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Background: National and international experts have been attempting to find diagnostic tools for the early identification of symptoms to facilitate early identification and intervention of the disease. Objective: Detection of urine Alzheimer-associated neuronal thread protein (AD7c-NTP) and serum 25-hydroxyvitamin D (25(OH)D) in the diagnosis of Alzheimer’s disease (AD). Methods: Subjects aged >50 years who underwent a physical examination at the Taihu Sanatorium of Jiangsu Province, had no clinical evidence of AD-related issues, and had normal Mini-Mental State Exam and Montreal Cognitive Assessment scores were enrolled in the present study. There were 35 males and 15 females, who were aged 51–91 years. Urine AD7c-NTP levels and serum 25(OH)D concentrations were measured. Results: The Pearson correlation analysis revealed that the urine AD7c-NTP levels in these subjects were negatively correlated with the serum 25(OH)D concentrations (r = –0.460, p

Tumor metastasis is the primary cause of mortality in patients with cancer. Several chemokines are identified as important mediators of tumor growth and/or metastasis. The level of CXCL13 has been reported to be elevated in serum or tumor tissues in patients, which mainly functions to attract B cells and follicular B helper T cells. However, the role of CXCL13 in cancer growth and metastasis is not fully explored. In the current study, we found that CXCL13 is not a strong mediator to directly promote tumor growth; however, the mice deficient in CXCL13 had far fewer pulmonary metastatic foci than did the wild-type mice in experimental pulmonary metastatic models. In addition, Cxcl13−/− mice also had fewer IL-10–producing B cells (CD45+CD19+IL-10+) in the metastatic tumor immune microenvironment than those of wild-type C57BL/6 mice, resulting in an enhanced antitumor immunity. Notably, CXCL13 deficiency further improved the efficacy of a traditional chemotherapeutic drug (cyclophosphamide), as well as that of anti–programmed death receptor-1 immunotherapy. These results suggested that CXCL13 has an important role in regulating IL-10–producing B cells in tumor metastasis and might be a promising target for improving therapeutic efficiency and stimulating tumor immunity in future cancer therapy.

The study objective was to compare the effectiveness of microwave ablation (MWA) and laparoscopic liver resection (LLR) on solitary 3-5-cm HCC over time.From 2008 to 2019, 1289 patients from 12 hospitals were enrolled in this retrospective study. Diagnosis of all lesions were based on histopathology. Propensity score matching was used to balance all baseline variables between the two groups in 2008-2019 (n = 335 in each group) and 2014-2019 (n = 257 in each group) cohorts, respectively. For cohort 2008-2019, during a median follow-up of 35.8 months, there were no differences in overall survival (OS) between MWA and LLR (HR: 0.88, 95% CI 0.65-1.19, p = 0.420), and MWA was inferior to LLR regarding disease-free survival (DFS) (HR 1.36, 95% CI 1.05-1.75, p = 0.017). For cohort 2014-2019, there was comparable OS (HR 0.85, 95% CI 0.56-1.30, p = 0.460) and approached statistical significance for DFS (HR 1.33, 95% CI 0.98-1.82, p = 0.071) between MWA and LLR. Subgroup analyses showed comparable OS in 3.1-4.0-cm HCCs (HR 0.88, 95% CI 0.53-1.47, p = 0.630) and 4.1-5.0-cm HCCs (HR 0.77, 95% CI 0.37-1.60, p = 0.483) between two modalities. For both cohorts, MWA shared comparable major complications (both p 0.05), shorter hospitalization, and lower cost to LLR (all p 0.001).MWA might be a first-line alternative to LLR for solitary 3-5-cm HCC in selected patients with technical advances, especially for patients unsuitable for LLR.

Tumours growing in the sella turcica are mostly pituitary adenomas. We describe a rare case of primary intrasellar schwannoma with intratumoral bleeding. A 38-year-old man presented with headache in association with bilateral supratemporal quadrantopsia. MRI showed an intrasellar mixed signal mass lesion with suprasellar extension. The majority of the pituitary hormones were normal. He was diagnosed as non-functional pituitary adenoma with pituitary apoplexy. Subtotal resection was achieved eventually via an endoscopic transnasal trans-sphenoidal approach. The histopathologic diagnosis was schwannoma. It is the first intrasellar schwannoma with intratumoral hemorrhage in literature to date. It implied that the primary intrasellar schwannoma has potential risk of intratumoral bleeding, which should be considered in the differential diagnoses of sellar lesions.

Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.

Background Black opportunists Phialophora verrucosa complex species can cause different disease types in competent and in immunocompromised individuals, but are remarkably overrepresented in CARD9-related infections. Objectives To better understand the ecology and potential pathogenicity of opportunistic Phialophora species and reveal eventual genetic parameters associated with the behaviour in vivo and genetic profiles in patients with CARD9 immunodeficiency. Methods Genomes of 26 strains belonging to six species of the Phialophora verrucosa complex were sequenced. Using multilocus analysis, all environmental and clinical strains were identified correctly. We compared the genomes of agents from different disease types among each other including CARD9 immunodeficiency. Results We obtained genome sizes of the 26 Phialophora strains ranged between 32 and 37 MB. Some species showed considerable intraspecific genomic variation. P americana showed the highest degree of variability. P verrucosa was variable in CAZy enzymes, whereas P americana varied in PKS-related genes. Phialophora species, particularly P verrucosa, are relatively frequent in patients with CARD9-related immunodeficiency. Different mutations in the CARD9 gene seem to increase susceptibility for infection by different groups of species, that is either Candida, dermatophytes or black fungi. A number of patients with chromoblastomycosis revealed an as yet unknown CARD9 mutation. TNFα impairment was prevalent in patients with CARD9 infections, while CBM patients were invariably IFNγ. Conclusions From genomic investigations, the known virulence factors between clinical and environmental strains did not reveal any significant difference. Phialophora complex has an equal chance to cause infection in humans, either healthy or CARD9-impaired.

Introduction: There are few studies on the role of puncture feeling in thyroid nodules during ultrasound-guided fine-needle aspiration cytology (US-FNAC), although it is expected to become a new predictive technique. We aimed to analyze the importance of puncture feeling in combination with US-FNAC and investigate whether it can be used as an indicator to predict the nature of thyroid nodules. Materials and Methods: From January 1, 2018, to October 31, 2020, a total of 623 thyroid nodules were included. Puncture feeling was classified as “soft,” “hard,” or “hard with grittiness.” The correlation between puncture feeling and postoperative pathology and the diagnostic value of FNAC combined with puncture feeling were analyzed, and the influence of thyroid nodule size on puncture feeling, FNAC, and FNAC combined with puncture feeling was studied. We further explored the correlation between puncture feeling and histopathology in Bethesda III and IV thyroid nodules. Results: There was a significant correlation between puncture feeling and postoperative pathology (p < 0.001). The sensitivity, negative predictive value, and total coincidence rate of US-FNAC combined with puncture feeling for the diagnosis of thyroid nodules were higher than those of US-FNAC alone (96.1, 83.6, and 94.7% vs. 89.0, 65.5, and 89.7%, respectively). Thyroid nodule size was the influencing factor for puncture feeling, FNAC, and FNAC combined with puncture feeling (p < 0.05 for all). The area under the curve for puncture feeling, FNAC, and FNAC combined with puncture feeling for thyroid nodules of size ≤1 cm was greater than for modules of size >1 cm. Puncture feeling was of great value in diagnosing Bethesda III thyroid nodules (p < 0.001), and all Bethesda IV thyroid nodules had puncture feeling of soft. Conclusion: Puncture feeling is of great value during US-FNAC. “Hard” and “hard with grittiness” were indicators for malignancy, while “soft” indicated that the thyroid nodule was likely to be benign. The diagnostic value of US-FNAC combined with puncture feeling for thyroid nodules is higher than US-FNAC alone, especially when nodule size is ≤1 cm. Puncture feeling is of great value in predicting the nature of Bethesda III thyroid nodules.

