Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells.

Heme oxygenase-1 (HO-1) has several important roles in hepatocytes in terms of anti-inflammation, anti-apoptosis, and antioxidant properties. Interleukin-6 (IL-6) is a pleiotropic cytokine associated with liver regeneration and protection against injury. The aim of this study was to determine the potential crosstalk between HO-1 and IL-6, and to elucidate the signaling pathways involved in the induction of HO-1 by IL-6 in human hepatoma cells. Ectopic overexpression of HO-1 not only attenuated cell proliferation in vitro and in vivo, but also blocked the reactive oxygen species (ROS) induced by H2O2 and the pyocyanin in HepG2 or Hep3B cells. IL-6 expression was negatively regulated by HO-1, while IL-6 induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and HO-1 gene expression in HepG2 cells. The co-transfected HO-1 reporter vector and a protein inhibitor of the activated STAT3 (PIAS3) expression vector blocked the IL-6-induced HO-1 reporter activity. Both interferon γ and interleukin-1ß treatments induced STAT1 but not STAT3 phosphorylation, which had no effects on the HO-1 expression. Treatments of AG490 and luteolin blocked the JAK/STAT3 signaling pathways which attenuated IL-6 activation on the HO-1 expression. Our results indicated that HO-1 is the antitumor gene induced by IL-6 through the IL-6/JAK/STAT3 pathways; moreover, a feedback circuit may exist between IL-6 and HO-1 in hepatoma cells.

Antioxidation and Antiapoptosis Characteristics of Heme Oxygenase-1 Enhance Tumorigenesis of Human Prostate Carcinoma Cells.

Heme oxygenase-1 (HO-1) has antiinflammatory and antioxidant properties and is deemed as a tissue protector. However, effects of HO-1 in prostate cancer remain in controversy. We evaluated the role of HO-1 in prostate carcinoma in vitro and in vivo. Overexpression of HO-1 did not affect prostate cell proliferation in the normal condition but enhanced cell proliferation under serum starvation. HO-1 overexpression enhanced cell invasion of PC-3 cells through epithelial-mesenchymal transition (EMT) induction, which was supported by increased Slug, N-cadherin, and vimentin expressions. In the xenograft animal study, HO-1 overexpression enhanced PC-3 cell tumor growth in vivo. HO-1 attenuated reactive oxygen species induced by H2O2 or pyocyanin treatment in PC-3 and DU145 cells. HO-1 further reduced PC-3 and DU145 cell apoptosis induced by H2O2 or serum starvation. Our results suggested that HO-1 was able to increase prostate carcinoma cell invasion in vitro and tumor growth in vivo. The EMT induction and antioxidant and antiapoptotic effects of HO-1 in the prostate carcinoma cells may be responsible for these findings.

Diagnostic pitfalls and therapeutic outcomes of the macrofollicular variant of papillary thyroid carcinoma.

BACKGROUND: The macrofollicular variant of papillary thyroid cancer (MFVPTC) is a rare histological variant of papillary thyroid cancer (PTC), with only 71 cases reported through 2014. This study analyzed the clinical, preoperative thyroid ultrasonography (US), and fine needle aspiration cytology (FNAC) features; and therapeutic outcomes of 11 patients with MFVPTC. METHODS: The records of 393 patients with histologically diagnosed follicular variant of papillary thyroid carcinoma (FVPTC), including 11 with MFVPTC, were retrospectively reviewed. Preoperative thyroid US findings, clinical presentation, treatment outcomes, and survival rates were analyzed. RESULT: Mean tumor size was significantly greater in patients with MFVPTC than that in those with FVPTC (4.2 ± 2.1 cm vs. 2.9 ± 1.7 cm; p = 0.016). No patient with MFVPTC had lymph node involvement, but one had a micrometastasis to the lung, which responded well to therapeutic radioiodine. All MFVPTC lesions were isoechoic on US. Eight nodules had calcifications and eight had irregular margins. FNAC showed that these tumors had low cellularity, absence or focal presence of enlarged clear nuclei, and subtle or focal nuclear features of PTC. Cells were, arranged in microfollicular pattern, with abundant colloid background. Multifocal PTCs were detected in the opposite lobe of two patients. All 11 patients with MFVPTC had excellent outcomes. No patient experienced recurrence, and survival rates were high. CONCLUSIONS: Malignant US criteria combined with FNAC features have a low preoperative diagnostic rate for MFVPTC. Surgery is recommended for patients with thyroid nodules larger than 4 cm and those with subtle and focal atypical nuclei in FNAC.

