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University governance is a core issue of higher education, and faculty plays a critical role. In a structured interview, 10 faculty members from a case university in central China elaborate on their university's governance structure and their own leadership in university governance. One distinctive feature revealed is that there are dual authorities: political and administrative. Although the faculty members believe they have some impact on the governance of curriculum, faculty governance, student governance, and organizational governance, the actual practice is different. The faculty members have less of a say in final decisions, and their leadership is often impinged upon by their administrators (including academic leaders with administrative functions). In spite of this, all of the interviewees still feel that they should participate in university governance and seek more involvement in final decisions. This article concludes with suggestions on effective governance practices for universities. [ABSTRACT FROM AUTHOR]

This study investigated the use of low-dose metronomic (LDM) chemotherapy with paclitaxel in a highly metastatic mouse model of 4T1 breast cancers, and compared it with the maximum tolerable dose (MTD) therapy. LDM therapy displayed a stronger anti-tumor activity in suppressing primary and metastatic breast tumors with less degree of side effects, and stronger anti-angiogenic and anti-lymphangiogenic activities than MTD therapy. But MTD therapy showed stronger pro-apoptotic and anti-proliferative activities in s itu. Paclitaxel therapy downregulated expression of vascular endothelial growth factor receptor-2 (VEGFR2) and up-regulated expression of thrombospondin-1. The results support the application of paclitaxel LDM therapy to treat advanced breast cancer. [ABSTRACT FROM AUTHOR]

Background: Apoptotic cells have immunosuppressive activity, whereas necrotic cells activate immune response, indicating they might have different effects on immune rejection against splenic allografts. The aim of this study was to determine whether administration of apoptotic or necrotic splenocytes of donor origin could impact the acute rejection of splenic allografts. Materials and methods: Apoptotic or necrotic splenocytes derived from donor rats were induced by irradiation or freeze thaw, respectively. Heterotopic vascularized spleen transplantation was performed from Wistar-Furth (donor) to Sprague-Dawley (recipient) rats, and splenocytes were intravenously injected into the recipients. At different time points, the recipients were sacrificed and the splenic allografts underwent histological examination. The interferon-γ (IFN-γ) and transforming growth factor-β1 (TGF-β1) in sera, spleens of recipients, and donor splenocytes before administration were measured. Mixed leukocyte reaction (MLR) was detected with recipient splenocytes as effectors and donor splenocytes as stimulators. Results: Exposure to γ-irradiation at dose of 10,000 rad caused over 80% splenocytes to become apoptotic. The levels of TGF-β1 released by apoptotic splenocytes in vitro were significantly higher than that by untreated splenocytes, whereas there was almost no TGF-β1 detected in necrotic splenocytes culture medium. Administration of apoptotic splenocytes significantly attenuated acute rejection of splenic allografts, evidenced by less severe splenic histological alteration and reduction of histological scores compared with control; whereas necrotic splenocytes exacerbated the acute rejection. Apoptotic splenocytes inhibited production of IFN-γ but increased the levels of TGF-β1, whereas necrotic splenocytes showed opposite activity in production of those cytokines. Administration of apoptotic splenocytes inhibited MLR, and necrotic splenocytes promoted MLR. Conclusions: The apoptotic and necrotic splenocytes exhibited opposite effects on acute rejection against splenic allografts, and IFN-γ and TGF-β1 have been involved in the effects. [Copyright &y& Elsevier]

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]

Investigates the difference of rejection in single versus combined pancreas and kidney transplantation in rats. Mean survival time of pancreas in simultaneous pancreas and kidney transplant and in pancreas alone; Suggestion that different organs differ in immunoallergenization and immunoregulation; Effectiveness of cyclosporine A in prolonging the MST of pancreas and kidney.

Objective. To investigate the cold preservation effect of rat livers by modified storage method with self-made HYD solution. Methods. The modified method was that the vascular bed of rat livers was expanded with an additional 20 to 40ml self-made HYD solution/100g liver. After removing the liver, the extra HYD solution expressed as % liver weight was entrapped via portal infusion by tying off the supra-and infra hepatic inferior vena cava. According to the amount of extra HYD solution, 40 rats were randomly divided into four groups including: control group with conventional storage method, 20% group, 30% group and 40% group. The preservation effect of modified storage method with that of conventional storage method by using isolated perfused rat liver model was compared. Results. Bile production and all the indices of hepatic microcirculation including portal perfusion pressure, endothelin-1 in the effluent, trypan blue distribution time and histology in modified method groups were significantly superior to those in control group (P < 0.05). The liver enzymes in 30% group was the best among the modified method groups. Conclusion. The modified cold storage method is effective and may have potential for clinical application for liver preservation. [ABSTRACT FROM AUTHOR]

Examines the effectiveness of spleen transplantation for hemophilia A in China. Suitability of the transplantation for perfusion and preservation of spleen; Examination on the efferent fluids from the splenic vein; Observations of morphological changes in extracorporeal spleen.

Investigates the effects of cold preservation on rat fatty liver. Changes of portal perfusion pressure; Enzymes release in the effluent; Mortality of sinusoid lining cell.

Background & Aims: Hypoxia-inducible factors (HIFs) and nuclear factor-κB (NF-κB) regulate genes involved in carcinogenesis and progression of cancers including hepatocellular carcinoma (HCC). The von Hippel–Lindau (VHL) protein (pVHL) targets HIFα subunits for destruction and participates in modulating the activity of NF-κB. The present study aimed to investigate whether the overexpression of pVHL synergizes with doxorubicin in the treatment of HCC. Methods: Overexpression of pVHL was induced by infecting mouse HCC Hepa1–6 and H22 cells, or injecting subcutaneous Hepa1–6 tumors in C57BL/c mice, with adenoviral vectors encoding mouse VHL gene. Cell proliferation, apoptosis, tumoral angiogenesis, and gene expression and DNA-binding activity of NF-κB were examined. The therapeutic effects of pVHL were also evaluated in orthotopic Hepa1–6 tumors by intraportal delivery of Ad-VHL. Results: Ad-VHL enhanced the anti-tumor activity of doxorubicin by inhibiting cell proliferation, and causing cell cycle arrest and apoptosis. The Ad-VHL infection downregulated HIF-1α and HIF-2α expression, and inhibited NF-κB activity and the expression of genes involved in apoptosis, proliferation, angiogenesis, invasion, and metastasis. Injection of Ad-VHL into HCC tumors augmented doxorubicin-induced suppression of tumor growth by inhibiting cell proliferation and tumor angiogenesis, and by inducing cell apoptosis. Effects on the expression of HIFαs, activity of NF-κB, and their downstream genes were in accordance with the in vitro findings. Intraportal injection of Ad-VHL enhanced the efficacy of doxorubicin to suppress the growth of orthotopic liver tumors. Conclusions: By targeting HIF and NF-κB, overexpression of pVHL enhances the efficacy of doxorubicin, and warrants consideration as a potential therapeutic strategy for treating HCC. [Copyright &y& Elsevier]

Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer mortality world wide. Despite continuing development of new therapies, the prognosis for patients with HCC remains extremely poor. In part, this may relate to molecular abnormalities that stimulate HCC tumorigenesis and also contribute to reduced sensitivity to standard treatment. Increasing evidence has revealed the importance of liver cancer stem cells in hepatocarcinogenesis. Although widely investigated, the signaling pathways important for liver cancer stem cells in liver tumor initiation and progression are poorly understood. The Hippo signaling pathway was identified in Drosophila as an essential regulator of cell proliferation and apoptosis. Recently, Hippo pathway has been implicated in multiple events during development and it has also been proposed to play a vital role in several tumor types, especially in hepatocellular carcinoma. Strong evidences also proved the significant role of the Hippo signaling pathway in oval cell activation. As suggested, hippo signaling has a dual regulation of Hippo in liver tumor suppression as well as transition of oval cells to fully differentiated hepatocytes. Delineation of the malfunction of Hippo signaling pathway in HCC may lead to better understanding of hepatocarcinogenesis, rational medical therapy for HCC and possible therapy for other tumors. Here, we provide a historical review of this potent growth-regulatory pathway in HCC and highlight outstanding questions that will likely be the focus of future investigation. [Copyright &y& Elsevier]

Acute mesenteric ischemia (AMI) is a highly lethal clinical entity associated with high morbidity and mortality. Bowel necrosis often results, usually necessitating bowel resection; however, deciding on the extent of resection is problematic as accurate identification of ischemic bowel that may undergo subsequent infarction is difficult. Therefore, a second-look laparotomy after the first operation is usually recommended. While the second-look procedure is widely accepted, its optimal indications and mode are still controversial, raising questions such as “second-look or not?,” “planned relaparotomy or relaparotomy on demand?,” and “open or laparoscopic?” In this review we discuss the relevant literature and reassess the role of the second-look operation in the treatment of AMI. [ABSTRACT FROM AUTHOR]

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]

The success of surgery to remove primary tumors can be compromised by the subsequent outgrowth of metastases. It is recognized that primary tumors secrete antiangiogenic factors that suppress the outgrowth of their daughter metastases. In accord we show here that surgical removal of primary EL-4 lymphomas led to a marked decrease in the levels of circulating angiostatin and endostatin, and promoted the growth of distant nodular tumors. Expression vectors encoding angiostatin and endostatin, formulated with poly-N-vinyl pyrrolidone (PVP), were injected into the tibialis and gastrocnemia muscles, leading to expression of angiostatin and endostatin in muscle fibers. High levels of biologically active exogenous proteins were secreted into the circulation. Intramuscular gene therapy with angiostatin and endostatin plasmids significantly inhibited tumor vascularity and induced tumor cell apoptosis, and thereby suppressed the growth of secondary subcutaneous and disseminated metastatic tumors in the lung and liver. Simultaneous intramuscular delivery of both angiostatin and endostatin plasmids significantly prolonged the survival of mice after removal of primary tumors. These results suggest that intramuscular gene transfer of angiostatin and endostatin might serve as a prophylactic cancer-prevention strategy to combat the recurrence of cancer after surgical resection of primary tumors.Cancer Gene Therapy (2005) 12, 35-45. doi:10.1038/sj.cgt.7700766 Published online 15 October 2004 [ABSTRACT FROM AUTHOR]

Background & aims: Pyogenic liver abscesses (PLA) are space‐occupying lesions in the liver that produce high morbidity and mortality. The clinical characteristics and prognosis of abscesses is different depending on the bacterial culture results and require different strategies for management. The aim of this study was to investigate the clinical characteristics and prognostic factors of patients with PLA. Methods: Clinical features, laboratory tests and etiology of PLA between 2006 to 2011 and 2012 to 2017 in a single hospital were retrospectively reviewed. The incidence and mortality of PLA caused by Escherichia coli and Klebsiella pneumoniae were compared and the risk factors for multiple organ dysfunction (MODS) and endophthalmitis were evaluated. Results: Among the 1,572 PLA patients, the proportion with PLA increased from 333 (21.2%) in 2006‐2011 to 1,239 (78.8%) in 2012‐2017 without any investigation and treatment procedure differences. K pneumoniae was the main isolate in analysed pus cultures (85.6%). The mortality rate of patients with K pneumoniae infection was lower in the latter period (6.7% vs 0.7%, P =.035). Multivariate analyses revealed that age, fever, MODS and length of hospital stay were factors affecting poor prognosis (death + unhealed/uncured) in PLA patients after treatment and that cardiovascular disease, pleural effusion and pulmonary infection were risk factors for MODS, while diabetes mellitus was the only risk factor for endophthalmitis. Most patients (95.5%) with PLA recovered after abscess drainage/puncture and antibiotic therapy. Conclusions: Pleural effusion, fever, MODS and length of hospital stays were factors useful in predicting PLA outcomes. [ABSTRACT FROM AUTHOR]

Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α′s role in cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular reactive oxygen species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment. Image 1 • Low expression of PGC1α and MPC1 was associated with the poor prognosis of HCC. • PGC1α and MPC1 could inhibit HCC cell proliferation and induce apoptosis. • PGC1α/NRF1-MPC1 axis activates mitochondrial biogenesis and drives ROS production. • PGC1α/NRF1-MPC1 axis attenuates HCC progression. • PGC1α could enhance the sensitivity to sorafenib/doxorubicin treatment in HCC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a gastrointestinal malignancy originating from either the colon or the rectum. A growing number of researches prove that the unfolded protein response (UPR) is closely related to the occurrence and progression of colorectal cancer. The UPR has three canonical endoplasmic reticulum (ER) transmembrane protein sensors: inositol requiring kinase 1 (IRE1), pancreatic ER eIF2α kinase (PERK), and activating transcription factor 6 (ATF6). Each of the three pathways is closely associated with CRC development. The three pathways are relatively independent as well as interrelated. Under ER stress, the activated UPR boosts the protein folding capacity to maximize cell adaptation and survival, whereas sustained or excessive ER triggers cell apoptosis conversely. The UPR involves different stages of CRC pathogenesis, promotes or hinders the progression of CRC, and will pave the way for novel therapeutic and diagnostic approaches. Meanwhile, the correlation between different signal branches in UPR and the switch between the adaptation and apoptosis pathways still need to be further investigated in the future. [ABSTRACT FROM AUTHOR]

3 Depletion of SNHG1 enhances the effects of sorafenib in promoting apoptosis and autophagy of sorafenib-resistant cells. " " (P < 0.05) and " " (P < 0.001) indicate a significant difference Reference 1 Li W, Dong X, He C. LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. [Extracted from the article]

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. Methods: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. Results: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. Conclusion: The present study has identified a novel functional PDAC signature, which has the potential to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation. Video Abstract [ABSTRACT FROM AUTHOR]

Whether continuous intraoperative nerve monitoring (C-IONM) can further reduce the incidence of recurrent laryngeal nerve injury compared with intermittent intraoperative nerve monitoring (I-IONM) in high-risk thyroid surgery is still controversial. This observational study aimed to evaluate the incidence of vocal cord paralysis (VCP) in high-risk thyroid surgeries performed with I-IONM and C-IONM. High-risk thyroid surgical patients operated with I-IONM or C-IONM by the same group of surgeons in the thyroid surgery department of our institution between January 2014 and February 2018 were analyzed. Differences in the incidence rates of temporary and permanent VCP between the two groups were compared. A P -value < 0.05 was considered statistically significant. A total of 344 patients who underwent high-risk thyroid surgery (550 nerves at risk [NARs]) were observed, with 238 patients (374 NARs) operated with I-IONM and 106 patients (173 NARs) operated with C-IONM. The incidence of temporary and permanent VCP was 1.9% (7/374) and 0.8% (3/374) in the I-IONM group and 1.2% (2/173) and 0% (0/173) in the C-IONM group, respectively, showing no statistical difference (P = 0.726 and P = 0.555). The incidence rate of impending recurrent laryngeal nerve injuries successfully prevented in the C-IONM group was 5.2% (9/173). Both I-IONM and C-IONM are equally safe and effective in high-risk thyroid surgery. C-IONM can help predict impending recurrent laryngeal nerve injury in real time and has a good warning feature, thereby minimizing critical maneuvers in high-risk thyroid surgery. [ABSTRACT FROM AUTHOR]

Objective: The low pre‐ and intraoperative diagnostic rates in follicular thyroid carcinoma (FTC) often lead to inadequate surgical resection and necessitate further completion surgery. Therefore, the preoperative prediction of FTC in thyroid nodules is essential. Design and Patient: Patients were categorized into two data sets: the modelling data set, which included 3649 patients admitted to our centre between January 2014 and December 2016, and the validation data set, which included 1253 patients admitted between January and December 2017. Patient data from the FTC and non‐FTC groups were initially included in a modelling data set to establish a preoperative prediction model. This model was subsequently employed in a validation data set for external validation of the predictive value. The positivity rate for FTC predicted by the model was compared with that of the intraoperative frozen sections. Results: The preoperative serum thyroglobulin level, nodule diameter, calcification status, solidity and blood supply were selected as predictors for the model. The regression equation was as follows: Y = 0.010 × (thyroglobulin level) + 0.556 × (nodule diameter) + 0.675 × (calcification status) + 2.355 × (nodule component) + 1.072*(blood flow) − 9.787. The model positively predicted FTC at values of Y ≥ −4.11. The accuracy, sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of the prediction model were 89.2%, 90.2%, 87.7%, 39.2 and 0.11, respectively. External validation of the model demonstrated acceptable results. The positive prediction rate of the model was 90.7% (78/86), which was significantly higher than that of the intraoperative frozen sections (10.5% [9/86]; P < 0.0001). Conclusions: We successfully established and validated a simple and reliable preoperative prediction model for FTC using the preoperative thyroglobulin level and ultrasonographic features of the thyroid nodules. This model may improve the preoperative evaluation of FTC in clinical settings and facilitate the development of a reasonable surgical programme for FTC. [ABSTRACT FROM AUTHOR]

Introduction. The purpose of this study was to investigate the difference in surgical outcomes between symptomatic and asymptomatic patients with primary hyperparathyroidism (PHPT) and between patients with high serum calcium and those with normal blood calcium, as well as to explore the epidemiological trend of PHPT in northern China. Methods. Clinicopathologic data of 197 patients (50 men and 147 women) with PHPT who underwent surgery at the First Affiliated Hospital of Harbin Medical University from 2008 to 2017 were analyzed. Changes in clinicopathology were compared among different subgroups of patients. Patients were categorized into subgroups based on serum calcium levels, whether or not they presented with symptoms, and admission time. Results. Of the total patients, 82.23% had hypercalcemic primary hyperparathyroidism (HCPHPT), 17.77% had normocalcemic primary hyperparathyroidism (NCPHPT), 45.18% had symptomatic primary hyperparathyroidism (SPHPT), and 54.82% had asymptomatic primary hyperparathyroidism (ASPHPT). Seventy-seven cases of PHPT involved thyroid nodules, with 22 confirmed as papillary thyroid carcinoma, and 29 confirmed as nodular goiter. There was no significant difference in the success rate of surgery, postoperative recurrence rate, and the symptoms of temporary hypocalcemia between the HCPHPT and NCPHPT groups, and between the SPHPT and ASPHPT groups. The incidence of PHPT has increased threefold since 2013. Conclusions. Symptoms and serum calcium levels did not affect the results of surgical treatment for PHPT. The incidence of PHPT in northern China is increasing. Moreover, PHPT manifestation has shifted from the symptomatic to the asymptomatic form. Thyroid surgery should be performed in PHPT patients with thyroid nodules. [ABSTRACT FROM AUTHOR]

