Effect of triggering receptor expressed on myeloid cells 2-associated alterations on lipid metabolism in macrophages in the development of non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in metabolic homeostasis and inflammatory response. Altered metabolic function in macrophages could modulate their activation and immune phenotype. The present study aimed to investigate the expression of TREM2 in non-alcoholic fatty liver disease (NAFLD) and to clarify the underlying mechanism of TREM2 on macrophages lipid metabolism and oxidative stress. METHODS: Hepatic TREM2 expression and its relationship with NAFLD progression were analyzed in patients with NAFLD and mice fed a high-fat diet. Lipid metabolism and oxidative stress were investigated in macrophages from NAFLD mice or stimulated with saturated fatty acids. Knockdown and overexpression of TREM2 were further explored. RESULTS: Triggering receptor expressed on myeloid cells 2+ macrophages were increased along with NAFLD development, characterized by aggravated steatosis and liver damage in humans and mice. TREM2 expression was upregulated and lipid metabolism was changed in macrophages from NAFLD mice or metabolically activated by saturated fatty acid in vitro, as demonstrated by increased lipid uptake and catabolism, but reduced de novo synthesis of fatty acids (FAs). Regulation of TREM2 expression in lipid-laden macrophages reprogrammed lipid metabolism, especially the fatty acid oxidation capacity of mitochondria. TREM2 knockdown promoted oxidative stress by aggravating FAs deposition in mitochondria. Intervention of mitochondrial FAs transport in lipid-laden macrophages alleviated FA deposition and reactive oxygen species production induced by TREM2 knockdown. CONCLUSIONS: Triggering receptor expressed on myeloid cells 2 expression was associated with the lipid metabolic profile and reactive oxygen species production in macrophages. High expression of TREM2 in macrophages may protect the liver from oxidative stress in NAFLD.

First Family Case of Hemoglobinopathy Titusville in China with Falsely Low SpO2 and Unmeasurable SaO2.

BACKGROUND: Normal hemoglobin is a tetrameric structure, consisting of two alpha-globin chains and two nonalpha (beta, gamma, delta) chains. Hemoglobinopathies occur when the presence of gene mutations affect the molecular structure or expression of the globin chains. METHODS: We reported the case of a 9-year-old Chinese girl who presented with abnormal low oxygen saturation values on pulse oximetry and no oximetry results were obtained during blood gas analysis (BGA). RESULTS: High-performance liquid chromatography (HPLC) and capillary electrophoresis demonstrated that the presence of a low oxygen affinity hemoglobin variant, characterized as hemoglobin Titusville, was proven by gene sequencing. The patient's mother and aunt also carry the hemoglobin variant, representing the first Chinese family case reported. CONCLUSIONS: Hemoglobin Titusville is a rare genetic hemoglobin structural defect. early diagnosis can help patients and clinicians avoid unnecessary anxiety and costly or excessive clinical investigations.

Diatom Frustules Decorated with Co Nanoparticles for the Advanced Anode of Li-Ion Batteries.

Silica is regarded as a promising anode material for lithium-ion batteries (LIBs) because of its high theoretical capacity. However, large volume variation and poor electrical conductivity are limiting factors for the development of SiO2 anode materials. To solve this problem, combining SiO2 with a conductive phase and designing hollow porous structures are effective ways. In this work, The Co(II)-EDTA chelate on the surface of diatom biosilica (DBS) frustules and obtained DBS@C-Co composites decorated with Co nanoparticles by calcination without a reducing atmosphere is first precipitated. The unique three-dimensional structure of diatom frustules provides enough space for the volume change of silica during lithiation/delithiation. Co nanoparticles effectively improve the electrical conductivity and electrochemical activity of silica. Through the synergistic effect of the hollow porous structure, carbon layer and Co nanoparticles, the DBS@C-Co-60 composite delivers a high reversible capacity of >620 mAh g-1 at 100 mA g-1 after 270 cycles. This study provides a new method for the synthesis of metal/silica composites and an opportunity for the development of natural resources as advanced active materials for LIBs.