Interferon α-inducible protein 27 is an oncogene and highly expressed in cholangiocarcinoma patients with poor survival.

OBJECTIVE: Cholangiocarcinoma (CCA) is a devastating disease. Interferon α-inducible protein 27 (IFI27), originally known to involve in innate immunity, is later found to intervene in cell proliferation, leading to inventive studies regarding the role of IFI27 in cancer treatment. We aimed to investigate the role of IFI27 in CCA. MATERIALS AND METHODS: Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofluorescent and immunohistochemical stains, and xenograft animal model were applied. RESULTS: IFI27 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI27 knockdown attenuated CCA cell migration and invasion through inhibition of epithelial-mesenchymal transition, which was supported by increased E-cadherin and decreased N-cadherin and fibronectin. Filamentous actin level was also reduced. IFI27 knockdown further repressed expression and secretion of vascular endothelial growth factor (VEGF-A), a strong stimulator of angiogenesis, through downregulation of c-jun and c-fos, which was supported in vitro by the finding that human vascular endothelial cells grew more slowly in conditioned medium of IFI27 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI27 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI27 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI27 expression was linked to inferior overall survival of CCA patients. CONCLUSION: Our data strongly suggest that IFI27 could be deemed as a potential target for CCA treatment.

Melatonin Attenuates Acute Pancreatitis-Induced Liver Damage Through Akt-Dependent PPAR-γ Pathway.

BACKGROUND: Despite melatonin treatment diminishes inflammatory mediator production and improves organ injury after acute pancreatitis (AP), the mechanisms remain unknown. This study explores whether melatonin improves liver damage after AP through protein kinase B (Akt)-dependent peroxisome proliferator activated receptor (PPAR)-γ pathway. METHODS: Male Sprague-Dawley rats were subjected to cerulein-induced AP. Animals were treated with vehicle, melatonin, and melatonin plus phosphoinositide 3-kinase (PI3K)/Akt inhibitor wortmannin 1 h following the onset of AP. Various indicators and targeted proteins were checked at 8 h in the sham and AP groups. RESULTS: At 8 h after AP, serum alanine aminotransferase/aspartate aminotransferase levels, histopathology score of hepatic injury, liver myeloperoxidase activity, and proinflammatory cytokine production were significantly increased and liver tissue adenosine triphosphate concentration was lower compared with shams. AP resulted in a marked decrease in liver Akt phosphorylation and PPAR-γ expression in comparison with the shams (relative density, 0.442 ± 0.037 versus. 1.098 ± 0.069 and 0.390 ± 0.041 versus ± 1.080 0.063, respectively). Melatonin normalized AP-induced reduction in liver tissue Akt activation (1.098 ± 0.054) and PPAR-γ expression (1.145 ± 0.083) as well as attenuated the increase in liver injury markers and proinflammatory mediator levels, which was abolished by coadministration of wortmannin. CONCLUSIONS: Collectively, our findings suggest that melatonin improves AP-induced liver damage in rats, at least in part, via Akt-dependent PPAR-γ pathway.

