Circular RNA circ_0002137 regulated the progression of osteosarcoma through regulating miR-433-3p/ IGF1R axis.

Current clinical treatment targeting osteosarcoma (OS) are limited for OS patients with pulmonary metastasis or relapse, which led to high mortality (70%-85%) for advanced osteosarcoma patients. Although ongoing efforts have been made to illustrate the mechanisms of tumorigenesis and progression in OS; however, it was far for us to learn a comprehensive molecular mechanism implies in OS development. In our study, we implicated a circRNA hsa_circ_0002137, which was higher expressed in osteosarcoma tumours compared with paracancerous tissue. The dysregulated expression pattern was also found in osteosarcoma cell lines. The role of circ_0002137 was explored via down- or up-regulated experiments. It was proved that down-regulation of circ_0002137 suppressed the progress of OS, including cell invasion, cell cycle and cell apoptosis. Furthermore, the correlation between circ_0002137 and miR-433-3p was predicted using bioinformatic tools and verified utilizing RNA pull-down assay and luciferase reporter assay. Interestingly, we found that the inhibitory effect of circ_0002137 on OS was dependent of insulin-like growth factor-1 receptor (IGF1R). In conclusion, it was demonstrated that circ_0002137 could restrain the progression of OS through regulating miR-433-3p/IGF1R axis, providing a comprehensive landscape of circ_0002137 in the generation and development of OS.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition.

Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo. Further mechanistic studies reveal that ACOT12 regulates the cellular acetyl-CoA levels and histone acetylation in HCC cells and that down-regulation of ACOT12 promotes HCC metastasis by epigenetically inducing TWIST2 expression and the promotion of epithelial-mesenchymal transition. Taken together, our findings link the alteration of acetyl-CoA with HCC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for combating HCC metastasis.

Pattern of distant metastases in primary extrahepatic bile-duct cancer: A SEER-based study.

Extrahepatic bile duct cancer (EBDC) is a combined type of malignancy mainly consisting of extrahepatic cholangiocarcinoma and gallbladder cancer. Clinically, it is featured with latent symptoms and early metastasis, leading to a poor prognosis. Therefore, this cohort study aimed to depict the possible metastatic patterns of EBDC of diverse sub-types and evaluate the prognostic significance of diverse metastatic destinations with data from the clinical database. Relevant data of total 4061 confirmed EBDC patients diagnosed between 2010 and 2013 from the Surveillance, Epidemiology and End Results (SEER) database was obtained. We applied t test to describe the baseline data of patients included and used chi-square test to compare the distribution of distant metastatic sites. We further adopted odds ratio assess the combined metastatic patterns and compared survival difference of patients with different distal metastasis organ by Kaplan-Meier analysis. We identified totally 4061 patients over 18 years old diagnosed with extrahepatic bile tract malignancies between 2010 and 2013, with clear metastatic status and follow-up data, without primary malignancies. Liver and distant lymph (DL) are the two most common sites as a single metastasis organ. In combined metastasis patterns, bi-organ is more frequent than the other types. Lung is the organ preferentially for bi-organ metastasis, while bone and distant lymph similarly intend to co-metastasize with brain. Distal metastasis in EBDC patients indicates an extremely poor prognosis. According to the final analysis results, malignancies in extrahepatic bile duct exhibit similar metastatic patterns, suggesting that we can regard them as a unity to assess its development. Profound differences exist in distribution of distant extrahepatic metastatic sites and their combinations. Results from our studies would provide some information for follow-up strategies and future studies.

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis.

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

LINC00968 functions as an oncogene in osteosarcoma by activating the PI3K/AKT/mTOR signaling.