Colchicine protects against the development of experimental abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterized by at least 1.5-fold enlargement of the infrarenal aorta, a ruptured AAA is life-threatening. Colchicine is a medicine used to treat gout and familial Mediterranean fever, and recently, it was approved to reduce the risk of cardiovascular events in adult patients with established atherosclerotic disease. With an AAA mice model created by treatment with porcine pancreatic elastase (PPE) and ß-aminopropionitrile (BAPN), this work was designed to explore whether colchicine could protect against the development of AAA. Here, we showed that colchicine could limit AAA formation, as evidenced by the decreased total aortic weight per body weight, AAA incidence, maximal abdominal aortic diameter and collagen deposition. We also found that colchicine could prevent the phenotypic switching of vascular smooth muscle cells from a contractile to synthetic state during AAA. In addition, it was demonstrated that colchicine was able to reduce vascular inflammation, oxidative stress, cell pyroptosis and immune cells infiltration to the aortic wall in the AAA mice model. Finally, it was proved that the protective action of colchicine against AAA formation was mainly mediated by preventing immune cells infiltration to the aortic wall. In summary, our findings demonstrated that colchicine could protect against the development of experimental AAA, providing a potential therapeutic strategy for AAA intervention in the clinic.

Terminalia bellirica Fruit Extract Alleviates DSS-Induced Ulcerative Colitis by Regulating Gut Microbiota, Inflammatory Mediators, and Cytokines.

Ulcerative colitis (UC) is a chronic inflammatory disease significantly impacting patients' lives. This study aimed to elucidate the alleviating effect of ethyl acetate extract (TBEA) from Terminalia bellirica fruit on UC and to explore its mechanism. TBEA was the fraction with the best anti-inflammatory activity screened using in vitro anti-inflammatory assays, and HPLC initially characterized its composition. The mice model of ulcerative colitis was established after free drinking of 2.5% dextran sulfate sodium for six days, and the experimental group was treated with 50 mg/kg and 100 mg/kg TBEA for seven days. We found that TBEA significantly alleviated symptoms in UC mice, including a physiologically significant reduction in disease activity index and pathological damage to colonic tissue. TBEA dramatically slowed down oxidative stress and inflammatory process in UC mice, as evidenced by decreasing myeloperoxidase and malondialdehyde activities and increasing glutathione and catalase levels by reducing the concentrations of IL-6, IL-1ß, TNF-α, and NO in UC mice, as well as by regulating key proteins in the IL-6/JAK2/STAT3 pathway. Meanwhile, TBEA maintained intestinal homeostasis by regulating intestinal flora structure. Our study provides new ideas for developing TBEA into a new drug to treat UC.

Natamycin Has an Inhibitory Effect on Neofusicoccum parvum, the Pathogen of Chestnuts.

This research aimed to investigate natamycin's antifungal effect and its mechanism against the chestnut pathogen Neofusicoccum parvum. Natamycin's inhibitory effects on N. parvum were investigated using a drug-containing plate culture method and an in vivo assay in chestnuts and shell buckets. The antifungal mechanism of action of natamycin on N. parvum was investigated by conducting staining experiments of the fungal cell wall and cell membrane. Natamycin had a minimum inhibitory concentration (MIC) of 100 µg/mL and a minimum fungicidal concentration (MFC) of 200 µg/mL against N. parvum. At five times the MFC, natamycin had a strong antifungal effect on chestnuts in vivo, and it effectively reduced morbidity and extended the storage period. The cell membrane was the primary target of natamycin action against N. parvum. Natamycin inhibits ergosterol synthesis, disrupts cell membranes, and causes intracellular protein, nucleic acid, and other macromolecule leakages. Furthermore, natamycin can cause oxidative damage to the fungus, as evidenced by decreased superoxide dismutase and catalase enzyme activity. Natamycin exerts a strong antifungal effect on the pathogenic fungus N. parvum from chestnuts, mainly through the disruption of fungal cell membranes.

Enhancement of behavioral nociceptive responses but not itching responses by viewing mirror images in adult mice.