Over-expression of TNNI3K is associated with early-stage carcinogenesis of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a devastating disease with very poor prognosis due to late diagnosis and resistance to traditional chemotherapies and radiotherapies. Herein, thioacetamide (TAA)-induced rat CCA model and CGCCA cell line were used; we aim to study the cytogenetic features during tumoral development of CCA and uncover the mystery regarding carcinogenesis of CCA. The Array comparative genomic hybridization analysis, in silico method, gene knockdown, Western blot, cell count proliferation assay, clonogenecity assay, and IHC staining were applied in this study. Array comparative genomic hybridization analysis was performed on all different TAA-induced phases of rat tissues to reveal the certain pattern, +2q45, +Xq22, -12p12, have been identified for the tumor early stage, where involve the gene TNNI3K. In addition, 16 genes and 3 loci were associated with rapid tumor progression; JAK-STAT signaling pathway was highly correlated to late stage of CCA. In silico database was used to observe TNNI3K was highly express at tumor part compared with normal adjacent tissue in CCA patients from TCGA dataset. Furthermore, the growth of TNNI3K-knockdown SNU308 and HuCCT1 cells decreased when compared with cells transfected with an empty vector cell demonstrated by proliferation and colonogenecity assay. Besides, over expression of TNNI3K was especially confirmed on human CCA tumors and compared with the intrahepatic duct stone bile duct tissues and normal bile duct tissues (P < 0.001). Our findings might uncover the mystery regarding carcinogenesis of CCA, and provide the potential genetic mechanism to the clinicians some ideas for the patients' treatment.

HO-1 is a favorable prognostic factor for HBV-HCC patients who underwent hepatectomy.

BACKGROUND: More than 500,000 people suffered from hepatocelluar carcinoma (HCC) annually and the relative incidence to mortality rate indicates its unfavorable prognosis. Several studies have proved that heme-oxygenase-1 (HO-1) is indirectly engaged in the invasion and the metastasis of some types of malignancies, including breast cancer, prostate cancer, and lung cancer. The role of HO-1 in hepatitis B virus (HBV)-related HCC is still not clarified. MATERIALS AND METHODS: The Western blot, doubling time, cell cycle analysis, migration assay, invasion assay, gene transfection, xenograft animal model, immunohistochemistry staining, and clinical validation study were applied in this study. RESULTS: HO-1 overexpression not only decreased the growth but also inhibited the migration and invasion in human HBV-HCC cells (Hep-3B vs PLC/PRF/5). The inhibitory effect on growth, migration, and invasion is further demonstrated by the overexpression of HO-1 in Hep-3B cell by transfection study. Furthermore, HO-1 decreasing the growth of HBV-HCC was confirmed in animal study. The clinical validation illustrated that higher HO1 expression was also associated with favorable disease-free survival of HBV-HCC patients who underwent hepatectomy. CONCLUSIONS: We identified HO-1 as a favorable prognostic factor for HBV-HCC patients who underwent hepatectomy.

Surgical Margin Status of Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgery with Radical Intent: Risk Factors for the Survival Impact of Positive Margins.

BACKGROUND: For pancreatic ductal adenocarcinoma (PDAC), surgical margin status is an important pathological factor for evaluating surgical adequacy. In this study, we attempted to investigate predictive factors for the survival impact of positive surgical margins. MATERIALS AND METHODS: From February 2004 to December 2013, 204 patients were diagnosed with PDAC and underwent surgery with radical intent; 189 patients fulfilled our selection criteria and were enrolled for analysis. RESULTS: For the 189 enrolled patients with PDAC, we found male predominance (112/189, 59%) and a median age of 64 years; most patients were diagnosed with stage IIB disease (n=115, 61%). The positive surgical margin rate was 21% (n=40). Carbohydrate antigen 19-9 (CA19-9) level higher than 246 U/ml (odds ratio (OR)=2.318; 95% confidence interval (CI)=1.037-5.181 p=0.040) and lesion location in the uncinate process (OR=2.996; 95% CI=1.232-7.284 p=0.015) were the only two independent risk factors for positive surgical margins. Positive retroperitoneal soft-tissue margins were the most frequently observed (24/40, 60%). Overall, positive surgical margins had no survival impact in the 189 patients with PDAC who underwent surgery; however, positive surgical margins had an unfavorable survival impact on patients with stage IIA PDAC who underwent surgery. CONCLUSION: Retroperitoneal soft-tissue was the most common site for positive surgical margins. Additionally, surgical margin positivity was more likely for tumors located in the uncinate process than for other tumors. Positive surgical margins had an unfavorable survival impact on patients with stage IIA PDAC who underwent surgery.