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.

Acute heart failure (AHF) is a severe complication after cardiac surgery with cardiopulmonary bypass (CPB). Although some AHF biomarkers have been used in clinic, they have limitations when applied in the prediction and diagnosis of AHF after cardiac surgery with CPB, and there are still no effective and specific biomarkers. We and other researchers have shown that circulating microparticles (MPs) increased in a variety of cardiovascular diseases. However, whether the concentration of circulating MPs could be a new biomarker for AHF after cardiac surgery remains unknown. Here, 90 patients undergoing cardiac surgery with CPB and 45 healthy subjects were enrolled. Patients were assigned into AHF (n=14) or non-AHF (n=76) group according to the diagnosis criteria of AHF. The concentrations of circulating MPs were determined before, as well as 12 h and 3 days after operation with nanoparticle tracking analysis technique. MPs concentrations in patients before surgery were significantly higher than those of healthy subjects. Plasma levels of MPs were significantly elevated at 12 h after surgery in patients with AHF, but not in those without AHF, and the circulating MPs concentrations at 12 h after surgery were higher in AHF group compared with non-AHF group. Logistic regression analysis indicated that MPs concentration at postoperative 12 h was an independent risk factor for AHF. The area under receiver operating characteristic curve for MPs concentration at postoperative 12 h was 0.81 and the best cut-off value is 5.20×108 particles mL-1 with a sensitivity of 93% and a specificity of 10%. These data suggested that the concentration of circulating MPs might be a new biomarker for the occurrence of AHF after cardiac surgery with CPB.

Rheumatoid arthritis (RA), which normally manifests as a multi‑joint inflammatory reaction, is a common immunological disease in clinical practice. However, the pathogenesis of RA has not yet been fully elucidated. Rituximab (RTX) is an effective drug in the treatment of RA, however its therapeutic efficacy and mechanism of action require further investigation. Thus, the present study aimed to screen the candidate key regulatory genes and explain the potential mechanisms of RA. Gene chips of RA and normal joint tissues were analyzed and, gene chips of RTX before and after treatment were investigated. In the present study, strong evidence supporting the pathogenesis of RA and mechanism of action of RTX were also revealed. Differentially expressed genes (DEGs) were analyzed using the limma package of RStudio software. A total of 1,150 DEGs were detected in RA compared with normal joint tissues. The upregulated genes were enriched in 'interleukin‑12 production', 'I‑κB kinase/NF‑κB signaling', 'regulation of cytokine production involved in immune response' and 'cytokine metabolic process'. Functional enrichment analysis showed that RTX was primarily involved in the inhibition of 'adaptive immune response', 'B cell activation involved in immune response' and 'immune effector process'. Subsequently, leukocyte immunoglobulin‑like receptor subfamily B member 1 (LILRB1), a hub gene with high connectivity degree, was selected, and traditional Chinese medicine libraries were molecularly screened according to the structure of the LILRB1 protein. The results indicated that kaempferol 3‑O‑β‑D‑glucosyl‑(1→2)‑β‑D‑glucoside exhibited the highest docking score. In the present study, the DEGs and their biological functions in RA and the pharmacological mechanism of RTX action were determined. Taken together, the results suggested that LILRB1 may be used as a molecular target for RA treatment, and kaempferol 3‑O‑β‑D‑glucosyl‑(1→2)‑β‑D‑glucoside may inhibit the pathological process of RA.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (M

The bromodomain protein BRD4 exerts carcinogenic effects in many cancers. However, its roles in glioma occurrence are still confused. Here, it is found that BRD4 expression is increased in glioma tissues and negatively correlated with the overall survival of glioma patients. We construct cellular experiments indicating that BRD4 promotes glioma cell stemness by analyzing ALDH1 activity, master stemness regulator expression, and sphere formation ability. Mechanistically, BRD4 knockdown triggers a switch of miR-142-5p promoter methylation, which targets Wnt3a and thus further inactivates Wnt/β-catenin signaling. Importantly, inhibition of miR-142-5p or reactivation of Wnt/β-catenin signaling rescues the inhibition of BRD4 knockdown on glioma cell stemness. As a result, these results not only indicate an unforeseen connection between BRD4, miR-142-5p, and Wnt/β-catenin signaling, but also reveal a promising epigenetic-based therapeutic strategy that might be explored for glioma patients.

Up-regulation of family with sequence similarity 83 member D (FAM83D) has been acknowledged as a vital contributor for the carcinogenesis of numerous cancers. The relevance of FAM83D in glioblastoma (GBM), however, is not well understood. This current work aimed to determine the possible roles and mechanisms of FAM83D in GBM. By analyzing The Cancer Genome Atlas (TCGA) data, we found dramatic increases in FAM83D expression in GBM tissue. We also observed elevated levels of FAM83D in the clinical specimens of GBM. In vitro data showed that silencing FAM83D resulted in remarkable antitumor effects via inhibiting the proliferation, invasion and epithelial-mesenchymal transition of GBM cells. Moreover, the knockdown of FAM83D improved sensitivity to the chemotherapy drug temozolomide. In-depth mechanism research revealed that the silencing of FAM83D strikingly decreased the phosphorylation levels of AKT and glycogen synthase kinase-3β, and prohibited activation of the Wnt/β-catenin pathway. The suppression of AKT abolished FAM83D-mediated activation of the Wnt/β-catenin pathway. The re-expression of β-catenin reversed FAM83D-silencing-induced antitumor effects in GBM cells. In addition, GBM cells with FAM83D silencing exhibited reduced tumorigenic potential in vivo. Overall, the data from this work show that the inhibition of FAM83D displays antitumor effects in GBM via down-regulation of the AKT/Wnt/β-catenin pathway and propose FAM83D as a new therapeutic target for GBM.

