L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity.

L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration-resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1-specific inhibitor, JPH203, in cabazitaxel-resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel-resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel-resistant strains in vitro. Phosphoproteomics using liquid chromatography-mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle-related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin-dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer.

The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1 via p38 MAPK activation.

L-type amino acid transporter 1 (LAT1, SLC7A5) is upregulated in various cancers and associated with disease progression. Nanvuranlat (Nanv; JPH203, KYT-0353), a selective LAT1 inhibitor, suppresses the uptake of large neutral amino acids required for rapid growth and proliferation of cancer cells. Previous studies have suggested that the inhibition of LAT1 by Nanv induces the cell cycle arrest at G0/G1 phase, although the underlying mechanisms remain unclear. Using pancreatic cancer cells arrested at the restriction check point (R) by serum deprivation, we found that the Nanv drastically suppresses the G0/G1-S transition after release. This blockade of the cell cycle progression was accompanied by a sustained activation of p38 mitogen-activated protein kinase (MAPK) and subsequent phosphorylation-dependent proteasomal degradation of cyclin D1. Isoform-specific knockdown of p38 MAPK revealed the predominant contribution of p38α. Proteasome inhibitors restored the cyclin D1 amount and released the cell cycle arrest caused by Nanv. The increased phosphorylation of p38 MAPK and the decrease of cyclin D1 were recapitulated in xenograft tumor models treated with Nanv. This study contributes to delineating the pharmacological activities of LAT1 inhibitors as anti-cancer agents and provides significant insights into the molecular basis of the amino acid-dependent cell cycle checkpoint at G0/G1 phase.

Identification of tumor-suppressive miRNAs that target amino acid transporter LAT1 and exhibit anti-proliferative effects on cholangiocarcinoma cells.

Amino acid transporter LAT1 is highly upregulated in various cancer types, including cholangiocarcinoma (CHOL), and contributes to the rapid proliferation of cancer cells and disease progression. However, the molecular mechanisms underlying the pathological upregulation of LAT1 remain largely unknown. This study pursued the possibility of miRNA-mediated regulation of the LAT1 expression in CHOL cells. Using online target prediction methods, we extracted five candidate miRNAs commonly predicted to regulate the LAT1 expression. Three of them, miR-194-5p, miR-122-5p, and miR-126-3p, were significantly downregulated in CHOL cancer compared to normal tissues. Correlation analysis revealed weak-to-moderate negative correlations between the expression of these miRNAs and LAT1 mRNA in CHOL cancer tissues. We selected miR-194-5p and miR-122-5p for further analyses and found that both miRNAs functionally target 3'UTR of LAT1 mRNA by a luciferase-based reporter assay. Transfection of the miRNA mimics significantly suppressed the LAT1 expression at mRNA and protein levels and inhibited the proliferation of CHOL cells, with a trend of affecting intracellular amino acids and amino acid-related signaling pathways. This study indicates that the decreased expression of these LAT1-targeting tumor-suppressive miRNAs contributes to the upregulation of LAT1 and the proliferation of CHOL cells, highlighting their potential for developing novel cancer therapeutics and diagnostics.

Upregulation of ATF4 mediates the cellular adaptation to pharmacologic inhibition of amino acid transporter LAT1 in pancreatic ductal adenocarcinoma cells.

L-type amino acid transporter 1 (LAT1) is recognized as a promising target for cancer therapy; however, the cellular adaptive response to its pharmacological inhibition remains largely unexplored. This study examined the adaptive response to LAT1 inhibition using nanvuranlat, a high-affinity LAT1 inhibitor. Proteomic analysis revealed the activation of a stress-induced transcription factor ATF4 following LAT1 inhibition, aligning with the known cellular responses to amino acid deprivation. This activation was linked to the GCN2-eIF2α pathway which regulates translation initiation. Our results show that ATF4 upregulation counteracts the suppressive effect of nanvuranlat on cell proliferation in pancreatic ductal adenocarcinoma cell lines, suggesting a role for ATF4 in cellular adaptation to LAT1 inhibition. Importantly, dual targeting of LAT1 and ATF4 exhibited more substantial anti-proliferative effects in vitro than individual treatments. This study underscores the potential of combining LAT1 and ATF4 inhibition as a therapeutic strategy in cancer treatment.