Role of PLK1 signaling pathway genes in gastrointestinal stromal tumors.

In previous studies by the authors, aurora kinase A (AURKA) was demonstrated as an independent poor prognostic marker for the recurrence of localized gastrointestinal stromal tumors (GISTs) and for the progression of advanced GISTs. In the present study, the prognostic effect of genes involved in cell cycle regulation in GISTs was further examined. Leading edge analysis in gene set enrichment analysis was used to identify the most common genes in the top 10 enriched gene sets of high-risk patients with GISTs in a Japanese study. The obtained gene list was uploaded to the Pathway Interaction Database to search for critical pathways. Selected genes within the pathway were subsequently verified through immunohistochemistry (IHC) in another cohort of patients. A total of 5 genes in 'PLK1 signaling events,' namely AURKA, polo-like kinase 1 (PLK1), cell division cycle 25C (CDC25C), budding uninhibited by benzimidazoles (BUB1), and targeting protein for Xklp2 (TPX2), were identified for subsequent study. Among the Japanese cohort, all 5 genes, except BUB1, were significant prognostic factors for poor recurrence-free survival (RFS). Among 141 patients enrolled for the IHC study, all 5 genes exhibited variable expression patterns. In the association study, only AURKA exhibited significant overexpression in non-gastric tumors. Although all 5 genes were considered as risk factors for poor RFS based on a univariate analysis, only the mitotic count and expression levels of CDC25C, BUB1, and TPX2 retained prognostic effects in the multivariate analysis. The PLK1 signaling pathway is crucial in the disease progression of GISTs. Genes within this pathway may serve as predictive markers for adjuvant therapy.

Nab-paclitaxel is effective against intrahepatic cholangiocarcinoma via disruption of desmoplastic stroma.

Intrahepatic cholangiocarcinoma (IH-CCA) is the second predominant hepatic malignancy worldwide. However, effective treatment strategies for IH-CCA have not yet been developed. Nab-paclitaxel may be an effective drug against IH-CCA, a type of desmoid-like tumor, and its antitumor effects may be attributable to its ability to disrupt the cancer-associated fibroblasts. In the present study, MTT and Annexin-V apoptosis detection kits were used to evaluate the efficacy of paclitaxel and nab-paclitaxel against human cholangiocarcinoma KKU-100 and KKU-213 cell lines. A rat model of thioacetamide-induced spontaneous desmoplastic IH-CCA was used to compare the treatment response of four different drug regimens: Control, paclitaxel, nab-paclitaxel and gemcitabine/oxaliplatin. Positron emission tomography and immunofluorescence analysis were used to measure the tumor volume and to study the resected tumor, respectively. In vitro, paclitaxel and nab-paclitaxel induced anti-proliferative effects in KKU-100 and KKU-M213 cells. With regards to the treatment regimes, only nab-paclitaxel and gemcitabine/oxaliplatin induced antitumor effects in the rat model of thioacetamide-induced IH-CCA. The immunofluorescence study indicated that nab-paclitaxel was more efficient in disrupting cancer-associated fibroblasts than paclitaxel. In conclusion, nab-paclitaxel is effective against IH-CCA owing to its ability to markedly disrupt the desmoplastic stroma.

MART-10, a 1α,25(OH)2D3 Analog, Potently Represses Metastasis of ER+ Breast Cancer Cells with VEGF-A Overexpression.

