Objective: Cholangiocarcinoma (CCA) is a devastating disease. Interferon alpha-inducible protein 27 (IFI29), originally known to involve in innate immunity, is later found to intervene in cell ...proliferation, leading to inventive studies regarding the role of IFI29 in cancer treatment. We aimed to investigate the role of IFI29 in CCA. Materials and methods: Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofuorescent and immunohistochemical stains, and xenograft animal model were applied. Results: IFI29 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI29 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 fbronectin. Filamentous actin level was also reduced. IFI29 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 IFI29 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI29 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI29 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI29 expression was linked to inferior overall survival of CCA patients. Conclusion: Our data strongly suggest that IFI29 could be deemed as a potential target for CCA treatment. Keywords: IFI29, cholangiocarcinoma, oncogene, angiogenesis, VEGF-A, metastasis, tumor growth, cell cycle
Although studies have shown that 17 beta -estradiol (estradiol) normalized Kupffer cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. ...Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-kappaB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-kappaB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35 +/- 5 mmHg not, vert, similar90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-kappaB. This was accompanied by normalization of Kupffer cell production capacities of IL-6, TNF- alpha , macrophage inflammatory protein (MIP)-1 alpha , and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer cell p38 MAPK and NF-kappaB activation, cytokine production, or the increase in circulating cytokine levels following trauma- hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF- kappaB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this study, we tested the hypothesis that 17beta-estradiol (E2) administration after trauma-hemorrhage reduces lung injury through a mechanism involving estrogen receptor (ER)-dependent activation ...of the endothelial nitric oxide (NO) synthase (eNOS)/protein kinase G (PKG)/vasodilator-stimulated phosphoprotein (VASP) pathway.
Estrogen provides protection after injury via activation of multiple signaling cascades, including the cyclic GMP-dependent PKG pathway. Phosphorylation of VASP at Ser239 (p-VASP) can be used to assess PKG signaling activity.
Male Sprague-Dawley rats (275-325 g) underwent soft tissue trauma (midline laparotomy) and hemorrhagic shock (mean blood pressure 35-40 mm Hg for 90 minutes) followed by fluid resuscitation. Animals were pretreated with a nonselective NOS inhibitor (N(omega)-nitro-L-arginine methyl ester; 30 mg/kg), a soluble guanylyl cyclase (sGC) inhibitor 1H-(1, 2, 4) oxadiazolo (3, 4-alpha) quinoxalin-1-one; 10 mg/kg or an ER antagonist (ICI 182,780; 3 mg/kg) 30 minutes before E2 (100 microg/kg) or vehicle administration. Animals were killed at 2 hours after resuscitation.
Lung injury induced by trauma-hemorrhage is evidenced by edema (wet/dry ratio), neutrophil infiltration (myeloperoxidase activity), and with an increased expression of cytokines, chemokines, and adhesion molecules. E2 treatment after trauma-hemorrhage resulted in an increase in eNOS expression/phosphorylation, PKG-I activation, and VASP/p-VASP expression, which paralleled a decrease in lung injury. Inhibition of NOS and sGC abolished the E2-induced increase in PKG-I activity, VASP/p-VASP expression. Blockade of eNOS, PKG-I, and ER exacerbated lung inflammation and injury.
These results collectively suggest that activation of the eNOS-PKG/VASP pathway by E2 protects against trauma-hemorrhage-induced lung injury.
Background: Cytomegalovirus (CMV) colitis is considered rare in immunocompetent patients. Objective: The predictors of mortality and the differences between immunocompetent and immunocompromised ...patients with this disease remain unknown. Thus, the aim of this retrospective cohort study was to clarify these issues. Patients and methods: We enrolled all patients who were histologically diagnosed with CMV colitis between April 2002 and December 2016 in the Linkou Chang Gung Memorial Hospital. Patients were divided into two groups: immunocompetent and immunocompromised, and the differences between them were analyzed to develop in-hospital mortality predictors. Results: A total of 69 patients (42, immunocompetent; 27, immunocompromised) were enrolled. The most common symptoms were melena in the immunocompetent group and diarrhea in the immunocompromised group. The in-hospital mortality rate showed no statistically significant difference between the two groups (26.2% vs 25.9%, P=0.981). Early diagnosis was the only significant independent predictor of in-hospital mortality (odds ratio OR 1.075, 95% CI 1.005-1.149, P=0.035). The cutoff of diagnostic timing was 9 days from admission, derived from the receiver operating characteristic curve using the Youden index. Conclusion: CMV colitis in immunocompetent patients is markedly more common and fatal than has generally been acknowledged. Being alert to different ways in which this disease can present itself will enable early diagnosis and significantly reduce mortality. Keywords: cytomegalovirus colitis, immunocompetent, immunocompromised
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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)
D
, a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)
D
) analog, on PanNET cell metastasis after VEGF-A stimulation.
Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study.
VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)
D
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)
D
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)
D
and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)
D
and MART-10.
Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.
Cholangiocarcinoma (CCA) is a devastating disease without effective treatments. 1α,25(OH)₂D₃, the active form of Vitamin D, has emerged as a new anti-cancer regimen. However, the side effect of ...hypercalcemia impedes its systemic administration. 25(OH)D is biologically inert and needs hydroxylation by CYP27B1 to form 1α,25(OH)₂D₃, which is originally believed to only take place in kidneys. Recently, the extra-renal expression of CYP27B1 has been identified and in vitro conversion of 25(OH)D to 1α,25(OH)₂D₃ has been found in some cancer cells with CYP27B1 expression. In this study, CYP27B1 expression was demonstrated in CCA cells and human CCA specimens. 25(OH)D effectively represses SNU308 cells growth, which was strengthened or attenuated as CYP27B1 overexpression or knockdown. Lipocalcin-2 (LCN2) was also found to be repressed by 25(OH)D. After treatment with 800 ng/mL 25(OH)D, the intracellular 1α,25(OH)₂D₃ concentration was higher in SNU308 cells with CYP27B1 overexpression than wild type SNU308 cells. In a xenograft animal experiment, 25(OH)D, at a dose of 6 μg/kg or 20 μg/kg, significantly inhibited SNU308 cells' growth without inducing obvious side effects. Collectively, our results indicated that SNU308 cells were able to convert 25(OH)D to 1α,25(OH)₂D₃ and 25(OH)D CYP27B1 gene therapy could be deemed as a promising therapeutic direction for CCA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background The addition of splenectomy to a D2 gastrectomy in patients with gastric adenocarcinoma (GA) has remained controversial. This study aimed to assess the impact of splenectomy on ...the overall survival of patients undergoing total gastrectomy for GA. Methods This was a retrospective review of 463 GA patients (excluding positive resection margins and pathologic spleen invasion) undergoing curative total gastrectomy with (TS) and without splenectomy (T) between 1994 and 2008. Clinicopathologic factors affecting the prognosis of these patients were collected prospectively and analyzed. Results Two hundred and ninety one patients had T and 172 patients underwent TS. Patient clinicopathological characteristics were comparable between the 2 groups except for tumor size. There were no significant differences in postoperative morbidity and mortality between T and TS groups. Patients in the T group had similar 3- and 5-year survival rates compared with those in the TS groups ( p = 0.181). The addition of splenectomy to a total gastrectomy did not impact on the overall survival rates in patients with GA in terms of depth of tumor invasion and nodal metastasis. Conclusions The addition of splenectomy is not associated with survival advantage in GA patients undergoing total gastrectomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background The addition of splenectomy to a D2 gastrectomy in patients with gastric adenocarcinoma (GA) has remained controversial. This study aimed to assess the impact of splenectomy on ...the overall survival of patients undergoing total gastrectomy for GA. Methods This was a retrospective review of 463 GA patients (excluding positive resection margins and pathologic spleen invasion) undergoing curative total gastrectomy with (TS) and without splenectomy (T) between 1994 and 2008. Clinicopathologic factors affecting the prognosis of these patients were collected prospectively and analyzed. Results Two hundred and ninety one patients had T and 172 patients underwent TS. Patient clinicopathological characteristics were comparable between the 2 groups except for tumor size. There were no significant differences in postoperative morbidity and mortality between T and TS groups. Patients in the T group had similar 3- and 5-year survival rates compared with those in the TS groups ( p = 0.181). The addition of splenectomy to a total gastrectomy did not impact on the overall survival rates in patients with GA in terms of depth of tumor invasion and nodal metastasis. Conclusions The addition of splenectomy is not associated with survival advantage in GA patients undergoing total gastrectomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background The addition of splenectomy to a D2 gastrectomy in patients with gastric adenocarcinoma (GA) has remained controversial. This study aimed to assess the impact of splenectomy on ...the overall survival of patients undergoing total gastrectomy for GA. Methods This was a retrospective review of 463 GA patients (excluding positive resection margins and pathologic spleen invasion) undergoing curative total gastrectomy with (TS) and without splenectomy (T) between 1994 and 2008. Clinicopathologic factors affecting the prognosis of these patients were collected prospectively and analyzed. Results Two hundred and ninety one patients had T and 172 patients underwent TS. Patient clinicopathological characteristics were comparable between the 2 groups except for tumor size. There were no significant differences in postoperative morbidity and mortality between T and TS groups. Patients in the T group had similar 3- and 5-year survival rates compared with those in the TS groups ( p = 0.181). The addition of splenectomy to a total gastrectomy did not impact on the overall survival rates in patients with GA in terms of depth of tumor invasion and nodal metastasis. Conclusions The addition of splenectomy is not associated with survival advantage in GA patients undergoing total gastrectomy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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