Transcriptomic Analysis Provides Insights into Candidate Genes and Molecular Pathways Involved in Growth of Mytilus coruscus Larvae.

Growth is a fundamental aspect of aquaculture breeding programs, pivotal for successful cultivation. Understanding the mechanisms that govern growth and development differences across various stages can significantly boost seedling production of economically valuable species, thereby enhancing aquaculture efficiency and advancing the aquaculture industry. Mytilus coruscus, a commercially vital marine bivalve, underscores this importance. To decipher the intricate molecular mechanisms dictating growth and developmental disparities in marine shellfish, we conducted transcriptome sequencing and meticulously analyzed gene expression variations and molecular pathways linked to growth traits in M. coruscus. This study delved into the molecular and gene expression variations across five larval development stages, with a specific focus on scrutinizing the differential expression patterns of growth-associated genes using RNA sequencing and quantitative real-time PCR analysis. A substantial number of genes-36,044 differentially expressed genes (DEGs)-exhibited significant differential expression between consecutive developmental stages. These DEGs were then categorized into multiple pathways (Q value < 0.05), including crucial pathways such as the spliceosome, vascular smooth muscle contraction, DNA replication, and apoptosis, among others. In addition, we identified two pivotal signaling pathways-the Hedgehog (Hh) signaling pathway and the TGF-beta (TGF-ß) signaling pathway-associated with the growth and development of M. coruscus larvae. Ten key growth-related genes were pinpointed, each playing crucial roles in molecular function and the regulation of growth traits in M. coruscus. These genes and pathways associated with growth provide deep insights into the molecular basis of physiological adaptation, metabolic processes, and growth variability in marine bivalves.

Combination effects of amino acid transporter LAT1 inhibitor nanvuranlat and cytotoxic anticancer drug gemcitabine on pancreatic and biliary tract cancer cells.

BACKGROUND: Cytotoxic anticancer drugs widely used in cancer chemotherapy have some limitations, such as the development of side effects and drug resistance. Furthermore, monotherapy is often less effective against heterogeneous cancer tissues. Combination therapies of cytotoxic anticancer drugs with molecularly targeted drugs have been pursued to solve such fundamental problems. Nanvuranlat (JPH203 or KYT-0353), an inhibitor for L-type amino acid transporter 1 (LAT1; SLC7A5), has novel mechanisms of action to suppress the cancer cell proliferation and tumor growth by inhibiting the transport of large neutral amino acids into cancer cells. This study investigated the potential of the combined use of nanvuranlat and cytotoxic anticancer drugs. METHODS: The combination effects of cytotoxic anticancer drugs and nanvuranlat on cell growth were examined by a water-soluble tetrazolium salt assay in two-dimensional cultures of pancreatic and biliary tract cancer cell lines. To elucidate the pharmacological mechanisms underlying the combination of gemcitabine and nanvuranlat, we investigated apoptotic cell death and cell cycle by flow cytometry. The phosphorylation levels of amino acid-related signaling pathways were analyzed by Western blot. Furthermore, growth inhibition was examined in cancer cell spheroids. RESULTS: All the tested seven types of cytotoxic anticancer drugs combined with nanvuranlat significantly inhibited the cell growth of pancreatic cancer MIA PaCa-2 cells compared to their single treatment. Among them, the combined effects of gemcitabine and nanvuranlat were relatively high and confirmed in multiple pancreatic and biliary tract cell lines in two-dimensional cultures. The growth inhibitory effects were suggested to be additive but not synergistic under the tested conditions. Gemcitabine generally induced cell cycle arrest at the S phase and apoptotic cell death, while nanvuranlat induced cell cycle arrest at the G0/G1 phase and affected amino acid-related mTORC1 and GAAC signaling pathways. In combination, each anticancer drug basically exerted its own pharmacological activities, although gemcitabine more strongly influenced the cell cycle than nanvuranlat. The combination effects of growth inhibition were also verified in cancer cell spheroids. CONCLUSIONS: Our study demonstrates the potential of first-in-class LAT1 inhibitor nanvuranlat as a concomitant drug with cytotoxic anticancer drugs, especially gemcitabine, on pancreatic and biliary tract cancers.

