 4. ETVSS was 70 in 3 patients, 80 in 34 patients, and 90 in 13 patients. ETV success rate was 80%. ETVSS 70 showed the trend in short-term survival compared to ETVSS 90 and 80. ETV complications included epidural hematoma requiring operation in one patient, transient hemiparesis in two patients, and infection in two patients. Preoperative abnormal orbital MRI findings were found in 18 patients and postoperative findings in 7 patients. Four of six patients with visual symptoms had abnormal MR findings. Three patients did not show VIS improvement, including two with severe visual symptoms. CONCLUSIONS: Patients with severe visual impairment were found to have bad outcomes. The visual symptoms related with increased intracranial pressure should be carefully monitored and controlled to improve outcomes.

CSN5 promotes renal cell carcinoma metastasis and EMT by inhibiting ZEB1 degradation.

CSN5 (also known as COPS5) is a newly characterized oncogene involved in various types of cancer. However, its expression pattern and biological functions in renal cell carcinoma (RCC) is unknown. Here, we found that CSN5 expression was elevated in RCC tissues than those in paired normal renal tissues. Additionally, we demonstrated that high CSN5 level was closely correlated with tumor progression and poor survival in RCC patients. Our results showed that increased expression of CSN5 was observed in RCC cell lines and knockdown of CSN5 significantly suppressed the migration and invasion of RCC cells in vitro and in vivo. Additionally, CSN5 contributes to the metastasis and EMT (epithelial-mesenchymal transition) of RCC cells. Further investigation revealed that CSN5 led to the metastasis and EMT activation of RCC cells through increasing ZEB1 expression. Mechanistically, we found that CSN5 directly bound ZEB1 and decreased its ubiquitination to enhance the protein stability of ZEB1 in RCC cells. Taken together, our data identified CSN5 as a critical oncoprotein involved in migration and invasion of RCC cells, which could serve as a potential therapeutic target in RCC patients.

A dominant variant in DMXL2 is linked to nonsyndromic hearing loss.

PURPOSE: To explore the genetic etiology of deafness in a dominant family with late-onset, progressive, nonsyndromic hearing loss. METHODS: Genome-wide linkage analysis was performed for 21 family members. Candidate pathogenic variants were identified by whole-exome sequencing of selected family members and confirmed by Sanger sequencing of all family members. Cochlear expression of Dmxl2 was investigated by reverse-transcription polymerase chain reaction (RT-PCR) and immunostaining of the organ of Corti from mice. RESULTS: The causative gene was mapped to a 9.68-Mb candidate region on chromosome 15q21.2 (maximum logarithm of the odds score = 4.03) that contained no previously described deafness genes. Whole-exome sequencing identified heterozygous c.7250G>A (p.Arg2417His) in DMXL2 as the only candidate pathogenic variant segregating the hearing loss. In mouse cochlea, expression of DMXL2 was restricted to the hair cells and the spiral ganglion neurons. CONCLUSION: Our data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function.Genet Med advance online publication 22 September 2016.

LncRNA-CCAT1 Promotes Migration, Invasion, and EMT in Intrahepatic Cholangiocarcinoma Through Suppressing miR-152.

BACKGROUND: Increasing evidence has suggested that lncRNA CCAT1 is upregulated and functions as a potential tumor promoter in many cancers. However, the potential biological roles and regulatory mechanisms of CCAT1 in intrahepatic cholangiocarcinoma (ICC) remain unclear. METHODS: We used real-time PCR to measure CCAT1 expression in ICC tissues and the adjacent normal tissues. The statistical analyses were applied to evaluate the prognostic value and associations of CCAT1 expression with clinical parameters. The CCAT1 was silenced with siRNA in ICC cells. The migration and invasion of ICC cells were detected with Transwell assay. The expressions of epithelial-mesenchymal transition (EMT)-related proteins were evaluated to discover whether the process of EMT was involved. RESULTS: We found that CCAT1 expression was elevated in ICC tissues compared to the adjacent normal tissues. We also found that high CCAT1 expression is closely correlated with tumor progression in ICC patients. Furthermore, our results show that knockdown of CCAT1 significantly suppressed the migration and invasion of ICC cells. Additionally, CCAT1 silencing remarkably reverses the EMT phenotype of ICC cells. Moreover, bioinformatics analysis and luciferase reporter assay revealed that CCAT1 directly bound to the miR-152, which has been reported to serve as a tumor suppressor in variety cancers. Further investigation demonstrated that CCAT1 led to the metastasis and EMT activation of ICC cells through inhibiting miR-152. CONCLUSIONS: Our results suggested that CCAT1 functions as an oncogenic lncRNA in ICC, which could serve as a potential diagnostic and therapeutic target for ICC patients.