Vanadium and its compounds exhibit concentration- and time-dependent anticancer effects on various types of tumor; however, the effects of sodium orthovanadate (SOV) on anaplastic thyroid carcinoma (ATC) have not yet been reported. In the present study, the anticancer effects of SOV on ATC were evaluated. In vitro experiments, including cell viability assays, plate colony formation assays, cell cycle analysis and apoptosis analysis were used to study the role of SOV in ATC. Using in vivo experiments, the effects of SOV on the growth and apoptosis of an ATC-xenograft tumor were studied by comparing the SOV-treatment with the control group. The results revealed that treatment of the human ATC cell line 8505C with SOV inhibited cell viability, induced G2/M phase cell cycle arrest, stimulated apoptosis and reduced mitochondrial membrane potential in a concentration-dependent manner. These findings were confirmed in vivo in a nude mouse ATC xenograft model. In conclusion, the present study demonstrated that SOV inhibited human ATC by regulating proliferation, cell cycle progression and apoptosis, thus suggesting that SOV may be considered a novel option for the treatment of ATC. [ABSTRACT FROM AUTHOR]

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]

Thromboangiitis obliterans (TAO) (also known as Buerger's disease) is an inflammatory vascular disease that predominantly affects small- and medium-sized blood vessels of extremities. Endothelial cells play critical roles in the initiation and progression of this disease, but the underlying mechanisms remain unclear. In the present study, we demonstrate that patients with TAO had significantly higher levels of interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in their plasmas, and the involved arterial tissues expressed higher levels of phosphorylated signal transducer and activator of transcription 3 (p-STAT3), ICAM-1 and VCAM-1. In exploring the molecular mechanisms with human aortic endothelial cells (HAECs), we found that recombinant IL-6 activated the STAT3 pathway, leading to the upregulation and overproduction of ICAM-1 and VCAM-1. RhoA (Ras homolog family member A), eNOS (endothelial nitric oxide synthase) and MMP-9 (matrix metalloproteinase-9) participated in this cellular signaling, and their interaction regulated the expression of ICAM-1 and VCAM-1. The activated STAT3 pathway by IL-6 also modulated the cytoskeleton of HAECs by regulating phosphorylation of focal adhesion kinase (FAK) and acetylation of α-tubulin through interplaying with RhoA. In summary, the present results indicate that activation of the IL-6/STAT3 pathway contributes to the pathogenesis of TAO by regulating cellular adhesion molecules and cytoskeleton of vascular endothelial cells, suggesting that targeting this pathway may provide a potential approach for the management of TAO. [ABSTRACT FROM AUTHOR]

Background & Aims: Neuropilin-1 (NRP-1) activates signalling pathways as multifunctional co-receptors in cancer cells. However, its role and how it is regulated by miRNAs in cholangiocarcinoma (CCA) have not yet been investigated. Methods: The expression of NRP-1, miR-320 and key molecules involved in cell proliferation, migration and related signalling pathways were detected by immunohistochemistry, immunoblotting and qRT-PCR. Stable transfectants depleted of NRP-1 were generated. The regulatory effect of miR-320 on NRP-1 was evaluated by luciferase reporter assays. Cell proliferation, cell cycle distribution and migration were examined. Xenograft tumour models were established to assess tumourigenesis, tumour growth and lung metastasis. Results: Cholangiocarcinoma tissues expressed higher levels of NRP-1 than adjacent normal biliary tissues, and its expression negatively correlated with miR-320. NRP-1 depletion inhibited cell proliferation and induced cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2; and reduced cell migration by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumourigenesis, tumour growth and lung metastasis by inhibiting cell proliferation and tumour angiogenesis in experimental animals. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective ligands. MiR-320 negatively regulated the expression of NRP-1 by binding to the 3'-UTR of NRP-1 promoter, and miR-320 mimics inhibited cell proliferation and migration, and the growth of established tumours in animals by downregulating NRP-1. Conclusions: The present results indicate that NRP-1 is negatively regulated by miR-320, and both of them may be potentially therapeutic targets for CCA. [ABSTRACT FROM AUTHOR]

In the original article, there was one misplaced image in Fig. 4a (the representative MDM2 blot in Hep3B cells). [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]

Objective: The present study aims to investigate the underlying mechanisms accounting for the activities of everolimus to inhibit the growth of vascular smooth muscle cells (VSMCs), which contributes to restenosis. Methods: Primary VSMCs were cultured in media containing smooth muscle growth supplements and incubated with testing agents. Cell proliferation, cell cycle distribution, apoptosis and autophagy, and the key molecules involved, were examined. Results: Everolimus inhibited the proliferation of VSMCs by inhibiting the activation of ribosomal protein S6 kinase and phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, and downregulating proliferating cellular nuclear antigen. Everolimus induced cell cycle arrest at the G1 phase by downregulating cyclin D1 and upregulating p27, and increased apoptosis by downregulating Bcl-2, upregulating Bad and activating capsase-3 and poly ADP ribose polymerase. Everolimus enhanced autophagy by increasing the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II, and upregulating Beclin 1. Specific autophagy inhibitors, 3-methyladenine and bafilomycin A1, significantly attenuated the inhibition of cell proliferation, the increased apoptosis and the altered expression of the above key proteins induced by everolimus. Conclusions: Enhanced autophagy by everolimus contributes to its antirestenotic activity and its abilities to inhibit cell proliferation and to induce apoptosis of VSMCs. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The present study aimed to investigate the anti-cancer effects of hydroxytyrosol (HT) in human hepatocellular carcinoma (HCC) cells. Our results show that HT could inhibit proliferation, induce G2/M cell cycle arrest and apoptosis in human HCC cells. Mechanically, we found that HT could suppress the activation of AKT and nuclear factor-kappa B (NF-κB) pathways. HT also significantly inhibited the tumor growth, angiogenesis and the activation of AKT and NF-κB pathways in an orthotopic model of human HCC in vivo. These data suggest that HT may be a promising candidate agent for the treatment of HCC. [Copyright &y& Elsevier]