Insights into the Deep Phylogeny and Novel Gene Rearrangement of Mytiloidea from Complete Mitochondrial Genome.

The extant marine mussels which belong to the Mytiloidea are widespread species inhabiting mostly coastal waters, with some distributed in the deep sea. To clarify the classification systems and phylogenetic relationships range from genus to family level within Mytiloidea, new sequence was used in a phylogenetic analysis including all the available Mytiloidea mitochondrial genomes. In this study, the complete mitochondrial genome of Vignadula atrata is 15,624 bp in length and contains 12 protein-coding genes (PCGs, atp8 is absent), two ribosomal RNA genes, and 22 transfer RNA genes. Phylogenetic analysis based on 12 PCGs showed that it has a close relationship to Bathymodiolus. The analysis of gene rearrangements in the Pteriomorphia showed that the arrangements are highly variable across species, novel gene rearrangements were found within Mytiloidea. The V. atrata mitogenome was provided in detail, with notes on the sequence and a key to the species of Vignadula. This study provides a perspective on the taxonomic histories of the marine mussels and refines the unclear relationship between the origin and evolution of species in Mytiloidea within Bivalvia.

Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells.

L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids, is highly upregulated in various cancers. LAT1 supplies cancer cells with amino acids as substrates for enhanced biosynthetic and bioenergetic reactions and stimulates signalling networks involved in the regulation of survival, growth and proliferation. LAT1 inhibitors show anti-cancer effects and a representative compound, JPH203, is under clinical evaluation. However, pharmacological impacts of LAT1 inhibition on the cellular amino acid transport and the translational activity in cancer cells that are conceptually pivotal for its anti-proliferative effect have not been elucidated yet. Here, we demonstrated that JPH203 drastically inhibits the transport of all the large neutral amino acids in pancreatic ductal adenocarcinoma cells. The inhibitory effects of JPH203 were observed even in competition with high concentrations of amino acids in a cell culture medium. The analyses of the nutrient-sensing mTORC1 and GAAC pathways and the protein synthesis activity revealed that JPH203 downregulates the global translation. This study demonstrates a predominant contribution of LAT1 to the transport of large neutral amino acids in cancer cells and the suppression of protein synthesis by JPH203 supposed to underly its broad anti-proliferative effects across various types of cancer cells.

Comprehensive Analysis of Glutamate Receptor-like Genes in Rice (Oryza sativa L.): Genome-Wide Identification, Characteristics, Evolution, Chromatin Accessibility, gcHap Diversity, Population Variation and Expression Analysis.

Glutamate receptors (GLR) are widely present in animals and plants, playing essential roles in regulating plant growth, development and stress response. At present, most studies of GLRs in plants are focused on Arabidopsis thaliana, while there have been few studies on rice. In this study, we identified 26 OsGLR genes in rice (Oryza sativa L.). Then, we analyzed the chromosomal location, physical and chemical properties, subcellular location, transmembrane (TM) helices, signal peptides, three-dimensional (3D) structure, cis-acting elements, evolution, chromatin accessibility, population variation, gene-coding sequence haplotype (gcHap) and gene expression under multiple abiotic stress and hormone treatments. The results showed that out of the 26 OsGLR genes, ten genes had the TM domain, signal peptides and similar 3D structures. Most OsGLRs exhibited high tissue specificity in expression under drought stress. In addition, several OsGLR genes were specifically responsive to certain hormones. The favorable gcHap of many OsGLR genes in modern varieties showed obvious differentiation between Xian/indica and Geng/japonica subspecies. This study, for the first time, comprehensively analyzes the OsGLR genes in rice, and provides an important reference for further research on their molecular function.