Can mice recognize themselves in a mirror? The answer is unclear. Previous studies have reported that adult mice - when shown itch-like videos - demonstrated itch empathy. However, this was proven to be unreproducible in other studies. In the present study, we wanted to examine whether adult mice were able to recognize their mirror image. In our testing, we found that mice spent more time in the central area in an open field with mirrors surrounding the chamber than those in a normal open field. In a similar open field test with four mice placed in four directions, mice showed similar behavioral responses to those with mirrors. These results indicate that mice are able to recognize images in the mirror, however, they cannot distinguish their own mirror images from the mirror images of other mice. To repeat the experiments of itch empathy, we compared the itch responses of mice in the mirrored environment, to those without. No significant difference in itching responses was detected. Differently, in the case of chemical pain (formalin injection), animals' nociceptive responses to formalin during Phase II were significantly enhanced in the mirrored open field. A new format of heat map was developed to help the analysis of the trace of mice in the open field. Our results suggest that mice do recognize the presence of mice in the mirror, and their nociceptive - but not itch - responses are enhanced.

Mapping thalamic-anterior cingulate monosynaptic inputs in adult mice.

The anterior cingulate cortex (ACC) is located in the frontal part of the cingulate cortex, and plays important roles in pain perception and emotion. The thalamocortical pathway is the major sensory input to the ACC. Previous studies have show that several different thalamic nuclei receive projection fibers from spinothalamic tract, that in turn send efferents to the ACC by using neural tracers and optical imaging methods. Most of these studies were performed in monkeys, cats, and rats, few studies were reported systematically in adult mice. Adult mice, especially genetically modified mice, have provided molecular and synaptic mechanisms for cortical plasticity and modulation in the ACC. In the present study, we utilized rabies virus-based retrograde tracing system to map thalamic-anterior cingulate monosynaptic inputs in adult mice. We also combined with a new high-throughput VISoR imaging technique to generate a three-dimensional whole-brain reconstruction, especially the thalamus. We found that cortical neurons in the ACC received direct projections from different sub-nuclei in the thalamus, including the anterior, ventral, medial, lateral, midline, and intralaminar thalamic nuclei. These findings provide key anatomic evidences for the connection between the thalamus and ACC.

Regulation of the macrophage-hepatic stellate cell interaction by targeting macrophage peroxisome proliferator-activated receptor gamma to prevent non-alcoholic steatohepatitis progression in mice.

BACKGROUND & AIMS: Macrophages display remarkable plasticity and can interact with surrounding cells to affect hepatic immunity and tissue remodelling during the progression of liver diseases. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in macrophage maturation, polarization and metabolism. In this study, we investigated the role of PPARγ in macrophage-hepatic stellate cell (HSC) interaction during non-alcoholic steatohepatitis (NASH) development. METHODS: Wild-type, Ppargfl/fl and PpargΔLyz2 mice were fed a methionine- and choline-deficient (MCD) diet to induce NASH. Depletion of macrophages was performed using an injection of gadolinium chloride intraperitoneally. PPARγ-overexpressing or PPARγ-knockout macrophages were stimulated with saturated fatty acid (SFA) and cocultured with HSCs in a conditioned medium or the transwell coculture system. RESULTS: Depletion of macrophages inhibited HSC activation and ameliorated NASH progression in MCD diet-fed mice. Coculturing HSCs with macrophages or culturing HSCs in a macrophage-conditioned medium-facilitated HSC activation, and this effect was magnified when macrophages were metabolically activated by SFA. Moreover, the absence of PPARγ in macrophages enhanced metabolic activation, promoting the migration and activation of HSCs through IL-1ß and CCL2. In contrast, overexpression of PPARγ in macrophages obtained the opposite effects. In vivo, macrophage-specific PPARγ knockout affected the phenotype of hepatic macrophages and HSCs, involving the MAPK and NLRP3/caspase-1/IL-1ß signalling pathways. Infiltrating hepatic monocyte-derived macrophages became the predominant macrophages in NASH liver, especially in PpargΔLyz2 mice, paralleling with aggravated inflammation and fibrosis. CONCLUSIONS: Regulating macrophage PPARγ affected the metabolic activation of macrophages and their interaction with HSCs. Macrophage-specific PPARγ may be an attractive therapeutic target for protecting against NASH-associated inflammation and fibrosis.

Identifying peripheral arterial disease in the elderly patients using machine-learning algorithms.