Abstract: Sorafenib, the first-line systemic drug for advanced hepatocellular carcinoma (HCC), has demonstrated limited benefits with very low response rates. Thus it is essential to investigate the underlying mechanisms for the resistance to sorafenib and seek potential strategy to enhance its efficacy. Hypoxic cells inside solid tumors are extremely resistant to therapies as their survival ability is increased due to the cellular adaptive response to hypoxia, which is controlled by hypoxia-inducible factor (HIF)-1 and HIF-2. Sorafenib inhibits HIF-1α synthesis, making the hypoxic response switch from HIF-1α- to HIF-2α-dependent pathways and providing a mechanism for more aggressive growth of tumors. The present study has demonstrated that upregulation of HIF-2α induced by sorafenib contributes to the resistance of hypoxic HCC cells by activating the transforming growth factor (TGF)-α/epidermal growth factor receptor (EGFR) pathway. Blocking the TGF-α/EGFR pathway by gefitinib, a specific EGFR inhibitor, reduced the activation of STAT (signal transducer and activator of transcription) 3, AKT and ERK (extracellular signal-regulated kinase), and synergized with sorafenib to inhibit proliferation and induce apoptosis of hypoxic HCC cells. Transfection of HIF-2α siRNA into HCC cells downregulated the expression of VEGF (vascular endothelial growth factor), cyclin D1, HIF-2α and TGF-α, and inhibited the activation of EGFR. HIF-2α siRNA inhibited the proliferation and promoted the apoptosis of HCC cells in vitro, and synergized with sorafenib to suppress the growth of HCC tumors in vivo. The results indicate that targeting HIF-2α-mediated activation of the TGF-α/EGFR pathway warrants further investigation as a potential strategy to enhance the efficacy of sorafenib for treating HCC. [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]

Background: Cyclooxygenase (COX)-2 is overexpressed in many types of cancers including hepatocellular carcinoma (HCC). Meloxicam, a selective COX-2 inhibitor, has shown potential therapeutic effects against HCC, but the mechanisms accounting for its anti-cancer activities remain unclear. Methods and Findings: Meloxicam inhibited the ability of human HCC cells expressing higher levels of COX-2 to migrate, invade, adhere and form colonies through upregulating the expression of E-cadherin and downregulating the expression of matrix metalloproteinase (MMP) -2. Meloxicam induced cell apoptosis by upregulating pro-apoptotic proteins including Bax and Fas-L, and downregulating anti-apoptotic proteins including survivin and myeloid cell leukemia-1 (Mcl-1), through inhibiting phosphorylation of AKT. Addition of prostaglandin E2 (PGE2), the major product of COX-2, could abrogate the effects of meloxicam on the expression of survivin and myeloid cell leukemia-1 (Mcl-1), but not Bax and Fas-L, indicating that meloxicam induces cell apoptosis via both COX-2-dependent and -independent pathways. Meloxicam also induced cell autophagy by upregulating Beclin 1 and light chain 3-II. Specific inhibition of autophagy by 3-methyladenine and chloroquine had little effect on cell apoptosis but could enhance the pro-apoptotic effects of meloxicam by further upregulating the expression of Bax. Conclusions: Meloxicam executes its antitumor effects by targeting the COX-2/MMP-2/E-cadherin, AKT, apoptotic and autophagic pathways in COX-2-dependent and -independent pathways, and inhibition of cell autophagy could help to overcome the resistance to meloxicam-induced apoptosis in HCC. [ABSTRACT FROM AUTHOR]

This study investigated the contribution of survivin and its upstream regulators, AKT and hypoxia-inducible factor 1α ( HIF-1α), to the resistance of gastric cancer cells to cisplatin ( CDDP). We found that over-expression of survivin increased the resistance of SGC7901 and BGC823 gastric cancer cells to CDDP. Its over-expression abrogated CDDP-induced inhibition of cell proliferation and CDDP-induced cell apoptosis. In contrast, down-regulation of survivin expression using small hairpin RNA (sh RNA) vectors and the small-molecule inhibitor YM155, or inhibition of survivin function using a recombinant cell-permeable dominant-negative survivin protein (d NSur9), promoted CDDP-induced apoptosis. CDDP-resistant sub-lines generated from the parental SGC7901 and BGC823 cells by exposure to increasing concentrations of CDDP expressed higher levels of HIF-1α and survivin in response to hypoxia, and higher levels of phosphorylated AKT (p AKT). Specific inhibition of AKT reduced the expression of HIF-1α and survivin, whereas specific inhibition or depletion of HIF-1α reduced survivin expression but had no effect on the expression of phosphorylated AKT. The expression levels of survivin affected the therapeutic efficacy of CDDP in treating gastric tumors in mice. Specific inhibition of survivin, AKT and HIF-1α enhanced the sensitivity of CDDP-resistant cells to CDDP. Specific inhibition of survivin, AKT and HIF-1α synergized with CDDP to suppress the growth of gastric tumors that had been engineered to overexpress survivin. In summary, the results provide evidence that up-regulation of survivin by AKT and HIF-1α contributes to CDDP resistance, indicating that inhibition of these pathways may be a potential strategy for overcoming CDDP resistance in the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: “Tilt” of surgical view was commonly shown on the monitor due to unintentional rotation of camera along its long axis by camera driver. Surgeons may be influenced on identification of anatomical structures by the tilt vision. We aimed to analyze the surgical records and videos of laparoscopic surgery, and to reveal the correlation between intraoperative complications and tilt view. Methods: A series of 425 consecutive patients who received laparoscopic low anterior resection and abdominoperineal resection were studied, and 398 surgery videos were reviewed. Still pictures showing intraoperative injury were selected. A method was established to measure tilt angle in the still pictures according to the reference line based on several anatomic landmarks. The patients were grouped with two methods according to different study purposes. Incidence of intraoperative complication and tilt angle were calculated, and statistical analysis was performed. Results: The incidence of intraoperative complications was 8.3 %. Tilt of the surgical field at different degrees (<15°, 15°–30° and >30°) was found in a relatively high rate in these surgery videos (31.4 %). Compared with controls, comparatively bigger tilt angles were found in all cases of complication group. It is interesting to note that intraoperative complications happened more often when the tilt angle was in the range of 15°–30° (72.7 %) than >30° (18.2 %). We also noted a high incidence of complication (72.7 %), while tilt angle was over 15° (26 %) in the first 100 cases; comparatively a steady declining low rate of complication occurrence (5–7 %) and also tilt angle over 15° (9–11 %) were noted in the later 298 cases. Conclusions: Rotation of camera is common during laparoscopic procedures. The tilt view increased the risk of laparoscopic procedures. Tilt angle at 15–30° is the most dangerous rotation for laparoscopic surgeries. Therefore, we propose the “Gravity Line Strategy” principle as one of the basic operating criteria to correct the tilt angle. [ABSTRACT FROM AUTHOR]