YAP1, a key mediator of the Hippo pathway, plays an important role in tumorigenesis. Alternative splicing of human YAP1 mRNA results in two major isoforms: YAP1-1, which contains a single WW domain, and YAP1-2, which contains two WW domains, respectively. We here investigated the functions and the underlying regulatory mechanisms of the two YAP1 isoforms in the context of EGF-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Human NSCLC cell lines express both YAP1-1 and YAP1-2 isoforms-although when compared to YAP1-1, YAP1-2 mRNA levels are higher while its protein expression levels are lower. EGF treatment significantly promoted YAP1 expression as well as EMT process in NSCLCs, whereas EGF-induced EMT phenotype was significantly alleviated upon YAP1 knockdown. Under normal culture condition, YAP1-1 stable expression cells exhibited a stronger migration ability than YAP1-2 expressing cells. However, upon EGF treatment, YAP1-2 stable cells showed more robust migration than YAP1-1 expressing cells. The protein stability and nuclear localization of YAP1-2 were preferentially enhanced with EGF treatment. Moreover, EGF-induced EMT and YAP1-2 activity were suppressed by inhibitor of AKT. Our results suggest that YAP1-2 is the main isoform that is functionally relevant in promoting EGF-induced EMT and ultimately NSCLC progression.

Background Mitochondria have been shown to play vital roles during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) development. Currently, it is unclear whether mitochondrial DNA (mtDNA) variants, which define mtDNA haplogroups and determine oxidative phosphorylation performance and reactive oxygen species production, are associated with COVID-19 risk. Methods A population-based case–control study was conducted to compare the distribution of mtDNA variations defining mtDNA haplogroups between healthy controls (n = 615) and COVID-19 patients (n = 536). COVID-19 patients were diagnosed based on molecular diagnostics of the viral genome by qPCR and chest X-ray or computed tomography scanning. The exclusion criteria for the healthy controls were any history of disease in the month preceding the study assessment. MtDNA variants defining mtDNA haplogroups were identified by PCR-RFLPs and HVS-I sequencing and determined based on mtDNA phylogenetic analysis using Mitomap Phylogeny. Student’s t-test was used for continuous variables, and Pearson’s chi-squared test or Fisher’s exact test was used for categorical variables. To assess the independent effect of each mtDNA variant defining mtDNA haplogroups, multivariate logistic regression analyses were performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) with adjustments for possible confounding factors of age, sex, smoking and diseases (including cardiopulmonary diseases, diabetes, obesity and hypertension) as determined through clinical and radiographic examinations. Results Multivariate logistic regression analyses revealed that the most common investigated mtDNA variations (> 10% in the control population) at C5178a (in NADH dehydrogenase subunit 2 gene, ND2) and A249d (in the displacement loop region, D-loop)/T6392C (in cytochrome c oxidase I gene, CO1)/G10310A (in ND3) were associated with a reduced risk of severe COVID-19 (OR = 0.590, 95% CI 0.428–0.814, P = 0.001; and OR = 0.654, 95% CI 0.457–0.936, P = 0.020, respectively), while A4833G (ND2), A4715G (ND2), T3394C (ND1) and G5417A (ND2)/C16257a (D-loop)/C16261T (D-loop) were related to an increased risk of severe COVID-19 (OR = 2.336, 95% CI 1.179–4.608, P = 0.015; OR = 2.033, 95% CI 1.242–3.322, P = 0.005; OR = 3.040, 95% CI 1.522–6.061, P = 0.002; and OR = 2.890, 95% CI 1.199–6.993, P = 0.018, respectively). Conclusions This is the first study to explore the association of mtDNA variants with individual’s risk of developing severe COVID-19. Based on the case–control study, we concluded that the common mtDNA variants at C5178a and A249d/T6392C/G10310A might contribute to an individual’s resistance to developing severe COVID-19, whereas A4833G, A4715G, T3394C and G5417A/C16257a/C16261T might increase an individual’s risk of developing severe COVID-19.

Background Management of the disproportionately large communicating fourth ventricle is still problematic. Case presentation Two cases of disproportionately large communicating fourth ventricle were treated successfully. One was a case of a 51-year-old Han Chinese woman with a complaint of headache and dizziness of 1 year’s duration. Magnetic resonance imaging (MRI) demonstrated hydrocephalus with a disproportionately large fourth ventricle. She underwent a ventriculo-peritoneal shunt of the right lateral ventricle. Her symptoms were relieved totally. Five years later, magnetic resonance imaging showed she had a normal ventricular system. The other case was a 24-year-old Han Chinese man with a 2-month history of headache and dizziness accompanied by progressive loss of bilateral vision. Magnetic resonance imaging revealed hydrocephalus with a disproportionately large fourth ventricle, crowded posterior cranial fossa, and syringomyelia extending from C1 to C5. He underwent suboccipital and C1 decompression and duraplasty. Shortly after the surgery, his symptoms were relieved completely, the syringomyelia completely disappeared, and the fourth ventricle became significantly smaller. Conclusions The management of the disproportionately large communicating fourth ventricle should be individualized. If it coexists with crowded posterior cranial fossa or syringomyelia, posterior fossa decompression could be an option for initial management. If there is no sign of crowded posterior cranial fossa or syringomyelia, shunt of the lateral ventricles might be the first choice.

We explored the potential clinical value of material separation enabled by dual-energy spectral computed tomography in detecting left atrial appendage thrombi. The study enrolled 24 patients who were scheduled to undergo atrial fibrillation ablation (12 with and 12 without left atrial appendage thrombi). Computed tomograms were acquired in gemstone spectral imaging mode; the densities in the regions of the left atrial appendage cavities, pectinate muscles, and left atrial appendage thrombi were analyzed on monochromatic 70-keV images. Iodine and blood were chosen as the material basis pair; the iodine and blood densities were observed and quantitatively determined from the iodine- and blood-specific material decomposition images. On the 70-keV monochromatic and iodine-specific images, the left atrial appendage pectinate muscles and thrombi appeared as areas of hypodense attenuation. On the blood-specific images, similar areas of high attenuation were observed in the thrombi and cavities, whereas lower attenuation was noticed in the pectinate muscles. The quantitative iodine and blood densities in the pectinate muscles were lower than those in the cavities (P Spectral computed tomography-enabled material separation is a novel method for differentiating left atrial appendage thrombi from pectinate muscles. The potential applications of this technology warrant further studies.

Toads produce potent toxins, named bufadienolides, to defend against their predators. Pharmacological research has revealed that bufadienolides are potential anticancer drugs. In this research, we reported nine bufadienolides from the eggs of the toad Bufo bufo gargarizans, including two new compounds (1 and 3). The chemical structures of 1 and 3, as well as of one previously reported semisynthesized compound (2), were elucidated on the basis of extensive spectroscopic data interpretation, chemical methods, and X-ray diffraction analysis. Compound 1 is an unusual 19-norbufadienolide with rearranged A/B rings. A biological test revealed that compounds 2 and 4–8 showed potent cytotoxic activities toward human melanoma cell line SK-MEL-1 with IC(50) values less than 1.0 μM. A preliminary mechanism investigation revealed that the most potent compound, 8, could induce apoptosis via PARP cleavage, while 5 and 6 significantly suppressed angiogenesis in zebrafish. Furthermore, an in vivo biological study showed that 5, 6, and 8 inhibit SK-MEL-1 cell growth significantly.