Osteosarcoma is recognized as a malignant tumor in the skeletal system. Long non-coding RNAs (lncRNAs) have been exhibited to play crucial roles in osteosarcoma development. Our current study focused on the biological effects and mechanism of LINC00968 in osteosarcoma pathogenesis. We observed that LINC00968 was dramatically elevated in osteosarcoma cells including U2OS, MG63, Saos-2, SW1353, and 143-B cells compared to human osteoblast cell line hFOB. Silence of LINC00968 inhibited osteosarcoma cell growth and proliferation in vitro. Reversely, overexpression of LINC00968 promoted osteosarcoma cell survival and cell colony formation ability in Saos-2 and 143-B cells. In addition, LINC00968 was able to induce osteosarcoma cell migration and invasion through up-regulating MMP-2 and MMP-9 protein levels. The phosphoinosmde-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been reported to participate in several cancer types. Here, in our study, we found that PI3K/AKT/mTOR pathway was involved in osteosarcoma progression. Knockdown of LINC00968 inactivated PI3K/AKT/mTOR signaling pathway in vitro. Subsequently, in vivo tumor xenografts were established using 143-B cells to investigate whether LINC00968 can induce osteosarcoma development in vivo. Consistently, it was indicated that inhibition of LINC00968 significantly inhibited osteosarcoma progression in vivo. Taken these together, in our research, LINC00968 could be provided as a novel prognostic biomarker and therapeutic target in osteosarcoma diagnosis and treatment.

Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target.

Therapeutic intervention in neddylation pathway is an emerging area for cancer treatment. Herein, we evaluated the clinical relevance and therapeutic potential of targeting this pathway in intrahepatic cholangiocarcinoma (ICC). Immunohistochemistry of neddylation pathway components in a cohort of 322 cases showed that E1 (NAE1 and UBA3) and E2 (UBC12) enzymes, as well as global NEDD8 conjugation, were upregulated in over 2/3 of human ICC. Notably, NAE1 was identified as an independent prognosticator for postoperative recurrence (P=0.009) and a combination of NEDD8 and NAE1 provided a better power for predicting patient clinical outcomes. In vitro treatment with MLN4924, a small-molecule NEDD8-activating enzyme inhibitor, led to a dose-dependent decrease of viability in both established and primary cholangiocarcinoma cell lines. Additionally, MLN4924 exhibited at least additive effect when combined with cisplatin. By blocking cullins neddylation, MLN4924 inactivated Cullin-Ring ligase (CRL) and caused the accumulation of CRL substrates that triggered cell cycle arrest, senescence or apoptosis. Meanwhile, MLN4924 was well-tolerated and significantly inhibited tumor growth in xenograft model of cholangiocarcinoma. Taken together, our findings indicated that upregulated neddylation pathway was involved in ICC progression and interference in this pathway could be a promising target for ICC therapy.

Photodynamic therapy of condyloma acuminata in pregnant women / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) is an emerging technique for the treatment of genital human papillomavirus (HPV)-induced benign and premalignant lesions. We report here in a case series of condyloma acuminata (CA) in pregnancy successfully treated with ALA-PDT.</p><p><b>METHODS</b>Five pregnant patients with CA received three to four times treatment respectively. Patients were followed up for 6 - 23 months after treatment.</p><p><b>RESULTS</b>The clearance rate of genital warts was 100%. No recurrence was found during the follow-up period. Major adverse events reported were mild erosion, pain, and local edema. All pregnancies resulted in healthy live births without delivery complications.</p><p><b>CONCLUSIONS</b>PDT with topical ALA seems to be safe and effective in the treatment of CA in pregnancy. It demonstrated high clearance rate of warts, was well-tolerated by patients, and showed no adverse effects on mothers or fetuses. ALA-PDT may be an ideal strategy of treatment for pregnant women with CA.</p>

Studies of the spin-Hamiltonian parameters and defect structures for the tetragonal and cubic Yb3+ centers in AgCl crystal.

The spin-Hamiltonian parameters, g factors and hyperfine structure constants, for the tetragonal and cubic Yb(3+) centers in AgCl crystal are calculated from the complete diagonalization (of energy matrix) method. The calculations are based on the defect models that the tetragonal Yb(3+) center is formed by the substitutional Yb(3+) associated with two nearest Ag(+) vacancy (V(Ag)) along <001> and <001¯> axes (i.e., C(4) axis) owing to charge compensation and in cubic Yb(3+) center the two compensators V(Ag) are remote. From the calculations, the spin-Hamiltonian parameters of both Yb(3+) centers in AgCl are explained reasonably, the signs of hyperfine structure constants A(i)((171)Yb(3+)) and A(i)((173)Yb(3+)) are suggested, the above defect models of both Yb(3+) centers are confirmed and their defect structures are determined.