Functional coupling of organic anion transporter OAT10 (SLC22A13) and monocarboxylate transporter MCT1 (SLC16A1) influencing the transport function of OAT10.

OAT10 (SLC22A13) is a transporter highly expressed in renal tubules and transporting organic anions including nicotinate, ß-hydroxybutyrate, p-aminohippurate, and orotate. In transport assays using Xenopus oocytes and HEK293 cells, we found that apparent substrate selectivity of OAT10 was different between the expression systems, particularly less pronounced uptake of ß-hydroxybutyrate in HEK293 cells. Because functional coupling between transporters may interfere with functional properties of the transporter, we searched for endogenous transporters in HEK293 cells that could affect OAT10. By means of comprehensive approach with co-immunoprecipitation followed by LC-MS/MS analysis, we identified monocarboxylate transporter MCT1 (SLC16A1) as physically coupled with OAT10. The knockdown of MCT1 in OAT10-expressing HEK293 cells increased the uptake of ß-hydroxybutyrate and nicotinate, common substrates of OAT10 and MCT1, whereas the uptake of orotate, a substrate of only OAT10, was not affected. MCT1 is supposed to act as an escape route and mediate the efflux of nicotinate and ß-hydroxybutyrate taken up by OAT10 localized nearby MCT1, as suggested by co-immunoprecipitation. This functional coupling would explain altered apparent substrate selectivity in HEK293 cells compared with Xenopus oocytes. The findings in this study warn in transporter studies that the expression system can interfere with assessing correct transport properties due to unexpected interactions with endogenous transporters.

Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor.

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.

Interaction of Halogenated Tyrosine/Phenylalanine Derivatives with Organic Anion Transporter 1 in the Renal Handling of Tumor Imaging Probes.

Halogenated tyrosine/phenylalanine derivatives have been developed for use in tumor imaging and targeted alpha therapy. 3-Fluoro-α-methyl-l-tyrosine (FAMT), targeting amino acid transporter LAT1 (SLC7A5), is a cancer-specific positron emission tomography probe that exhibits high renal accumulation, which is supposed to be mediated by organic anion transporter OAT1 (SLC22A6). In the present study, we investigated the structural requirements of FAMT essential for interaction with OAT1. OAT1 transported FAMT with a K m of 171.9 µM. In structure-activity relationship analyses, removal of either the 3-halogen or 4-hydroxyl group from FAMT or its structural analog 3-iodo-α-methyl-l-tyrosine greatly decreased the interaction with OAT1, reducing the [14C]p-aminohippurate uptake inhibition and the efflux induction. By contrast, the α-methyl group, which is essential for LAT1 specificity, contributed to a lesser degree. In fluorinated tyrosine derivatives, fluorine at any position was accepted by OAT1 when there was a hydroxyl group at the ortho-position, whereas ortho-fluorine was less interactive when a hydroxyl group was at meta- or para-positions. The replacement of the ortho-fluorine with a bulky iodine atom greatly increased the interaction. In in vivo studies, probenecid decreased the renal accumulation (P < 0.001) and urinary excretion (P = 0.0012) of FAMT, whereas the plasma concentration was increased, suggesting the involvement of OAT1-mediated transepithelial organic anion excretion. LAT1-specific 2-fluoro-α-methyltyrosine, which had lower affinity for OAT1, exhibited lower renal accumulation (P = 0.0142) and higher tumor uptake (P = 0.0192) compared with FAMT. These results would provide a basis to design tumor-specific compounds that can avoid renal accumulation for tumor imaging and targeted alpha therapy. SIGNIFICANCE STATEMENT: We revealed the structural characteristics of halogenated tyrosine derivatives essential for interaction with the organic anion transporter responsible for their renal accumulation. We have confirmed that such interactions are important for renal handling and tumor uptake. The critical contribution of hydroxyl and halogen groups and their positions as well as the role of α-methyl group found in the present study may facilitate the development of tumor-specific compounds while avoiding renal accumulation for use in tumor imaging and targeted alpha therapy.