IntroductionProvisional stenting using drug-eluting stent is effective for simple coronary bifurcation lesions. Kissing balloon inflation using conventional non-compliant balloon is the primary treatment of side branch (SB) after main vessel (MV) stenting. Drug-coating balloon (DCB) is reported to be associated with less frequent clinical events in in-stent restenosis and small vessel disease. The importance of DCB in bifurcation treatment is understudied. Accordingly, this trial is designed to investigate the superiority of DCB to non-compliant balloon angioplasty for SB after provisional stenting in patients with true coronary bifurcation lesions.Methods and analysisThe DCB-BIF trial is a prospective, multicentre, randomised, superiority trial including 784 patients with true coronary bifurcation lesions. Patients will be randomised in a 1:1 fashion to receive either DCB or non-compliant balloon angioplasty if SB diameter stenosis >70% after MV stenting. The primary endpoint is the composite of major adverse cardiac event at the 1-year follow-up, including cardiac death, myocardial infarction (MI) or clinically driven target lesion revascularisation. The major secondary endpoints include all-cause death, periprocedural MI, spontaneous MI, clinically driven target vessel revascularisation, in-stent restenosis, stroke and individual component of the primary endpoint. The safety endpoint is the risk of stent thrombosis.Ethics and disseminationThe study protocol and informed consent have been reviewed and approved by the Institutional Review Board of all participating centres. The written informed consent for participation in the trial will be obtained from all participants. The results of this study will be published in a peer-reviewed journal and disseminated at conferences.Trial registration numberNCT04242134.

Glioma is a type of brain tumor that is common globally, and is associated with a variety of genetic changes. It has been reported that isocitrate dehydrogenase 1 (IDH1) is overexpressed in glioma and in HeLa cells. The lncRNA IDH1-AS1 is believed to interact with IDH1, and when IDH1-AS1 is overexpressed, HeLa cell proliferation is inhibited. However, the effects of IDH1-AS1 on glioma were relatively unknown. The results from this work show that IDH1-AS1 is downregulated in the glioma tissues. We used primary glioblastoma cell lines U251 and U87-MG to study the effects of IDH1-AS1 on glioma cell growth, in vitro and in vivo. We found that when IDH1-AS1 is overexpressed cell proliferation is inhibited, cell cycle is arrested at the G1 phase, and the protein expression levels of cyclinD1, cyclinA, cyclinE, CDK2, and CDK4 are decreased. We found that cell apoptosis was increased when IDH1-AS1 was overexpressed, as evidenced by increases in the levels of cleaved caspase-9 and -3. Conversely, knockdown of IDH1-AS1 promoted cell proliferation. Moreover, we proved that overexpression of IDH1-AS1 inhibits the tumorigenesis of U251 cells, in vivo. Furthermore, IDH1-AS1 did not affect IDH1 protein expression, but altered its enzymatic activities in glioma cells. Silencing of IDH1 reversed the effects of IDH1-AS1 upregulation on cell viability. Hence, our study provides first-hand evidence for the effects of lncRNA IDH1-AS1 on gliomas. Because overexpressing IDH1-AS1 inhibited cell growth, IDH1-AS1 could also be considered as a potential target for glioma treatment.

Background Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion. Trial design DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure. Conclusions DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.

Patient: Female, 39-year-old Final Diagnosis: Atypical meningioma • meningioma • multiple meningioma Symptoms: Headache Medication:— Clinical Procedure: Surgery and radiotherapy Specialty: Neurosurgery Objective: Unusual clinical course Background: The pathogenesis of sporadic multiple meningiomas in the patients without history of neurofibromatosis type II remains unclear. We report whole exome sequencing (WES) of 2 metachronous multiple meningiomas of the same patient. Case Report: A 39-year-old female had a 5-month history of headache and her magnetic resonance imaging (MRI) revealed a significantly enhanced intracranial space-occupying pathology with dura tail sign and skull invasion. She had no history of neurofibromatosis type II or other tumors. Tumor resection achieved Simpson grade I and the pathological studies revealed an atypical meningioma. After surgery, she accepted focal external-beam radiation therapy. One year later, MRI showed a significantly enhanced intracranial space-occupying pathology near the primary site of the previous tumor. She had only a mild headache. Simpson grade I resection of the tumor was achieved. The pathological diagnosis was still an atypical meningioma. WES on both tumors identified 220 common somatic gene mutations and 43 different somatic gene mutations. Three deleterious mutated genes including QRICH2, KIF2C, and MUC16 were identified only in the first tumor, and 9 deleterious mutated genes including FCGBP, RPS6KA5, GOLGA6L2, IGHV3-66, RPTN, AGRN, USP6, CLTCL1, and PABPC3 were identified only in the second tumor. As shown by the identical result of 3 prediction tools, RPS6KA5 and AGRN were most likely to be related to the progress of multiple atypical meningiomas. Conclusions: The metachronous meningiomas with same World Health Organization (WHO) grades in the same patient could have distinct genetic aberration patterns. The roles of RPS6KA5 and AGRN in the rapid progress of multiple atypical meningiomas need further studies.

Transketolase (TKT), which is a metabolic enzyme in the nonoxidative phase of the pentose phosphate pathway (PPP), plays an important role in providing cancer cells with raw materials for macromolecular biosynthesis. The ectopic expression of TKT in hepatocellular carcinoma (HCC) was reported previously. However, the role of TKT in the initiation of liver cancer is still obscure. In our previous study, we found that TKT deficiency protects the liver from DNA damage by increasing levels of ribose 5-phosphate and nucleotides. What’s more interesting is that we found TKT deficiency reduced bile acids and loss of TKT promoted the farnesoid receptor (FXR) expression. We further showed that TKT translocated into the nucleus of HCC cell lines through interacting with the signal transducer and activator of transcription 1 (STAT1), and then the complex inhibited FXR expression by promoting the binding of histone deacetylase 3 (HDAC3) to FXR promoter.

To investigate the clinical pattern, survival rate, causes of death and risk factors in a large cohort of Chinese Han patients with systemic sclerosis (SSc). Inpatients treated from 2002 to 2014 were included in this study. Patients were classified into diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc-overlap syndrome groups. Data were analyzed using Chi-squared tests, Kaplan-Meier curves, log-rank tests, and Cox proportional hazards modeling. Among a total of 201 patients, dcSSc (50.2%) was the major subtype, followed by lcSSc (30.3%) and SSc-overlap (19.4%). Interstitial lung disease (ILD, 148/201, 74%) was the most frequent organ involvement. The overall survival rates were 98% and 95% at 5 and 10 years, respectively. The overall standard mortality ratio (SMR) was 2.22. The most common cause of death was ILD combined with infection (8/16, 50%), followed by kidney failure (2/16, 12.5%). On crude analysis, pulmonary hypertension, ILD, cardiac involvements, renal involvements, and digital ischemia were associated with poor prognosis. On multivariate analysis, pericardial effusion (p = 0.000) and digital ischemia (p = 0.016) were independent prognostic factors of death. The mortality rate of patients with SSc is mildly increased in comparison with the general population. ILD is the most common systemic involvement and the principal cause of death in SSc. Pericardial effusion and digital ischemia are independent factors associated with death.

