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Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12–1.64; P=0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12–1.88; P=0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61–1.58, P=0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer. [ABSTRACT FROM AUTHOR]

Purpose: Hepatocyte nuclear factor 6 (HNF6) is a liver-enriched transcription factor and highly expressed in mature bile duct epithelial cells. This study sought to investigate the role of HNF6, particularly the molecular mechanisms for how HNF6 is involved in the growth and metastasis of cholangiocarcinoma (CCA) cells. Methods: The expression of HNF6, miR-122 and key molecules was examined by Western blot analysis and real-time RT-PCR. Stable transfectants, HCCC-HNF and RBE-HNF, were generated from human CCA HCCC-9810 and RBE cells, respectively. The regulatory effect of HNF6 on miR-122 was evaluated by luciferase reporter assay. Cell proliferation, cycle distribution, migration and invasion were analyzed. The xenograft model was used to assess the effects of HNF6 overexpression on tumorigenesis, growth, metastasis and therapeutic potentials. Results: Human CCA tissues and cells expressed lower levels of HNF6, which positively correlated with miR-122. HNF6 regulated the expression of miR-122 by stimulating its promoter. HNF6 overexpression inhibited cell proliferation by inducing cell cycle arrest at G1 phase through regulating miR-122, cyclin G1 and insulin-like growth factor-1 receptor. HNF6 inhibited the migration and invasion of CCA cells by regulating matrix metalloproteinase-2 and metalloproteinase-9, reversion-inducing-cysteine-rich protein with kazal motifs, E-cadherin and N-cadherin. Co-transfection of anti-miR-122 abrogated the effects of HNF6. HNF6 overexpression inhibited the ability of cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors. Conclusions: The results indicate that HNF6 may serve as a tumor suppressor by regulating miR-122, and its overexpression may represent a mechanism-based therapy for CCA. [ABSTRACT FROM AUTHOR]

Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was recently reported to inhibit proliferation of various cancer cells significantly. Here we try to determine the effect and mechanism of EF24 on hepatocellular carcinoma. 2 mM EF24 was found to inhibit the proliferation of PLC/PRF/5, Hep3B, HepG2, SK-HEP-1 and Huh 7 cell lines. However, even 8 mM EF24 treatment did not affect the proliferation of normal liver LO2 cells. Accordingly, 20 mg/kg/d EF24 inhibited the growth of the tumor xenografts conspicuously while causing no apparent change in liver, spleen or body weight. In addition, significant apoptosis and G2/M phase cell cycle arrest were found using flow cytometry. Besides, caspases and PARP activation and features typical of apoptosis including fragmented nuclei with condensed chromatin were also observed. Furthermore, the mechanism was targeted at the reduction of nuclear factor kappa b (NFkB) pathway and the NF-kB-regulated gene products Bcl-2, COX-2, Cyclin B1. Our study has offered a strategy that EF24 being a therapeutic agent for hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (IRI) is a serious complication of liver surgery, especially for extended hepatectomy and liver transplantation. The aim of this study was to evaluate the protective effect of combined ischemic preconditioning (IPC) and salvianolic acid-B (Sal-B) pretreatment against IRI-induced hepatocellular injury.Methods: Sixty male Wistar rats weighing around 200 g were randomized into five groups (n=12): sham group: only anesthesia and laparotomy; IR group: 90 min sustained ischemia by blocking the left ortal vessels; IPC group: 10 min ischemia and 10 min reperfusion prior to the sustained ischemia; Sal-B group: 10 mg/kg injection of Sal-B intravenously 10 min prior to the sustained ischemia; IPC+Sal-B group: same IPC procedure as in IPC group, but proceeded by intravenous administration of Sal-B 10 min prior to sustained ischemia. After 5 h of reperfusion, serum levels of ALT and AST were measured; the amount of malondialdehyde (MDA) and adenine nucleotides in liver tissue was determined; the expression of Bcl-2 and caspase-3 was detected by immunofluorescent and western blotting techniques; the severity of apoptosis and pathological alterations was evaluated by TUNEL and H&E staining, respectively.Results: The serum aminotransferases, hepatic MDA concentration, and apoptotic index in groups IPC, Sal-B, and IPC+Sal-B were significantly lower than those in the IR group (P<0.001), while the IPC+Sal-B group had the lowest values among these groups (P<0.05). Compared with the IR group, groups IPC and Sal-B not only had statistically higher ATP levels and energy charge (EC) values (P<0.01), but also had upregulated Bcl-2 expression and downregulated cleaved caspase-3 expression in liver tissue. All these effects were further augmented in the IPC+Sal-B group. Liver histopathological findings were consistent with these results.Conclusions: Based on these results, the combined IPC and Sal-B pretreatment had a synergistically protective effect on liver tissue against IRI, which might be due to decreased post-ischemic oxidative stress, improved energy metabolism, and reduced hepatocellular apoptosis. [ABSTRACT FROM AUTHOR]