LncRNA ST8SIA6-AS1 promotes hepatocellular carcinoma cell proliferation and resistance to apoptosis by targeting miR-4656/HDAC11 axis.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) results in development of human diseases including hepatocellular carcinoma (HCC). Although several HCC related lncRNAs have been reported, the biological functions of many lncRNAs during the development of HCC remains unknown. METHODS: The expression of ST8SIA6-AS1 was studied by realtime PCR (RT-qPCR) and bioinformatic analysis. The biological functions of ST8SIA6-AS1 was examined by CCK-8 assay and flow cytometry analysis. The target of ST8SIA6-AS1 was analyzed by bioinformatic analysis and validated by dual luciferase reporter assay, western blotting and RT-qPCR. RESULTS: In this study we demonstrated that ST8SIA6-AS1 was an upregulated lncRNA in hepatocellular carcinoma. SiRNA-mediated knockdown of ST8SIA6-AS1 repressed cell proliferation and induced cell apoptosis in HCC cells. Bioinformatic analysis and RT-qPCR further showed that ST8SIA6-AS1 mainly located in cytoplasm. Dual luciferase reporter assay further revealed that ST8SIA6-AS1 interacted with miR-4656 in HCC cells. In addition, HDAC11 was identified as a target gene in HCC cells and ST8SIA6-AS1 could upregulate HDAC11 via sponging miR-4656. Transfection of recombinant HDAC11 partially rescued the inhibition of cell proliferation and increase of cell apoptosis inducing by knockdown of ST8SIA6-AS1. CONCLUSION: In conclusion, our findings suggested that ST8SIA6-AS1 was a novel upregulated lncRNA in HCC and could facilitate cell proliferation and resistance to cell apoptosis via sponging miR-4656 and elevation of HDAC11, which might be a promising biomarker for patients with HCC.

Presenilin1 exerts antiproliferative effects by repressing the Wnt/ß-catenin pathway in glioblastoma.

BACKGROUND: Glioblastoma and Alzheimer's disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. METHODS: Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. RESULTS: In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of ß-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of ß-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering ß-catenin-dependent cell proliferation. CONCLUSION: Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/ß-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. Video Abstract.

Risk factors associated with the progression of extra-axial hematoma in the original frontotemporoparietal site after contralateral decompressive surgery in traumatic brain injury patients.

PURPOSE: To introduced our experience with progressive extra-axial hematoma (EAH) in the original frontotemporoparietal (FTP) site after contralateral decompressive surgery (CDS) in traumatic brain injury patients and discuss the risk factors associated with this dangerous situation. METHODS: This retrospective study was conducted on 941 patients with moderate or severe TBI treated in Daping Hospital, Army Medical University, Chongqing, China in a period over 5 years (2013-2017). Only patients with bilateral lesion, the contralateral side being the dominant lesion, and decompressive surgery on the contralateral side conducted firstly were included. Patients were exclude if (1) they underwent bilateral decompression or neurosurgery at the original location firstly; (2) although surgery was performed first on the contralateral side, surgery was done again at the contralateral side due to re-bleeding or complications; (3) patients younger than 18 years or older than 80 years; and (4) patients with other significant organ injury or severe disorder or those with abnormal coagulation profiles. Clinical and radiographic variables reviewed were demographic data, trauma mechanisms, neurological condition assessed by Glasgow coma scale (GCS) score at admission, pupil size and reactivity, use of mannitol, time interval from trauma to surgery, Rotterdam CT classification, type and volume of EAH, presence of a skull fracture overlying the EAH, status of basal cistern, size of midline shift, associated brain lesions and types, etc. Patients were followed-up for at least 6 months and the outcome was graded by Glasgow outcome scale (GOS) score as favorable (scores of 4-5) and unfavorable (scores of 1-3). Student's t-test was adopted for quantitative variables while Pearson Chi-squared test or Fisher's exact test for categorical variables. Multivariate logistic regression analysis was also applied to estimate the significance of risk factors. RESULTS: Initially 186 patients (19.8%) with original impact locations at the FTP site and underwent surgery were selected. Among them, 66 met the inclusion and exclusion criteria. But only 50 patients were included because the data of the other 16 patients were incomplete. Progressive EAH developed at the original FTP site in 11 patients after the treatment of, with an incidence of 22%. Therefore the other 39 patients were classified as the control group. Multivariate logistic regression analysis showed that both the volume of the original hematoma and the absence of an apparent midline shift were significant predictors of hematoma progression after decompressive surgery. Patients with fracture at the original impact site had a higher incidence of progressive EAH after CDS, however this factor was not an important predictor in the multivariate model. We also found that patients with progressive EAH had a similar favorable outcome with control group. CONCLUSION: Progressive EAH is correlated with several variables, such as hematoma volumes ≥10 mL at the original impact location and the absence of an apparent midline shift (<5 mm). Although progressive EAH is devastating, timely diagnosis with computed tomography scans and immediate evacuation of the progressive hematoma can yield a favorable result.