The anti-oxidative effects of vitamin D3 (Vd3) on mesenchymal stem cells (MSCs) have not been studied before. The present study suggested that Vd3 could not only promote the osteogenic differentiation of MSCs under normal condition but also partly protect it from oxidative stress damage by activating the endogenous antioxidant system. Evolving evidence proved that oxidative stress caused by reactive oxygen species (ROS) overproduction might lead to bone loss. Vd3, a commonly used osteogenic induction drug, was proved to exhibit potent anti-oxidative effects on other cell types. The present study aims to investigate the protective effects of Vd3 on oxidative stress-induced dysfunctions of MSCs, as well as its underlying mechanisms. The H2O2 was used as exogenous reactive oxygen species (ROS). The influence of ROS and anti-oxidative protection of Vd3 on MSCs were analyzed too. Multi-techniques were used to assess the beneficial effects of Vd3 on MSCs under oxidative stress condition. The results demonstrated that Vd3 could significantly attenuate the H2O2-induced cell injury of MSCs via Sirt1/FoxO1 signaling pathway, and reduced the H2O2 exposure-induced intracellular oxidative stress status of MSCs. What’s more, the H2O2 exposure resulted in the decreased osteogenic differentiation of MSCs, as evidenced by decreased alkaline phosphatase activity, calcium deposition level, and osteogenic differentiation gene mRNA levels, but the injury was restored via Vd3 administration. The results suggested that Vd3 could not only promote the osteogenic differentiation of osteoblastic cells under normal condition but also partly protect the cell from oxidative stress damage by activating endogenous antioxidant system. The study shed light on the new roles of Vd3 in bone modeling and remodeling regulation.

Long noncoding RNAs (lncRNAs), with length of more than 200 nucleotides, are not translated into proteins but involved in multiple diverse diseases, especially tumorigenesis. The dysregulation of lncRNAs greatly contributes to the progression of various tumors through specific signaling pathways, including Wnt/β-catenin signaling pathway, which is associated with malignant features of tumors. The interactions between lncRNAs, which have specific expression characteristics in diverse cancer tissues, and Wnt/β-catenin signaling pathway, exhibit potential as novel biomarkers and therapeutic targets. In this review, we aim to present research findings on the roles of Wnt pathway-related lncRNAs and their effects on Wnt/β-catenin signaling to regulate tumorigenesis in different cancer types. Results may be used as basis to develop or improve strategies for treatment of different carcinomas.

Background Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) are a novel and promising strategy for tissue engineering because of their ability to differentiate into many cell types. We characterized the differentiation of WJ-MSCs into endometrial epithelial cell (EEC)-like and endometrial stromal cell (ESC)-like cells and assessed the effect of 17β-estradiol and 8-Br-cAMP on the differentiation system. Methods WJ-MSCs were treated in two ways to differentiate into EEC-like and ESC-like cells respectively: cocultured with ESCs in control/differentiation medium (17β-estradiol, growth factors); and cultured in control/differentiation medium (8-Br-cAMP alone or 8-Br-cAMP plus 17β-estrogen and growth factors). Three signaling pathway inhibitors (SB203580, PD98059, H89) were used to investigate the mechanism of WJ-MSC differentiation into ESC-like cells. Immunofluorescence, western blot and flow cytometry analyses were used to analyze expression of epithelial markers and stromal cell markers. Enzyme-linked immunosorbent assays were used to test the production of secretory proteins associated with the differentiation of ESC-like cells. Results 17β-estradiol at 1 μM downregulated vimentin and CD13 and upregulated cytokeratin and CD9 proteins, promoting the differentiation of WJ-MSCs into EEC-like cells in the coculture system. 8-Br-cAMP at 0.5 mM upregulated vimentin and CD13 and downregulated CK and CD9, promoting the differentiation of WJ-MSCs into ESC-like cells. Prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1) were upregulated and the protein kinase A (PKA) signaling pathway was activated, whereas extracellular signal-regulated (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) were not affected. Conclusions 17β-estradiol at 1 μM is a good inducer for facilitating the differentiation of WJ-MSCs into EEC-like cells. 8-Br-cAMP plus estrogen and growth factors can induce the differentiation of WJ-MSCs into ESC-like cells. During the differentiation of WJ-MSCs into ESC-like cells, PRL and IGFBP1 were upregulated by the treatment and the PKA signaling pathway was activated, whereas ERK1/2 and p38 MAPK were not affected. These findings suggest a promising approach to the treatment of endometrial damage and other endometrial diseases and suggest new applications for WJ-MSCs in clinical practice. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0700-5) contains supplementary material, which is available to authorized users.

Colorectal carcinoma (CRC) is the one of the most common cancers with considerable metastatic potential, explaining the need for new drug candidates that inhibit tumor metastasis. The signal transducers and activators of the transcription 3 (Stat3) signaling pathway has an important role in CRC and has been validated as a promising anticancer target for CRC therapy. In the present study, we report our findings on nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3. Our studies showed that nifuroxazide decreased the viability of three CRC cell lines and induced apoptosis of cancer cells in a concentration-dependent manner. Moreover, western blot analysis demonstrated that the occurrence of its apoptosis was correlated with the activation of Bax and cleaved caspase-3, and decreased the expression of Bcl-2. In addition, nifuroxazide markedly impaired CRC cell migration and invasion by downregulating phosphorylated-Stat3

Cancer has become a major health issue worldwide, contributing to a high mortality rate. Tumor metastasis is attributed to the death of most patients. Epithelial-to-mesenchymal transition (EMT) plays a vital role in inducing metastasis. During EMT, epithelial cells lose their characteristics, such as cell-to-cell adhesion and cell polarity, and cells gain motility, migratory potential, and invasive properties to become mesenchymal stem cells. Circular RNAs (circRNAs) are closely associated with tumor metastasis and patient prognosis, as revealed by increasing lines of evidence. CircRNA is a type of single-stranded RNA that forms a covalently closed continuous loop. CircRNAs are insensitive to ribonucleases and are widespread in body fluids. This work is the first review on EMT-related circRNAs. In this review, we briefly discuss the characteristics and functions of circRNAs. The correlation of circRNAs with EMT has been reported, and we discuss the ways circRNAs can regulate EMT progression through EMT transcription factors, EMT-related signaling pathways, and other mechanisms. This work summarizes current studies on EMT-related circRNAs in various cancers and provides a theoretical basis for the use of EMT-related circRNAs in targeted management and therapy.