Clinical experience of combined surgical thrombectomy and endovascular intervention for acute deep venous thrombosis / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the clinical outcome of surgical venous thrombectomy and simultaneous stenting in patients with acute, symptomatic iliofemoral deep venous thrombosis (DVT).</p><p><b>METHODS</b>From October 2008 to December 2010, a total of 15 patients with acute symptomatic DVT underwent combined surgical venous thrombectomy and endovascular stenting in ipsilateral iliac vein. There were 6 male and 9 female patients, with a mean age of 57.4 years (ranging from 36 to 71 years). All patients underwent Duplex ultrasonography for diagnosis of DVT. The location of thrombosis was femoro-ilio-caval vein in 2 cases, bilateral iliac vein in 1 case and left iliofemoral vein in 12 cases. All patients had leg swelling and 12 cases had severe leg pain. The mean time of symptomatic DVT occurring at operation was 3.3 d. The factors related to DVT were operation in 6 cases, DVT reoccur in 2 cases. Coexist diseases were digestive tract bleeding in 1 case, gastric ulcer in 1 case, hypertension in 3 cases and 1 case had cerebral infarction. The inferior vena cava filter was inserted before thrombectomy, iliac vein compression and residual stenosis were treated with a self-expandable stent after thrombectomy.</p><p><b>RESULTS</b>Intraoperative venography showed severe venous stenosis in all patients including 80% of iliac vein compression syndrome, 18 self-expandable stents were inserted successfully, the procedural successful rate was 100%, the 30-day mortality rate was 0.One case was suffered from hematoma at incision after operation. 3 patients were lost during follow-up. Median follow-up was 10.3 months (ranging from 2 to 26 months). There was no case of re-thrombosis. Leg pain was disappeared in all cases and only 2 patients showed slight leg swelling after excise.</p><p><b>CONCLUSION</b>Combined surgical thrombectomy and endovascular treatment for patients with acute symptomatic iliofemoral venous thrombosis is an effective and safe technique with low morbidity and good clinical results.</p>

Studies on the spin-Hamiltonian parameters of CuN(6) clusters and their tetragonal distortions due to Jahn-Teller effect for Cu2+ in trigonal M(1-propyltetrazole)6(BF4)2 (M=Zn, Fe) crystals.

This paper reports the theoretical calculations for the anisotropic and isotropic spin-Hamiltonian parameters (g factors and the hyperfine structure constants) of tetragonal CuN6 octahedral clusters due, respectively, to the static and dynamic Jahn-Teller effects for Cu2+ ion in the trigonal M(=Zn, Fe) sites of M(1-propyltetrazole)6(BF4)2 crystals. The calculations are carried out using the high-order perturbation formulas based on a two-mechanism model, in which besides the contributions to spin-Hamiltonian parameters due to the crystal-field mechanism concerning the crystal-field excited states in the extensively used crystal-field theory, the contributions due to charge-transfer mechanism concerning the charge-transfer excited states (which are neglected in the crystal-field theory) are included. The calculated results are in reasonable agreement with the experimental values. From the calculations the tetragonal elongations ΔR=R//-R⊥ (where R// and R⊥ denote the Cu-N distances parallel with and perpendicular to the C4 axis) of CuN6 octahedral clusters due to Jahn-Teller effect are obtained. The results are discussed.

Surgical treatment for varicose vein / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the techniques and outcomes of the surgical treatment for varicose vein.</p><p><b>METHODS</b>Totally 2 200 patients with varicose vein received surgical treatment in our hospital from July 2000 to January 2006. The latest techniques for endovenous occlusion were used for most cases, among which 1 802 cases were treated with endovenous laser treatment (EVLT) combined with transilluminated powered phlebectomy (TIPP), 82 cases with radiofrequency endovenous occlusion (RFO) combined with TIPP, and 218 cases with limited invaginated vein stripping and foam sclerotherapy. The remaining 98 cases were treated with laser, radiofrequency or ligation for saphenous vein trunk, and with resection, electric coagulation, and transfixation for vein clusters as additional methods. Perforators were also cut and ligated as well.</p><p><b>RESULTS</b>Satisfied surgical results were obtained in all cases. The average operative time was 40 minutes (range 20-78 minutes).</p><p><b>CONCLUSIONS</b>Limited invaginated vein stripping, EVLT, and RFO can be used to treat saphenous vein reflux. Surgical resection, transfixation, electric coagulation, and sclerotherapy are reasonable options for vein cluster or tributaries. Transection and ligation of the perforators are important. TIPP is ideal for the treatment of vein clusters.</p>