BACKGROUND: Peripheral artery disease (PAD) is a common syndrome in elderly people. Recently, artificial intelligence (AI) algorithms, in particular machine-learning algorithms, have been increasingly used in disease diagnosis. AIM: In this study, we designed an effective diagnostic model of PAD in the elderly patients using artificial intelligence. METHODS: The study was performed with 539 participants, all over 80 years in age, who underwent the measurements of Doppler ultrasonography and ankle-brachial pressure index (ABI). Blood samples were collected. ABI and two machine-learning algorithms (MLAs)-logistic regression and a random forest (RF) model-were established to diagnose PAD. The sensitivity and specificity of the models were analyzed. An additional RF model was designed based on the most significant features of the original RF model and a prospective study was conducted to demonstrate its external validity. RESULTS: Thirteen of the 28 features introduced to the MLAs differed significantly between PAD and non-PAD participants. The respective sensitivities and specificities of logistic regression, RF, and ABI were as follows: logistic regression (81.5%, 83.8%), RF (89.3%, 91.6%) and ABI (85.1%, 84.5%). In the prospective study, the newly designed RF model based on the most significant seven features exhibited an acceptable performance rate for the diagnosis of PAD with 100.0% sensitivity and 90.3% specificity. CONCLUSIONS: An RF model was a more effective method than the logistic regression and ABI for the diagnosis of PAD in an elderly cohort.

Functional analysis of the odorant receptor coreceptor in odor detection in Grapholita molesta (lepidoptera: Tortricidae).

The olfactory system must detect and discriminate various semiochemicals in the environment. In response to such diversity, insects have evolved a family of odorant-gated ion channels composed of a common receptor (coreceptor, Orco) and a ligand-binding tuning odorant receptor (OR) that confers odour specificity. This study aims to examine the expression pattern of Orco gene of Grapholita molesta (GmolOrco) and to elucidate the role of GmolOrco in detecting G. molesta sex pheromone and green leaf volatiles by using gene silencing via RNA interference (RNAi) coupled antennal electrophysiological (EAG). Multiple sequence alignment showed that GmolOrco shared high sequence similarities with the Orco ortholog of lepidopterans. The results of real-time quantitative PCR detection demonstrated that GmolOrco was predominantly expressed in adult antennae and had the highest expression quantity in adult period among the different developmental stages. Compared with the noninjected controls, GmolOrco expression in GmolOrcodouble-stranded RNA (dsRNA)-injected males was reduced to 39.92% and that in females was reduced to 40.43%. EAG assays showed that the responses of GmolOrco-dsRNA injected males to sex pheromones (Z)-8-dodecenyl acetate (Z8-12:OAc) and (Z)-8-dodecenyl alcohol (Z8-12:OH) were significantly reduced, and the GmolOrco-dsRNA-injected female to green leaf volatile (Z)-3-hexenyl acetate also significantly declined. We inferred that Orco-mediated olfaction was different in male and female G. molesta adults and was mainly involved in recognizing the sex pheromones released by female moths.

[Non-invasive electrical neuromodulation techniques: analgesic effects and neural mechanisms].

As non-pharmaceutical interventions, non-invasive electrical neuromodulation techniques are promising in pain management. With many advantages, such as low costs, high usability, and non-invasiveness, they have been exploited to treat multiple types of clinical pain. Proper use of these techniques requires a comprehensive understanding of how they work. In this article, we reviewed recent studies concerning non-invasive electrical peripheral nerve stimulation (transcutaneous electrical nerve stimulation and transcutaneous vagus/vagal nerve stimulation) as well as electrical central nerve stimulation (transcranial direct current stimulation and transcranial alternating current stimulation). Specifically, we discussed their analgesic effects on acute and chronic pain, and the neural mechanisms thereof. We then contrasted the four kinds of nerve stimulation techniques, pointing out limitations of existing studies and proposing directions for future research. With more extensive and in-depth research to overcome these limitations, we shall witness more clinical applications of non-invasive electrical nerve stimulations to alleviate patients' pain and ease the crippling medical and economic burden imposed on patients, their families, and the entire society.

miR-4709 overexpression facilitates cancer proliferation and invasion via downregulating NR3C2 and is an unfavorable prognosis factor in colon adenocarcinoma.