To investigate the characteristics, sources, and health risks of trace heavy metals in fine particles, PM

Background. Diabetes mellitus is a chronic disease with a steadfast increase in prevalence. Due to the chronic course of the disease combining with devastating complications, this disorder could easily carry a financial burden. The early diagnosis of diabetes remains as one of the major challenges medical providers are facing, and the satisfactory screening tools or methods are still required, especially a population- or community-based tool. Methods. This is a retrospective cross-sectional study involving 15,323 subjects who underwent the annual check-up in the Department of Family Medicine of Shengjing Hospital of China Medical University from January 2017 to June 2017. With a strict data filtration, 10,436 records from the eligible participants were utilized to develop a prediction model using the J48 decision tree algorithm. Nine variables, including age, gender, body mass index (BMI), hypertension, history of cardiovascular disease or stroke, family history of diabetes, physical activity, work-related stress, and salty food preference, were considered. Results. The accuracy, precision, recall, and area under the receiver operating characteristic curve (AUC) value for identifying potential diabetes were 94.2%, 94.0%, 94.2%, and 94.8%, respectively. The structure of the decision tree shows that age is the most significant feature. The decision tree demonstrated that among those participants with age≤49, 5497 participants (97%) of the individuals were identified as nondiabetic, while age>49, 771 participants (50%) of the individuals were identified as nondiabetic. In the subgroup where people were 34

// Qing-yong Chen 1, * , De-min Jiao 1, * , Yu-quan Wu 2 , Jun Chen 1 , Jian Wang 1 , Xia-li Tang 1 , Hao Mou 1 , Hui-zhen Hu 1 , Jia Song 1 , Jie Yan 1 , Li-jun Wu 1 , Jianyan Chen 3 , Zhiwei Wang 4, 5 1 Department of Respiratory Disease, The 117 th Hospital of PLA, Zhejiang, China 2 Department of Oncology, The 117 th Hospital of PLA, Zhejiang, China 3 Department of Anesthesiology, Shenzhen Baoan Hospital Affiliated to Southern Medical University, Guangdong, China 4 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 5 The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China * These authors contribute equally to this work Correspondence to: Jianyan Chen, e-mail: chenjianyan@yahoo.com Zhiwei Wang, e-mail: zwang6@bidmc.harvard.edu Qing-yong Chen, e-mail: cqyong117@163.com Keywords: miR-206, HGF, epithelial-mesenchymal transition, angiogenesis, lung cancer Received: November 05, 2015 Accepted: February 9, 2016 Published: February 22, 2016 ABSTRACT MiR-206 is low expression in lung cancers and associated with cancer metastasis. However, the roles of miR-206 in epithelial-mesenchymal transition (EMT) and angiogenesis in lung cancer remain unknown. In this study, we find that hepatocyte growth factor (HGF) induces EMT, invasion and migration in A549 and 95D lung cancer cells, and these processes could be markedly inhibited by miR-206 overexpression. Moreover, we demonstrate that miR-206 directly targets c-Met and inhibits its downstream PI3k/Akt/mTOR signaling pathway. In contrast, miR-206 inhibitors promote the expression of c-Met and activate the PI3k/Akt/mTOR signaling, and this effect could be attenuated by the PI3K inhibitor. Moreover, c-Met overexpression assay further confirms the significant inhibitory effect of miR-206 on HGF-induced EMT, cell migration and invasion. Notably, we also find that miR-206 effectively inhibits HGF-induced tube formation and migration of human umbilical vein endothelial cells (HUVECs), and the mechanism is also related to inhibition of PI3k/Akt/mTOR signaling. Finally, we reveal the inhibitory effect of miR-206 on EMT and angiogenesis in xenograft tumor mice model. Taken together, miR-206 inhibits HGF-induced EMT and angiogenesis in lung cancer by suppressing c-Met/PI3k/Akt/mTOR signaling. Therefore, miR-206 might be a potential target for the therapeutic strategy against EMT and angiogenesis of lung cancer.

Background To evaluate the efficacy of pelvic plexus block (PPB) in relief pain during transperineal template-guided prostate biopsy (TTPB), compared with conventional periprostatic nerve block (PNB). Methods From July 2016 to August 2017, 245 patients who were performed TTPB in Clinical Medical College of Yangzhou University were recruited. The patients were randomized into three groups using a random number table. Group-1 received prostate capsule local anesthesia with 22 ml of 1% lidocaine. Group-2 additionally received PNB on the basis of Group-1. To perform PNB, 5 ml 1% lidocaine was injected into the region of prostatic neurovascular bundle situated in the angle of prostate-bladder-seminal vesicle. Group-3 received prostate capsule local anesthesia plus PPB (5 ml of 1% lidocaine injection into the pelvic plexus which located on lateral to the bilateral seminal vesicle apex). The patients’ pain and satisfaction were evaluated by visual analogue scale and visual numerical scale, respectively. Results The age, total prostate volume, PSA and the number of cores were comparable among the three groups. The visual analog scale scores of group-3 were significantly lower than group-2 during biopsy (P = 0.003). Conversely, the visual numeric scale scores were higher in group-3 (P = 0.039). Both the group-2 and group-3 outperformed the group-1 in alleviating pain and had a higher quantification of satisfaction. There were no significant differences in the pain scores or the satisfaction scores at 30 min after the procedure among the three groups. Conclusions The analgesic efficacy of PPB guided by Doppler ultrasound in TTPB was better than that of PNB and both were superior to no nerve block. Trial registration ChiCTR-IOR-17013533, 01/06/2016.

To assess the prevalence and related factors of benign paroxysmal positional vertigo (BPPV) in patients with spontaneous intracranial hypotension (SIH).We retrospectively reviewed 156 consecutive inpatients with SIH, and collected the clinical and radiological data. These patients were divided into BPPV group and non-BPPV group according to the clinical manifestation and the results of Dix-Hallpike or supine roll tests during hospitalization period. We performed a univariate analysis and a further multiple logistic regression analysis to identify the related factors of the development of BPPV in SIH patients.BPPV was detected in 18 patients among the total 156 SIH patients (11.54%). The univariate analysis showed a low cerebrospinal fluid (CSF) pressure (P = 0.018), a small pontomesencephalic angle (P = 0.012) and a positive venous distension sign (VDS) (P = 0.045) were associated with the presence of BPPV. But the multivariate analysis only demonstrated a low CSF pressure was related to the presence of BPPV (OR = 1.022, 95% CI: 1.001-1.043, P = 0.044).BPPV is common in SIH patients. SIH patients with low CSF pressure may be prone to develop BPPV.