Highlights: [•] IFN-α regulates the LPS-induced expression of cytokines in the murine spleen. [•] IFN-α positively regulates the expression of KC and LIX in the LPS-activated spleen dependent on STAT-1. [•] IFN-α increases neutrophilic recruitment via the enhanced expression of KC and LIX in the spleen during LPS stimulation. [ABSTRACT FROM AUTHOR]

Abstract: The interleukin-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway mediates cell proliferation and migration. S-phase kinase-associated protein-2 (Skp2) catalyzes the ubiquitylation of p27 and p21. Here we investigated that the cross-talk of the two pathways regulates motility and invasion of gastric cancer SGC7901 and MGC803 cells. Both cell lines endogenously secret IL-6, and blockage of IL-6 or JAK2 inhibited the activation of JAK2 and STAT3. Depletion of STAT3 downregulated Skp2 expression, and thereby increased the expression of p27 and p21. The depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired the cellular cytoskeleton mainly microtubules; while the depletion of p27 partially restored the impaired ability to migrate, and reversed the impaired microfilaments, further inhibited the ability to invade, but had little effect on microtubules and cellular adhering ability of STAT3-depleted cells. STAT3 depletion inhibited the activity of RhoA and the interaction with stathmin, downregulated the expression of pFAK (phosphorylated focal adhesion kinase), acetylated-tubulin, RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and Sp1, upregulated E-cadherin, and reduced the activities of MMP (matrix metalloproteinase)-2 and -9. The depletion of p27 increased RhoA (Ras homolog family member A) activity, upregulated RECK, and downregulated E-cadherin and Sp1 in STAT3-depleted cells. The results indicate that the interaction between STAT3 and Skp2/p27/p21 pathway plays an important role in mediating the motility, migration and invasion of gastric cancer cells, and inhibition of STAT3 may be a useful therapeutic approach for metastasis of gastric cancer, but caution needs to be taken for its effects on Skp2/p27/p21 pathway. [Copyright &y& Elsevier]

Abstract: Context: Laparoscopic nephroureterectomy (LNU) has increasingly been used as a minimally invasive alternative to open nephroureterectomy (ONU), but studies comparing the efficacy and safety of the two surgical procedures are still limited. Objective: Evaluate the oncologic and perioperative outcomes of LNU versus ONU in the treatment of upper urinary tract urothelial carcinoma. Evidence acquisition: A systematic review and cumulative analysis of comparative studies reporting both oncologic and perioperative outcomes of LNU and ONU was performed through a comprehensive search of the Medline, Embase, and the Cochrane Library electronic databases. All analyses were performed using the Review Manager (RevMan) v.5 (Nordic Cochrane Centre, Copenhagen, Denmark) and Meta-analysis In eXcel (MIX) 2.0 Pro (BiostatXL) software packages. Evidence synthesis: Twenty-one eligible studies (1235 cases and 3093 controls) were identified. A significantly higher proportion of pTa/Tis was observed in LNU compared to ONU (27.52% vs 22.59%; p =0.047), but there were no significant differences in other stages and pathologic grades (all p >0.05). For patients who underwent LNU, the 5-yr cancer-specific survival (CSS) rate was significantly higher, at 9% (p =0.03), compared to those who underwent ONU, while the overall recurrence rate and bladder recurrence rate were notably lower, at 15% (p =0.01) and 17% (p =0.02), respectively. However, there were no statistically significant differences in 2-yr CSS, 5-yr recurrence-free survival (RFS), 5-yr overall survival (OS), 2-yr OS, and metastasis rates between LNU and ONU (all p >0.05). Moreover, there were no significant differences between LNU and ONU in terms of intraoperative complications, postoperative complications, and perioperative mortality (all p >0.05). The results of our study were mainly limited by the retrospective design of most of the individual studies included as well as selection biases based on different management of regional lymph nodes and pathologic characteristics. Conclusions: Our data suggest that LNU offers reliable perioperative safety and comparable oncologic efficacy when compared to ONU. Given that some limitations cannot be overcome, well-designed prospective trials are needed to confirm our findings. [Copyright &y& Elsevier]

Purpose: Hepatic ischemia/reperfusion (HIR) injury is an unavoidable consequence of major liver surgery, during which endotoxemia often takes place. This study aimed to investigate whether matrine has a protective effect against HIR-induced liver injury aggravated by endotoxin. Methods: Wistar rats were subjected to 30 min of HIR followed by lipopolysaccharide (LPS) (0.5 mg/kg) administration. At the indicated time points, six rats from each group (24 rats) were randomly euthanized to collect blood samples and livers. Results: Preadministration of matrine protected livers from injury induced by HIR+LPS as the histological score, myeloperoxidase activity and malondialdehyde contents, expression of macrophage-inflammatory protein-2, DNA-binding activity of nuclear factor κB, and serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, and nitric oxide were significantly reduced, and serum levels of interleukin-6 were further increased. HIR+LPS markedly induced cell apoptosis and necrosis, and upregulated the expression of cleaved caspase-3, Fas, and FasL. Matrine significantly reduced cell necrosis, but had a nonsignificant inhibitory effect on cell apoptosis and expression of cleaved caspase-3 and FasL Conclusions: Matrine attenuates endotoxin-induced acute liver injury after HIR mainly by its anti-inflammatory and antioxidative activities, and has little inhibitory effect on cell apoptosis. [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]