Background and Aim: Roux-en-Y hepaticojejunostomy (RYHJ) is usually used to treat benign strictures of hilar bile ducts. However, RYHJ might also induce ascending cholangitis and recurrent hepatolithiasis. The present study aims to introduce a modified hepatic portal choledochoplasty with a pedicled graft of gallbladder (HPC) to treat this disease. Methods: One hundred and forty-nine patients, who had undergone HPC or RYHJ from January 1997 to January 2006 in our institutions, were included in this study, and the clinical data were retrospectively collected and analyzed. Results: The incidences of perioperative bile leakage and inflammatory ileus in patients treated with HPC were slightly lower than RYHJ without significant difference (1.89% vs 2.08% and 3.77% vs 5.21%, both P > 0.05). However, in a long-term follow up, patients treated with HPC had significantly lower incidences of cholangitis and recurrent hepatolithiasis (5.66% and 3.77%, respectively) than those treated with RYHJ (cholangitis, 21.88%; hepatolithiasis, 16.67%; both P < 0.05). Conclusion: Compared to RYHJ, HPC is a safer and more efficient method to treat benign strictures of hilar biliary ducts. It preserves the sphincter of Oddi and normal biliary duct pressure, thus avoiding bile reflux into the bile duct. [ABSTRACT FROM AUTHOR]

Background: Critical limb ischemia often leads to disability and limb loss. Vascular endothelial growth factor (VEGF), delivered either as recombinant protein or as gene therapy, has been shown to promote arteriogenesis and angiogenesis in animal models of limb ischemia. However, most of the studies used a nonspecific targeting system. Materials and methods: Magnetic DNA nanospheres containing expression plasmids encoding VEGF were synthesized, and their morphology, magnetropism, and stability were analyzed. The magnetic DNA nanospheres were administrated via an artery into a rabbit limb ischemia model. The expression of VEGF and vascularization were examined by immunohistochemistry. The angiography was taken to evaluate arteriogenesis. Results: Magnetic DNA nanospheres were very stable and showed a high magnetropism. Gene delivery of such nanospheres via artery under a magnetic field led to the overexpression of VEGF in situ. The capillary density and capillary to muscle fiber ratio were doubled compared with those of the control animals. The arteriogenesis also was promoted in VEGF gene therapy group compared with controls but at later interval than capillary angiogenesis. Conclusions: Our results suggest that intra-arterial VEGF gene delivery by magnetic DNA nanosphere promotes angiogenesis and arteriogenesis and presents a potent therapeutic strategy for critical limb ischemia. [Copyright &y& Elsevier]

Abstract: The clinical benefit of gemcitabine for pancreatic cancer is low due to chemoresistance. Nuclear factor (NF)-κB, constitutively activated in pancreatic cancer, is a therapeutic target as it upregulates expression of genes controlling proliferation, apoptosis and angiogenesis. This study aimed to investigate whether downregulation of the p65 subunit of NF-κB by siRNA could enhance the efficacy of gemcitabine to treat pancreatic cancer. p65 siRNA synergized with gemcitabine to inhibit the proliferation and induce the apoptosis of pancreatic cancer cells in vitro and in vivo, and suppress the growth and angiogenesis of pancreatic tumors in nude mice. The mechanisms involved inhibition of NF-κB activity and consequent inhibition of Bcl-2, cyclin D1 and VEGF, and activation of caspase-3. The results suggest that downregulation of NF-κB p65 potentiates the efficacy of gemcitabine in combating pancreatic cancer. [Copyright &y& Elsevier]

Abstract: Although gemcitabine is currently the best chemotherapeutic agent available for the treatment of advanced pancreatic cancer, eventual failure of response is a significant clinical problem. Therefore, novel therapeutic approaches against this disease are highly needed. The aim of this study was to evaluate whether shikonin, a naphthoquinone derivative, has potential in the treatment of pancreatic cancer when used either alone or in combination with gemcitabine. Our in vitro results showed that shikonin inhibited the proliferation of three different human pancreatic cancer cell lines and potentiated the cytotoxic effect of gemcitabine, which correlated with the down-regulation of constitutive as well as gemcitabine-induced activation of NF-κB and NF-κB-regulated gene products. Most importantly, using a xenograft model of human pancreatic cancer, we found shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine. These effects also correlated with the down-regulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that shikonin can suppress the growth of human pancreatic tumors and potentiate the antitumor effects of gemcitabine through the suppression of NF-κB and NF-κB-regulated gene products. [Copyright &y& Elsevier]