To evaluate the clinical significance of permanentA retrospective study of 45 patients with castration-resistant prostate cancer from the Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China was carried out. Patients were divided into two groups according to different treatments: 21 patients received endocrine therapy alone (control group), and 24 patients underwent brachytherapy combined with endocrine therapy (treatment group). Prostate-specific antigen progression-free survival, cancer-specific survival, overall survival and quality of life of the two groups were compared.The median prostate-specific antigen progression-free survival and cancer-specific survival of the treatment group were 29 months (interquartile range 25-37 months) and 37 months (interquartile range 30-50 months), respectively. These were significantly longer than those of the control group (both P 0.05). Prostate-specific antigen (before androgen deprivation therapy and before brachytherapy), prostate volume, Gleason score, clinical stage and brachytherapy were associated with prostate-specific antigen progression-free survival and cancer-specific survival on univariate analysis. For the quality of life after treatment, urinary symptoms/problems at 1 month after brachytherapy compared with the control group had a statistically significant difference and clinically relevant deterioration, but after 6 months there were no statistically significant differences and clinically relevant deterioration. Compared with the control group, the physical functioning, social functioning, global health and general physical discomfort of the treatment group were significantly improved.Brachytherapy with

In-silico methods have been explored as potential tools for assessing ADME and ADME regulatory properties particularly in early drug discovery stages. Machine learning methods, with their ability in classifying diverse structures and complex mechanisms, are well suited for predicting ADME and ADME regulatory properties. Recent efforts have been directed at the broadening of application scopes and the improvement of predictive performance with particular focuses on the coverage of ADME properties, and exploration of more diversified training data, appropriate molecular features, and consensus modeling. Moreover, several online machine learning ADME prediction servers have emerged. Here we review these progresses and discuss the performances, application prospects and challenges of exploring machine learning methods as useful tools in predicting ADME and ADME regulatory properties.

Objective To present the clinical characteristics and prognostic factors of neurologic recovery in patients with cervical spinal tuberculosis (CST). Methods General description and multivariate analysis were used to detect possible predictors of the outcome of patients with neurologic deficit. Follow-up data were used to generate a Kaplan-Meier curve of neurologic recovery. Results Protective factors in neurologic recovery included less involved vertebrae, surgery, and higher Japanese Orthopaedic Association score before treatment; not shorter symptom duration was not a protective factor. Normal neurologic function was present in 30% of patients 6 months after treatment, in 56% of patients 12 months after treatment, and in 93% of patients 28 months after treatment. The cumulative complete neurologic recovery rates at 6 months, 12 months, and 28 months were 44%, 68%, and 91.7% in the surgery group and 16.7%, 38.8%, and 94.4% in the nonsurgery group. Conclusions Surgery and Japanese Orthopaedic Association score before treatment are important predictors of neurologic recovery in patients with CST. A neurologic recovery curve could predict neurologic recovery in patients with CST and indicate in patients with neurologic deficit how long it will take to achieve complete neurologic recovery. The effect of surgery is quick, and the effect of conservative treatment is slower, but no difference in neurologic recovery was found in the long-term. Conservative treatment should be tried in every patient with CST with no obvious indication for surgery. In contrast to patients with tuberculosis without cervical spine involvement but with more complications, comprehensive conservative therapy should be preferred for patients with neurologic deficit to avoid unnecessary surgery and overtreatment and to conserve medical resources. Indications for surgical intervention for CST should be carefully selected.

MiRNAs associated with the metastasis of lung cancer remain largely unexplored. In this study, gene and miRNA expression profiling were performed to analyze the global expression of mRNAs and miRNAs in human high- and low-metastatic lung cancer cell strains. By developing an integrated bioinformatics analysis, six miRNAs (miR-424-3p, miR-450b-5p, miR-335-5p, miR-34a-5p, miR-302b-3p and miR-206) showed higher target gene degrees in the miRNA-gene network and might be potential metastasis-related miRNAs. Using the qRT-PCR method, the six miRNAs were further confirmed to show a significant expression difference between human lung cancer and normal tissue samples. Since miR-206 showed lower expression both in lung cancer tissues and cell lines, it was used as an example for further functional verification. The wound healing assay and transwell invasion assay showed that miR-206 mimics significantly inhibited the cell migration and invasion of the high-metastatic lung cancer 95D cell strain. One of its predicted targets in our miRNA-gene network, MET, was also obviously decreased at the protein level when miR-206 was overexpressed. Instead, miR-206 inhibitors increased MET protein expression, cell migration and invasion of the low-metastatic lung cancer 95C cell strain. Meanwhile, the luciferase assay showed that MET was a direct target of miR-206. Furthermore, MET gene silence showed a similar anti-migration and anti-invasion effect with miR-206 mimics in 95D cells and could partially attenuate the migration- and invasion-promoting effect of miR-206 inhibitors in 95C cells, suggesting that miR-206 targets MET in lung cancer metastasis. Finally, we also demonstrated that miR-206 can significantly inhibit lung cancer proliferation and metastasis in mouse models. In conclusion, our study provided a miRNA-gene regulatory network in lung cancer metastasis and further demonstrated the roles of miR-206 and MET in this process, which enhances the understanding of the regulatory mechanism in lung cancer metastasis.

The association of intracranial aneurysm and hemangioblastoma is extremely rare. This report regards a patient affected by Von Hippel-Lindau syndrome with multiple hemangioblastoma and two intracranial aneurysms, of which one was on a hemangioblastoma feeder vessel and the other on an unrelated vessel. Review of the literature revealed 13 other previously reported cases. Possible mechanisms to explain the association are discussed.

CONTEXT: In patients with acromegaly, cardiovascular complications are the main cause of death; sudden death has been associated with ventricular tachyarrhythmias. In other patients with life-threatening malignant ventricular tachyarrhythmias, surgical placement of an implantable cardioverter-defibrillator (ICD) has proved highly effective in reducing sudden death rates. CASE REPORT: The present article reports the case of a 50-year-old male acromegalic patient who presented symptoms of syncope induced by ventricular tachycardia. An ICD was surgically implanted and a pituitary adenoma, which was responsible for the acromegaly, was completely removed in the same procedure. The surgery was successful and the ventricular arrhythmias were effectively terminated. During six months of follow-up, no documented arrhythmic episodes occurred. CONCLUSION: In patients with acromegaly, malignant ventricular tachyarrhythmia might be effectively controlled by implantation of an ICD and surgical removal of the pituitary adenoma.

The purpose of this study was to examine the tumor specificity, cytotoxicity and the antitumor activity of two conditionally replicating oncolytic adenoviruses, SKL001 and SKL002, which expressed granulocyte macrophage colony-stimulating factor (GM-CSF) or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA4) antibody, respectively, and determine their antitumor efficacy in A549 lung tumor model, B16F10 mouse melanoma tumor model and CMT-64 mouse small lung carcinoma tumor model. Virus yield and cytotoxicity were used to determine tumor specificity and virus replication-mediated cytotoxicity of SKL001 and SKL002 in a panel of human tumor cell lines and primary cells in vitro. Two subcutaneous (s.c.) tumor nexograft tumor models were used to assess their antitumor activity. Under the control of the E2F promoter, the expression of E1a genes appeared only in tumor cells, whereas the wild-type Ad5 expressed its E1a genes in both tumor cells and normal cells. GM-CSF and anti-CTLA4 production were significantly higher in tumor cells than normal cells. SKL001 and SKL002 replicated in Rb-defective cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. SKL001 and SKL002 was up to 1000-fold more cytotoxic in Rb pathway-defective human tumor cells in comparison with normal human cells. Antitumor activity of SKL001 and SKL002 following intravenous administration was shown in a human lung A549 s.c. xenograft tumor model and mouse B16F10 melanoma tumor model when compared with phosphate-buffered saline treatment. In immune-competent mice, the addition of GM-CSF produced a stronger antitumor activity and induced a higher number of mature dendritic cells and macrophages, whereas additive antitumor activity was observed in the group when SKL001 and SKL002 were combined. In vitro and in vivo studies showed the selective replication, cytotoxicity, gene production and antitumor efficacy of SKL001 and SKL002 in human tumor model, suggesting a potential utility of this oncolytic agent for the treatment of human cancer. Further studies are warranted to show the role of human GM-CSF and anti-CTLA4 antibody in the antitumor efficacy of these two oncolytic viruses.