BACKGROUND: Breast cancer ranks second in the list of cancer-related deaths for women. Even under multidisciplinary treatment, 25-50% of patients with breast cancer still ultimately develop metastasis, leading to poor prognosis. In addition to inducing angiogenesis, vascular endothelial growth factor-A (VEGF-A) is believed to directly increase cancer cell metastatic potential and overexpression of VEGF-A is associated with higher invasiveness of breast cancer. 1α,25(OH)2D3, the active form of vitamin D, and its analogs have been widely applied as anticancer agents in the past. MATERIAL AND METHODS: Western blot, migration and invasion assays, enzyme-linked immunosorbent assay, and immunofluorescent stain were applied in this study. RESULT: VEGF-A increased cell migration and invasion in estrogen receptor-positive (ER+) breast cancer MCF-7 cells. VEGF-A induced an autocrine loop in MCF-7 cells as VEGF-A treatment increased both VEGF-A expression and secretion. The expression of VEGF receptor type 2 (VEGFR2) and neuropilin 1 was also up-regulated by VEGF-A in MCF-7 cells. In addition, F-actin synthesis and LIM domain kinase 1 (LIMK-1) phosphorylation were increased by VEGF-A. VEGF-A also increased ß-catenin expression and nuclear translocation of both ß-catenin and nuclear factor-ĸB (NF-ĸB), indicating increased ß-catenin and NF-ĸB activity. 1α,25(OH)2D3 and MART-10, an analog of 1α,25(OH)2D3, effectively repressed VEGF-A-induced MCF-7 cell migration and invasion and other VEGF-A-induced effects on MCF-7 cells, with MART-10 being more potent than 1α,25(OH)2D3 Conclusion: MART-10 can be deemed as a promising agent for prevention and treatment of metastasis of ER+ breast cancer with VEGF-A overexpression.

MET­RON dual inhibitor, BMS­777607, suppresses cholangiocarcinoma cell growth, and MET­RON upregulation indicates worse prognosis for intra­hepatic cholangiocarcinoma patients.

Intra­hepatic cholangiocarcinoma (CCA) is an aggressive cancer with few effective therapeutic options. MET and RON have been found to be increased in a variety of tumors and to be associated with tumor progression and acquired resistance to therapy. The present study evaluated the efficacy of a MET­RON dual inhibitor (BMS­777607) for treating CCA and analyzed the prognostic significance of MET­RON upregulation. We treated CCA cell lines and rats with CCA with BMS­777607 to determine its effects on tumor growth and measured the MET­RON protein expression in samples obtained from 96 patients with CCA who previously underwent hepatectomies. A clonogenic assay revealed that BMS­777607 inhibited the growth of HuCCT1 and KKU­100 human CCA cells. It also decreased tumor growth in CCA rats. MET­RON upregulation independently predicted poor survival for CCA patients who previously underwent hepatectomies. In conclusion, MET­RON upregulation is a poor prognostic factor in CCA patients receiving hepatectomies and may be targeted using BMS­77760.

Caffeic Acid Phenethyl Ester Induces N-myc Downstream Regulated Gene 1 to Inhibit Cell Proliferation and Invasion of Human Nasopharyngeal Cancer Cells.

Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis, is widely studied due to its anti-cancer effect. Nasopharyngeal carcinoma (NPC) is distinct from other head and neck carcinomas and has a high risk of distant metastases. N-myc downstream regulated gene 1 (NDRG1) is demonstrated as a tumor suppressor gene in several cancers. Our result showed that CAPE treatment could repress NPC cell growth, through induction of S phase cell cycle arrest, and invasion. CAPE treatment stimulated NDRG1 expression in NPC cells. NDRG1 knockdown increased NPC cell proliferation and invasion and rendered NPC cells less responsive to CAPE growth-inhibiting effect, indicating CAPE repressed NPC cell growth partly through NDRG1indcution. CAPE treatment increased phosphorylation of ERK, JNK, and p38 in a dose- and time-dependent manner. Pre-treatments by inhibitors of ERK (PD0325901), JNK (SP600125), or p38 (SB201290), respectively, all could partly inhibit the CAPE effect on NDRG1 induction in NPC cells. Further, STAT3 activity was also repressed by CAPE in NPC cells. In summary, CAPE attenuates NPC cell proliferation and invasion by upregulating NDRG1 expression via MAPK pathway and by inhibiting phosphorylation of STAT3. Considering the poor prognosis of NPC patients with metastasis, CAPE could be a promising agent against NPC.