Objectives: To assess the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL) compared with standard or small-bore PCNL with a meta-analysis of randomized, controlled trials. Methods: All eligible studies were searched on MEDLINE, Embase, and the Cochrane Library databases. Risk ratio (RR), mean difference, or standardized mean difference (SMD), with its 95% CI, was used to evaluate the size effect. Results: Ten and 3 trials were identified for comparison I (tubeless PCNL vs standard PCNL, 320 cases and 323 controls) and comparison II (tubeless PCNL vs small-bore PCNL, 55 cases and 54 controls), respectively. Tubeless PCNL required significantly less analgesia relative to standard PCNL (SMD −1.72; 95% CI −2.30 to 1.13; P heterogeneity = 0.04) and small-pore PCNL (SMD −0.69; 95% CI −1.13 to 2.05; P heterogeneity = 0.94). Furthermore, there was a remarkably shorter hospital stay in comparison I (SMD −1.35; 95% CI −1.40 to 1.30; P heterogeneity = 0.60) and comparison II (SMD −0.49; 95% CI −0.76 to 0.21; P heterogeneity = 0.15). The return to normal activity days was also significantly decreased in comparison I (SMD −4.34; 95% CI −6.28 to 2.41; P heterogeneity = 0.02). However, no significant difference was observed in the analyses concerning stone-free blood transfusion and complications rate in both comparisons. In subgroup analyses by nephrostomy diameter (22-Fr) and drainage methods, most results were consistent with the overall findings except for that to evaluate the operative time in the double-J stent subgroup. Conclusions: Tubeless PCNL is associated with less pain and quicker recovery compared with standard or small-bore PCNL, in the management of uncomplicated renal calculi. [ABSTRACT FROM AUTHOR]

Nutlin-3, a selective small-molecule inhibitor of the p53-MDM2 interaction, has been shown to have antitumor activities in various tumors with wild-type p53. However, its effect on hepatocellular carcinoma (HCC) with different types of p53 remains unclear. This study is designed to determine nutlin-3′s antitumor efficacy and underlying mechanisms of action in human HCC cells. Cell viability assay, cell cycle analysis, apoptosis assay, western blot, co- immunoprecipitation and siRNA experiments were analyzed in three human HCC cells. Anti-tumoral effects of nutlin-3 targeting the p53 and p73 pathways were evaluated in HCC cell lines. Nutlin-3 exerted the greatest anti-tumoral effect to three human HCC cells with wild-type p53, mutant p53 and p53-null. Nutlin-3 not only upregulated p53 in HepG2 cells, but also p73 in Huh7 and Hep3B cells, and disrupted p53-MDM2 and p73-MDM2 complexes in HCC cells. The compound inhibited cell proliferation, induced G0/G1 phase arrest, decreased the levels of CyclinD1, CyclinE, CDK2, CDK4, PCNA and E2F-1, and increased the levels of p21 and p27. It also induced apoptosis, increased the Bax/Bcl-2 ratio, then activated caspase-9 and caspase-3. Nutlin-3 has significant anticancer effects against human HCC cells, regardless of p53 status, indicating that it is a promising therapy for human hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is a highly lethal malignancy mostly because of de novo and acquired resistance to conventional chemotherapy. Constitutive activation of Akt and nuclear factor-κB (NF-κB) represent major cellular abnormalities associated with both the pathogenesis and therapeutic resistance of HCC. The aim of the present study was to determine whether genistein, a natural Akt/NF-κB inhibitor, could enhance the anti-HCC efficacy of ATO both in vitro and in vivo. Our results demonstrated that genistein not only potentiated the proliferation-inhibiting and apoptosis-inducing effect of ATO on human HCC cell lines in vitro, but also dramatically augmented its suppressive effect on both tumor growth and angiogenesis in nude mice. The mechanism is at least partially due to the suppressive effect of genistein both on the proper and ATO-induced Akt activation, and on the activity of NF-κB, and the latter correlated with the suppression of NF-κB regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, c-myc, COX-2, and VEGF. These data suggest that the combination of ATO with genistein presents a promising therapeutic approach for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Matrine, one of the main components extracted from a traditional Chinese herb, Sophora flavescens Ait, has displayed anti-cancer activity in several types of cancer cells. This study aims to evaluate the therapeutic benefits of matrine on primary and metastatic breast cancer. Matrine inhibited the viability of and induced apoptosis in human MCF-7 and mouse 4T1 breast cancer cells in a dose-dependent manner in vitro as shown by MTT assay, flow cytometry and laser scanning confocal microscopy. Administration of matrine inhibited the growth of primary tumors and their metastases to lungs and livers, in a dose-dependent manner, in a highly metastatic model of 4T1 breast cancer established in syngeneic Balb/c mice. Tumors from matrine-treated mice had a smaller proliferation index, shown by immunostaining with an anti-Ki-67 antibody, a greater apoptosis index, shown by TUNEL-staining, and a less microvessel density, shown by immunostaining with an anti-CD31 A antibody, compared to the controls. Western blot analysis of tumoral homogenates indicated that matrine therapy reduced the ratio of Bcl-2/Bax, downregulated the expressions of VEGF and VEGFR-2, and increased the activation of caspase-3 and caspase-9. This study suggests matrine may be a potent agent, from a natural resource, for treating metastatic breast cancer because of its anti-apoptotic, anti-proliferative and anti-angiogenic activities. [ABSTRACT FROM AUTHOR]