To date, microRNA-4709 (miR-4709) has not been studied in colon adenocarcinoma (COAD) on the basis of experiments. In our study, we aimed to investigate the biological roles and clinical significance of miR-4709 in COAD. The expression difference between miR-4709 and NR3C2 was measured based on The Cancer Genome Atlas database and cells. Kaplan-Meier and logrank tests were applied to determine the overall survival (OS) differences according to the miR-4709 and NR3C2 expression levels. To measure whether the miR-4709 level was associated with COAD cell growth, migration, and invasion, we respectively conducted 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and transwell assays. A luciferase reporter assay was applied to confirm the relationship between miR-4709 and its predicted target. High expression of miR-4709 was found in COAD tissues and cells. The OS rate in the miR-4709 low expression group was significantly higher than that in the miR-4709 high expression group. Univariate and multivariate analyses exhibited that miR-4709 expression was an independent adverse prognostic factor. Exogenous miR-4709 overexpression promoted proliferation, migration, and invasion of LOVO and SW480 cells. Bioinformatics analysis and luciferase assay demonstrated that miR-4709 directly binds to the 3'-untranslated region of NR3C2. NR3C2 was lowly expressed in COAD and high expression of NR3C2 had a better prognosis compared with that in the low expression of NR3C2. Correlation analysis showed that there is a close association between the level of expression of NR3C2 and miR-4709. Accordingly, miR-4709 may function as an oncogene in COAD and provide a preclinical proof for candidate management to target new miR-4709-NR3C2 signaling for COAD therapy.

Hydroxytyrosol prevents dermal papilla cells inflammation under oxidative stress by inducing autophagy.

Hydroxytyrosol (HT), a primary phenolic antioxidant in olive oil, can afford protection from oxidative stress (OS) in different cells, including skin cells. In particular, it regulates several inflammation-associated processes as well as in improving the antioxidant defense system. However, there is no information about HT used in the treatment of hair loss. This work aimed at exploring the potential protective actions of HT against OS in rat dermal papilla cells. After treatment, the related expression of protein and messenger RNA were detected using morphological and molecular analyses. The results showed that HT significantly reduced intracellular reactive oxygen species level, apoptotic markers and inflammation induced by OS and enhanced cell survival by regulating autophagy. Furthermore, HT enhanced the secretion of hair growth factors in the anti-inflammation process. These results suggest that HT has a significant protective ability against OS and encourage the use of this biological ingredient as a possible tool to prevent alopecia.

ANKRD33 is overexpressed in gastric adenocarcinoma and predictive for poor prognosis.

The aim of the current study was to investigate and discuss the function of ANKRD33 gene in the pathogenesis of gastric adenocarcinoma. The marked up-regulated expression of ANKRD33 gene in gastric adenocarcinoma tissues compared to normal tissues was found by bioinformatics analysis. Kaplan-Meier analysis revealed that high expression of ANKRD33 is correlated with lower overall survival of gastric adenocarcinoma patients. The results of qPCR revealed that mRNA expression level of ANKRD33 was dramatically higher in AGS, SGC7901, and BGC823 cell lines than that in the GES1 cells. Knockdown of ANKRD33 remarkably inhibited the viability, invasion, and migration of AGS and BGC823 cells. Furthermore, the ratio of p-AKT/AKT and p-mTOR/mTOR was significantly decreased in AGS cells which transfected with si- ANKRD33. All the above results illustrated that ANKRD33 would act as a tumor forwarder in gastric adenocarcinoma development and have a high potential to be a marker molecule in the diagnosis and treatment of gastric tumors.

The Surgical Choice of Incidental Periampullary Carcinoma Management in Emergency Laparotomy.