LncRNA FOXD2-AS1 as a competitive endogenous RNA against miR-150-5p reverses resistance to sorafenib in hepatocellular carcinoma.

The current study elucidated the role of a long non-coding RNA (lncRNA), FOXD2-AS1, in the pathogenesis of hepatocellular carcinoma (HCC) and the regulatory mechanism underlying FOXD2-AS1/miR-150-5p/transmembrane protein 9 (TMEM9) signalling in HCC. Microarray analysis was used for preliminary screening of candidate lncRNAs in HCC tissues. qRT-PCR and Western blot analyses were used to detect the expression of FOXD2-AS1. Cell proliferation assays, luciferase assay and RNA immunoprecipitation were performed to examine the mechanism by which FOXD2-AS1 mediates sorafenib resistance in HCC cells. FOXD2-AS1 and TMEM9 were significantly decreased and miR-150-5p was increased in SR-HepG2 and SR-HUH7 cells compared with control parental cells. Overexpression of FOXD2-AS1 increased TMEM9 expression and overcame the resistance of SR-HepG2 and SR-HUH7 cells. Conversely, knockdown of FOXD2-AS1 decreased TMEM9 expression and increased the sensitivity of HepG2 and Huh7 cells to sorafenib. Our data also demonstrated that FOXD2-AS1 functioned as a sponge for miR-150-5p to modulate TMEM9 expression. Taken together, our findings revealed that FOXD2-AS1 is an important regulator of TMEM9 and contributed to sorafenib resistance. Thus, FOXD2-AS1 may serve as a therapeutic target against sorafenib resistance in HCC.

Inhibition of MicroRNA-195 Alleviates Neuropathic Pain by Targeting Patched1 and Inhibiting SHH Signaling Pathway Activation.

Trigeminal neuralgia (TN) is a type of chronic neuropathic pain that is caused by peripheral nerve lesions that result from various conditions, including the compression of vessels, tumors and viral infections. MicroRNAs (miRs) are increasingly recognized as potential regulators of neuropathic pain. Previous evidence has demonstrated that miR-195 is involved in neuropathic pain, but the mechanism remains unclear. To investigate the pathophysiological role of miR-195 and Shh signaling in TN, persistent facial pain was induced by infraorbital nerve chronic constriction injury (CCI-IoN), and facial pain responses were evaluated by Von Frey hairs. qPCR and Western blotting were used to determine the relative expression of miR-195 and Patched1, the major receptor of the Sonic Hedgehog (Shh) signaling pathway, in the caudal brain stem at distinct time points after CCI-IoN. Here, we found that the expression of miR-195 was increased in a rat model of CCI-IoN. In contrast, the expression of Patched1 decreased significantly. Luciferase assays confirmed the binding of miR-195 to Patched1. In addition, the overexpression of miR-195 by an intracerebroventricular (i.c.v) administration of LV-miR-195 aggravated facial pain development, and this was reversed by upregulating the expression of Patched1. These results suggest that miR-195 is involved in the development of TN by targeting Patched1 in the Shh signaling pathway, thus regulating extracellular glutamate.