Objective: Blockade of CD80-CD28 costimulatory pathway induces unresponsiveness of T cells to alloantigens and protects allografts against immune rejection. The aim of this study was to investigate whether downregulating the expression of B7.1 (CD80) in the donor livers by antisense B7.1 gene transfer could attenuate the acute immune rejection against liver allografts in rats. Methods: The liver grafts from 60 Dark Agouti rats were intraportally perfused with antisense B7.1 expression vector, before they were transplanted into Lewis rats. Empty vector pcDNA3 served as control to be perfused into livers of another group of 60 Dark Agouti rats. The orthotopic liver transplantation was performed. The rats were randomly sacrificed at scheduled time points to collect liver allografts, or monitored to record the survival rate. The livers were histologically examined to calculate Banff rejection activity index, or subjected to Western blot analysis or immunohistochemistry for examining the expression of B7.1, or counting CD4+ and CD8+ cells. Results: Antisense gene transfer resulted in markedly downregulation of B7.1 in the donor livers, attenuated acute immune rejection against liver allografts, prolonged the survival time of rats, and decreased the number of infiltrating CD4+ and CD8+ cells in livers. Conclusions: Blocking expression of B7.1 in liver by antisense gene therapy may represent a potential strategy to attenuate acute rejection against liver allografts. [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 Aims: Extramedullary hematopoiesis (EMH) is induced in spleens due to various diseases. The aim of this study is to investigate the role of spleen in cyclophosphamide (CTX)-induced hematosuppression and EMH in mice. Methods: Balb/c mice were IP injected with 300 mg/kg CTX 2 weeks after splenectomy or sham operation and randomly sacrificed 1, 3, 7, 14, and 21 days after injection. Blood samples were collected, and spleens were weighed, histologically analyzed, and then used for flow cytometry. Results: There were significant differences in white blood count, red blood count, platelet numbers and hemoglobin concentration between the splenectomized and sham-operated mice after CTX injection. The cellularity of the spleen was reduced 3 days following CTX treatment but then rose 7 days after CTX treatment. The numbers of colony-forming units in the spleen reached a peak 7 days after CTX injection, then declined. Flow cytometry demonstrated the percentage of CD34+ and CD117+ cells in the spleen increased 7 days after CTX injection, indicating the hematopoietic stem and progenitor cells in the spleen. Conclusions: The study indicates that EMH occurs as a compensatory reaction to CTX-induced hematosuppression in the murine spleen, implying that conservation of the spleen may promote the recovery of cancer patients from chemotherapy-induced hematosuppression. [Copyright &y& Elsevier]

Purpose: Intestinal ischemia/reperfusion (I/R) is a common and serious clinical condition. The anti-inflammatory and anti-apoptotic properties of oxymatrine, the extract from a traditional Chinese herb, Sophora flavescens Ait, have been shown to protect the liver from I/R injury and attenuate colitis. The objective of this study was to investigate if oxymatrine could attenuate intestinal I/R injury induced in rats. Methods: The experimental design consisted of three groups of 24 Wistar rats each: a sham-operation group (control group), a group subjected to intestinal I/R and then given saline (saline group), and a group subjected to intestinal I/R and then given oxymatrine (oxymatrine group). Intestinal I/R was induced by occluding the superior mesenteric artery for 45 min. Six rats from each group were killed at selected time points, and blood and intestinal samples were collected. Results: Morphological alteration, reduction of γ-glutamyl transpeptidase (γ-GGT) activity, and increased cell apoptosis confirmed intestinal I/R injury. The oxymatrine group had a significantly lower histological score and apoptosis index than the saline group, demonstrating that the preadministration of oxymatrine attenuated gut damage. Moreover, oxymatrine inhibited the production of lipid peroxides (LPO), decreased the serum levels of tumor necrosis factor (TNF)-α, and downregulated expression of phosphorylated p38 mitogen-activated protein kinase, Fas, and FasL, which had been elevated by I/R. Conclusions: These results provide further evidence of the anti-inflammatory and anti-apoptotic activities of oxymatrine, which may become a potent drug for protecting the intestines against I/R injury. [ABSTRACT FROM AUTHOR]

Background: Intestinal ischemia reperfusion (II/R) is a serious clinical condition associated with simultaneous multiple organ dysfunction. The purpose of this study was to investigate whether taurine, an anti-oxidative, anti-inflammatory, and anti-apoptotic agent, could attenuate multiple organ injury induced by II/R. Materials and methods: Taurine was intravenously injected to Wistar rats 30 min before II/R; physiological saline and sham operation served as controls. II/R was produced by occlusion of superior mesenteric artery for 60 min. Rats were randomly sacrificed 1.5, 3, 12, and 36 h after II/R; blood samples were collected for assessing alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and tumor necrosis factor-alpha (TNF-α), and intestines, livers, kidneys, and lungs were removed for histological examination of scoring injury severity and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis. The amount of lipid peroxides (LPO) was measured in intestinal tissues, and expression of caspase-3 was detected in all of the tissues with Western blot analysis. Results: II/R resulted in injury to intestines as well as livers, kidneys, and lungs, evidenced by morphological alteration, increased cell apoptosis, and elevated serum levels of ALT, AST, BUN, and Cr. The damage reached peak 3 h after II/R. The intestinal LPO and serum levels of TNF-α were increased after II/R. Pre-administration of taurine significantly attenuated multiple organ injury as the histological score, apoptosis index, LPO, and levels of ALT, AST, BUN, Cr, and TNF-α were significantly lower compared with saline controls. Conclusions: Taurine attenuates multiple organ injury induced by II/R. Although the mechanism needs further investigation, taurine inhibits production of intestinal LPO, release of TNF-α, cell apoptosis, and expression of caspase-3. [Copyright &y& Elsevier]

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]

Abstract: Background/Aims: B7H3 immunogene therapy is able to completely eradicate tumors when combined with an anti-vascular agent. The aim of this study was to determine whether vasostatin, a potent anti-angiogenic agent, could synergize with B7H3-mediated immunotherapy to combat hepatocellular carcinoma (HCC). Methods: Vasostatin and B7H3 expression plasmids were constructed, and the in vitro and in vivo expression and anti-angiogenic activity of recombinant vasostatin were measured. The anti-tumor activities of B7H3 and vasostatin alone and in combination were assessed using single and multiple H22 tumor models. Results: Gene transfer of vasostatin inhibited the proliferation of aortic endothelial cells, and angiogenesis in the chorioallantoic membrane assay. Subcutaneous H22 tumors established in BALB/c mice were completely eradicated in response to intratumoral injection of B7H3-expressing plasmids followed 24h later by vasostatin-expressing plasmids. In contrast, neither vasostatin nor B7H3 monotherapy was effective. Gene transfer of vasostatin inhibited tumor angiogenesis and enhanced infiltration of NK cells, whereas B7H3 therapy activated CD8+ and NK cells and increased their infiltration into tumors, and enhanced the levels of circulating IFN-γ. B7H3 and vasostatin combination gene therapy was effective in combating a systemic challenge of parental H22 cells, and caused the complete regression of multiple distant tumor nodules. Conclusions: Combining vasostatin anti-angiogenic therapy with B7H3-mediated immunotherapy warrants investigation as a therapeutic strategy to combat HCC, and other malignancies. [Copyright &y& Elsevier]