Effects of cholecystectomy on recurrent biliary complications after endoscopic treatment of common bile duct stone: a population-based cohort study.

BACKGROUND: The aim of this study was to evaluate the benefits of cholecystectomy on mitigating recurrent biliary complications following endoscopic treatment of common bile duct stone. METHODS: We used the data from the Taiwan National Health Insurance Research Database to conduct a population-based cohort study. Among 925 patients who received endoscopic treatment for choledocholithiasis at the first admission from 2005 to 2012, 422 received subsequent cholecystectomy and 503 had gallbladder (GB) left in situ. After propensity score matching with 1:1 ratio, the cumulative incidence of recurrent biliary complication and overall survival was analyzed with Cox's proportional hazards model. The primary endpoint of this study is recurrent biliary complications, which require intervention. RESULTS: After matching, 378 pairs of patients were identified with a median follow-up time of 53 (1-108) months. The recurrent rate of biliary complications was 8.20% in the cholecystectomy group and 24.87% in the GB in situ group (p < 0.001). In the multivariate Cox regression analysis, the only independent risk factor for recurrent biliary complications was GB left in situ (hazard ratio [HR] 3.55, 95% CI 2.36-5.33). CONCLUSIONS: Cholecystectomy after endoscopic treatment of common bile duct stone reduced the prevalence of recurrent biliary complications.

Differentiation of the Follicular Variant of Papillary Thyroid Carcinoma From Classic Papillary Thyroid Carcinoma: An Ultrasound Analysis and Complement to Fine-Needle Aspiration Cytology.

OBJECTIVES: It is difficult to establish a diagnosis of the follicular variant of papillary thyroid carcinoma (PTC) using fine-needle aspiration cytology (FNAC). Preoperative features on ultrasound (US) imaging are different between follicular PTC and classic PTC. This study developed a risk score system to differentiate follicular PTC from classic PTC and to correlate the risk score of follicular PTC with its FNAC categories and pathologic features. METHODS: The US features, FNAC results, and pathologic reports of 156 follicular PTC nodules and 152 classic PTC nodules from 296 patients with PTC along with their clinical characteristics were reviewed retrospectively. A risk score system based on US features was developed by multivariate logistic regression to differentiate classic PTC from follicular PTC nodules. The risk scores were then correlated with the FNAC category and pathologic features of the nodules. RESULTS: The US risk score (5 × echogenicity + 3 × calcifications + 3 × marginal regularity) had an area under the receiver operating characteristic curve of 0.85 and a cutoff value of 8.0, with specificity of 87% and sensitivity of 69% for predicting a classic PTC nodule. The follicular PTC nodules with low Bethesda categorization (I-III) had a median US risk score of 6 (range, 0-11), which was higher than that of nodules with high categorization (IV-VI; median, 3; range, 0-11). CONCLUSIONS: The US risk score may be useful in differentiating classic PTC from follicular PTC and complementary to FNAC in identifying follicular PTC.

BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells.