BACKGROUND Laparotomy patients are occasionally diagnosed as having incidental periampullary cancers, making emergency pancreaticoduodenectomy (PD) inevitable. In this situation is difficult to decide whether to perform an emergency PD or a two-stage PD. MATERIAL AND METHODS A total of 27 patients who underwent emergency abdominal laparotomy were diagnosed with periampullary or pancreatic cancer during the operation without enough preoperative preparation. Ten patients underwent emergency one-stage PD and 17 patients underwent two-stage PD. Data of 137 patients with elective PD were selected as the control group. The preoperative, operative, and postoperative parameters, including hospital stay, medical cost, blood loss, and postoperative complications between elective PD and emergency PD (one-stage and two-stage) and between one-stage PD and two-stage PD were analyzed by chi-square test, Fisher test, or t test. RESULTS Patients undergoing emergency two-stage PD had less blood loss (P=0.014), while patients with one-stage PD had shorter hospital stay (P=0.004), shorter operation time (P=0.047), and lower treatment costs (P=0.003). Additionally, the complications rates between one-stage and two-stage PD had no significant difference (P=0.365). Elective PD was the optimal method due to shorter hospital stay (P<0.001), less hemorrhage (P<0.001), shorter operative time (P<0.001), and lower cost (P<0.001) compared with emergency PD. CONCLUSIONS Based on our experience, one-stage PD had advantages of shorter hospital stay, shorter operation time, and lower treatment costs, while two-stage PD had less blood loss. The emergency two-stage PD may be more suitable for patients with unstable vital signs if emergency PD is inevitable in an emergency laparotomy.

Evaluation of changes in skin biophysical parameters and appearance after pneumatic injections of non-cross-linked hyaluronic acid in the face.

BACKGROUND: Pneumatic injections of non-cross-linked hyaluronic acid are effective in skin rejuvenation, however, the associated biophysical parameters and appearance have not been evaluated. OBJECTIVES: To determine the changes in skin biophysical parameters after facial pneumatic injections of non-cross-linked hyaluronic acid. PATIENTS AND METHODS: Twenty-eight healthy female volunteers received pneumatic injections of non-cross-linked hyaluronic acid into the face for consecutive 5 weeks. Skin biophysical parameter assessment and clinical evaluation were performed using the CK Multi-Probe Adapter and Visia system. Five of the volunteers also underwent retroauricular skin biopsy before and after the last treatment. The skin tissues were all stained with Masson-trichrome, Verhoeff-van Gieson stain, and hematoxylin-eosin to evaluate the changes in collagen, elastic fibers, and the epidermis, before and after the last treatment. RESULTS: Transepidermal water loss was significantly lower in week 4 (18.46 ± 4.70 g/h/m2) than at the baseline (22.03 ± 7.15 g/h/m2, p < 0.05). Skin texture was better in week 4 (599.29 ± 354.32) than at the baseline (668.43 ± 342.55, p < 0.05). Skin pores also improved significantly at week 4 (934.07 ± 458.78) compared to the baseline (1024.57 ± 415.31, p < 0.05). Skin wrinkles were improved at the 3-month follow-up (29.29 ± 11.11) compared to the baseline (35.83 ± 16.05, p < 0.05). CONCLUSION: Pneumatic injections of non-cross-linked hyaluronic acid improved skin TEWL, texture, pores, and wrinkles.

Secreted frizzled-related protein 1 (SFRP1) gene methylation changes in the human lung adenocarcinoma cells treated with L-securinine.

Lung cancer remains the leading cause of cancer-related death worldwide. It is important to explore the biomarkers of diagnosis and prognosis in lung cancer. To evaluate the cytotoxicity of L-securinine and the expression and methylation of secreted frizzled-related proteins (SFRPs) genes in the human lung adenocarcinoma cells, cell counting kit-8 (CCK-8) assay was used to assess the proliferation of lung adenocarcinoma cells treated with L-securinine. Quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR were used to detect the expression and the DNA methylation of SFRPs genes, respectively. L-securinine inhibited the proliferation of lung adenocarcinoma cells and induced the upregulation of SFRP1 gene expression and the methylation changes at CpG sites in the SFRP1 promoter region. L-securinine was a potential agent in the treatment of lung cancer by upregulation of SFRP1 gene expression and changing the SFRP1 gene methylation.

Access Scheme for Controlling Mobile Agents and its Application to Share Medical Information.

This study is showing the advantage of mobile agents to conquer heterogeneous system environments and contribute to a virtual integrated sharing system. Mobile agents will collect medical information from each medical institution as a method to achieve the medical purpose of data sharing. Besides, this research also provides an access control and key management mechanism by adopting Public key cryptography and Lagrange interpolation. The safety analysis of the system is based on a network attacker's perspective. The achievement of this study tries to improve the medical quality, prevent wasting medical resources and make medical resources access to appropriate configuration.

Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma.

Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P=0.002) and PHCC (P=0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P=0.045) and PHCC (P=0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial-mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.