Quercetin, a natural protective bioflavonoid, possesses diverse pharmacologic effects, such as antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic activities. Recently, quercetin's effect in cancer prevention and treatment was recognized. However, the poor water solubility and low-bioavailability of quercetin limit its clinical use in cancer therapy. Nanotechnology provides a method to create novel formulations for hydrophobic drug. Nanoparticles-delivered quercetin has attracted many attentions for its enhanced anticancer potential and promising clinical application. This review will discuss the application of nanotechnology in quercetin delivery for cancer therapy.

Chemotherapy-related hepatotoxicity is a limitation for the continuation of chemotherapy in patients with advanced colorectal cancer (CRC). This prospective study determined the efficacy of tiopronin infusion in chemotherapy-induced hepatoxicity.One hundred and fifty patients having advanced CRC treated with first-line palliative chemotherapy were included, of whom 86 were treated with mFOLFOX7 plus supplementation of tiopronin and 64 were treated with the same regimen without tiopronin. Aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), total bilirubin (TBIL), gamma-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), and albumin (ALB) were recorded before treatment and during every therapy cycle. In addition, course discontinuations, dose reductions, and chemotherapy efficacy were evaluated.The age and gender of the two groups were comparable (P0.05). The proportions of abnormal mean ALT (P = 0.042), AST (P = 0.045), TBIL (P = 0.044) and ALB (P = 0.043) were significantly lower in the tiopronin group than the control group. Course discontinuations (P = 0.002), dose reductions (P = 0.005) and efficacy (P = 0.012) were significantly different between the two groups. Multivariate logistic regression analysis showed that the hepatoprotective drug played an important role in clinical outcome (OR = 6.837; 95% CI, 1.845 to 25.333; P = 0.004).Tiopronin tends to decrease the incidence of chemotherapy-induced hepatoxicity, enhance patients' tolerance to mFOLFOX7 treatment, and even benefit the efficacy of chemotherapy.

d These authors contributed equally to this work Abstract Background: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs), is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. Methods: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs) in lung, spleens, peripheral blood and tumor. Results: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4 + and CD8 + T-cells were significantly increased in tumor and spleens. Conclusion: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.

Aim XELOX and FOLFOX4 have both been recommended as adjuvant therapy for stage III colon cancer. This study compared the two regimens in terms of monetary costs, assuming equal efficacy of the therapies. Method A retrospective financial audit was conducted of the medical records of patients treated with XELOX or FOLFOX4. All itemized expenses were classified as direct (chemotherapy, hospitalization, venous access and tests), related to adverse effects due to the adjuvant therapy, or societal (travel and time costs). The cost of supportive care was not included. Results XELOX involved less total cost to the patient than FOLFOX4 (a difference of US$2857.68), fewer costs related to adverse effects ($668.97), and less travel ($26.07) and time ($390.93) expenditure per patient. Conclusion The results indicate that, overall, XELOX is a more affordable option than FOLFOX4 in China.

The diethyl ether extract of the stems of Schisandra pubescens Hemsl. et Wils. (Schisandraceae) was found to exhibit cytotoxic activity in vitro. However, investigations of the bioactive constituents of this plant have been very limited.Elucidation of the cytotoxic constituents of S. pubescens was performed.Repeated silica gel column chromatography and preparative TLC were used for the chemical investigation of the diethyl ether extract of S. pubescens stems. All isolates were evaluated for their in vitro cytotoxicity against A549, PC-3, KB and KBvin human cancer cell lines.Nine known compounds were obtained, including four lignans, epischisandrone (1), tigloylgomisin P (2), cagayanone (3) and (-)-gomisin L₂ (4), together with five triterpenoids, micranoic acid B (5), lancifodilactone H (6), coccinic acid (7), schisanlactone B (8) and anwuweizonic acid (9). Compounds 2-6 and 8 showed moderate to marginal cytotoxicity, with GI₅₀ values of 11.83-35.65 μM.The isolation of 1-9 from S. pubescens and the cytotoxicities of 3-6 are first reported. Compounds 2-6 and 8 could be the active principles responsible for the anticancer effects of S. pubescens.

Oxytocin (OXT), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood-brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of OXT to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that OXT in the central nervous system rather than the blood circulation plays an important role in rat pain modulation. The communication tried to investigate the interaction between the OXT and pain modulation in Chinese patients with headache to understand the OXT effect on human pain modulation. The results showed that (1) intranasal OXT could relieve the human headache in a dose-dependent manner; (2) OXT concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients in relation with the pain level; and (3) there was a positive relationship between plasma and CSF OXT concentration in headache patients. The data suggested that intranasal OXT, which was delivered to the central nervous system through olfactory region, could treat human headache and OXT might be a potential drug of headache relief by intranasal administration.

Transfection of plasmid vectors coexpressing short hairpin RNA (shRNA) for focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) significantly inhibited protein level of FAK and EGFR. Knockdown of FAK and EGFR expression significantly inhibited cell proliferation and induced cell apoptosis of A549 lung cancer cells in vitro. In A549 subcutaneous xenograft model, mice treated for 3 weeks with plasmid that coexpresses FAK and EGFR shRNA had significantly smaller tumors than those in control mice (P

Fibroblast activation protein (FAP) is a specific serine protease expressed in tumor stroma proven to be a stimulatory factor in the progression of some cancers. The purpose of this study was to investigate the effects of FAP knockdown on tumor growth and the tumor microenvironment. Mice bearing 4T1 subcutaneous tumors were treated with liposome-shRNA complexes targeting FAP. Tumor volumes and weights were monitored, and FAP, collagen, microvessel density (MVD), and apoptosis were measured. Our studies showed that shRNA targeting of FAP in murine breast cancer reduces FAP expression, inhibits tumor growth, promotes collagen accumulation (38%), and suppresses angiogenesis (71.7%), as well as promoting apoptosis (by threefold). We suggest that FAP plays a role in tumor growth and in altering the tumor microenvironment. Targeting FAP may therefore represent a supplementary therapy for breast cancer. [BMB Reports 2013; 46(5): 252-257]