Although widely deemed as a tumor suppressor gene, the role of B-cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT-qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT-qPCR, or reporter assays. The 3 H-thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth. BTG2 expression was lower in human bladder cancer tissues than normal bladder tissues. Highly differentiated bladder cancer cells, RT4, expressed higher BTG2 than the less-differentiated bladder cancer cells, HT1376 and T24. Overexpression of BTG2 in T24 cells inhibited cell growth in vitro and in vivo. Camptothecin and doxorubicin treatments in RT-4 cells or transient overexpression of p53 into p53-mutant HT1376 cells induced p53 and BTG2 expression. Further reporter assays with site-mutation of p53 response element from GGGAAAGTCC to GGAGTCC within BTG2 promoter area showed that p53-induced BTG2 gene expression was dependent on the p53 response element. Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression, while reverse effect was found in PTEN-knockdown RT-4 cells. PTEN activity inhibitor (VO-OHpic) treatment decreased BTG2 expression in RT-4 and PTEN-overexpressed T24 cells. Our results suggested that BTG2 functioned as a bladder cancer tumor suppressor gene, and was induced by p53 and PTEN. Modulation of BTG2 expression seems a promising way to treat human bladder cancer.

1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Metastasis After VEGF-A Stimulation.

AIMS: Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)2D3) analog, on PanNET cell metastasis after VEGF-A stimulation. MATERIALS AND METHODS: Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study. RESULTS: VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)2D3 and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)2D3 and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)2D3 and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)2D3 and MART-10. CONCLUSION: Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.

Dataset on the synthesis and characterization of boron fenbufen and its F-18 labeled homolog.

The data presented in this article are related to the research article entitled "Synthesis and Characterization of Boron Fenbufen and its F-18 Labeled Homolog for Boron Neutron Capture Therapy of COX-2 Overexpressed Cholangiocarcinoma". The contents of the data article include 1) the set up for performing in vitro binding assay, 2) 1H-, 13C- and 19F-NMR of compounds described in main text, 3) HPLC chromatogram of the fluorination mixtures, 4) data of in vitro stability test, cell survival assay, western blot and PCR analysis, 5) the modules for fixing the two CCA rats for BNCT, and 6) bar diagram for tumor reduction using [18F]FDG-PET 24 h post treatment with BNCT.

Higher body weight and distant metastasis are associated with higher radiation exposure to the household environment from patients with thyroid cancer after radioactive iodine therapy.

There were insufficient data regarding radiation exposure to the household environment from patients with thyroid cancer who received radioactive iodine (RAI) therapy in Asia; we therefore performed the present study at the Chang Gung Memorial Hospital in Keelung, Taiwan.Patients with papillary or follicular thyroid cancer who received 3.7 GBq (100 mCi) RAI were enrolled in this prospective hospital-based study. The enrolled patients were asked to place a thermoluminescent dosimeter in the living room, bedroom, and bathroom of their houses for 4 weeks to measure radiation exposure to the household environment.A total of 43 patients (18 men and 25 women; mean age 51 ±â€Š13 years) who received 3.7 GBq (100 mCi) RAI completed the study. The mean value of total radiation exposure over 4 weeks from the patients to the bedroom, bathroom, and living room (eliminating the background radiation factor) was 0.446 ±â€Š0.304 (0.088-1.382) mSv. We divided the patients into 2 groups: those with more than and less than the mean value of total radiation exposure to the bedroom, bathroom, and living room. Factors associated with the higher amount of radiation exposure from the patients to the household environment were patient body weight (P = .025, univariate analysis; P = .037, multivariate analysis, odds ratio [95% confidence interval] 1.067 [1.004-1.134]) and distant metastases based on I post-therapy scanning (P = .041, univariate analysis; P = .058, multivariate analysis, odds ratio [95% confidence interval] 6.453 [0.938-44.369]); age, sex, body mass index, renal function, serum stimulated thyroglobulin level, and recombinant human thyroid-stimulating hormone use were not associated with the amount of radiation exposure from the patients to the household environment.Higher body weight and distant metastases may be the best predictors for higher radiation exposure to the household environment from patients with thyroid cancer after RAI therapy.

Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.

Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68µM) and COX-2 (IC50=0.33±0.24µM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.