The long-term clinical outcomes of microvascular decompression for treatment of trigeminal neuralgia compressed by the vertebra-basilar artery: a case series review.

BACKGROUND: Microvascular decompression (MVD) is a type of neurosurgery used to treat trigeminal neuralgia (TN) caused by the vertebrobasilar contact/compression. The surgery is not risk-free, however; it may cause recurrent facial pain or other side-effects. The objective of this study was to assess the long-term pain relief and the complications of MVD surgery for the vertebrobasilar compression treatment. METHODS: Twenty-three patients with TN compressed by the vertebra-basilar artery (VBA) were treated with MVD. Teflon felt was placed between the brain stem and the offending artery to mobilize the artery towards the skull base and the clivus. The Barrow Neurological Institute (BNI) Pain Intensity Scale score was used to assess pre- and post-surgical pains. RESULTS: Of 23 patients with pre-operative BNI IV to V, 19 patients (83%) were pain-free after surgery. Four patients experienced transient partial pain relief with BNI II-III, and 3 of them (13%) were completely pain-free within 3 months. The success rate was 96%. Three patients (13%) had pain recurrences, and one received a second MVD surgery for pain relief during the period of follow-up. Four patients suffered from TN hypesthesia, and only 2 patients (8.6%) had permanent facial hypesthesia, while one patient (4.3%) developed a gradual hearing loss after surgery. CONCLUSIONS: While our success rate of immediate pain relief after surgery was comparable with some reports, the percentage of patients who had pain recurrences was lower, and cases who had permanent facial hypesthesia or developed a gradual hearing loss were fewer after MVD surgery. Our rate of transient complications was higher, and the postoperative pain relief seemed unusually delayed. Our study indicates that MVD is an effective, reliable, and safe neurosurgery for treatment of TN compressed by the VBA albeit our small sample size. Failure of treatment and recurrence of the disease as well as complications could be minimized by preventing displacement of the Teflon implant and extraneous Teflon touching the trigeminal nerves.

Ferroelectric nanocomposite networks with high energy storage capacitance and low ferroelectric loss by designing a hierarchical interface architecture.

Nanoscale design of nanofillers and interfacial architecture are vital to achieve high-capacity and high-energy-conversion efficiency poly(vinylidene fluoride) [(PVDF)-based] nanocomposite materials for vast potential applications in modern electronic devices and electric power systems. Using traditional methods, the addition of ceramic nanoparticles can only produce one type of interface between the nanoparticles and this matrix, achieving an enhanced dielectric constant and energy density at the expense of the charge-discharge efficiency. Herein, we demonstrate a novel class of cross-linking nanofiller system, poly(vinylidene fluoride-chlorotrifluoroethylene)/γ-methacryloylpropyl trimethoxysilane@BaTiO3 [P(VDF-CTFE)/MPS@BT]. This novel approach can not only provide the interfaces between the nanoparticle and the matrix, but also scale down the size of crystalline domains, which results in producing more additional interfaces between the crystalline and amorphous phases to achieve an improved discharged energy density. Remarkably, the smaller crystalline domains, which were characterized by XRD and FTIR spectroscopy, could be beneficial for improving the dipole switchability from the polar phases to non-polar phases during the charge-discharge cycles, leading to unprecedented charge-discharge efficiency. Furthermore, the addition of MPS@BT NPs can regulate two stages of the discharge rate. The early discharge process can be accelerated, while the following stage is obviously delayed. The simplicity of the hierarchical interfacial engineering method provides a promising path to design ferroelectric polymer nanocomposites for dielectric capacitor applications.