The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2.

In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK-mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.

GDC-0980-induced apoptosis is enhanced by autophagy inhibition in human pancreatic cancer cells.

Pancreatic cancer remains fatal to the fast majority of affected patients. Activation of phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway plays an important role in pancreatic cancer progression and chemo-resistance. In the present study, we examined the activity of GDC-0980, a novel class I PI3K/mTOR kinase inhibitor, against pancreatic cancer cells in vitro. GDC-0980 inhibited AKT-mTOR activation and pancreatic cancer cell (PANC-1 and Capan-1 lines) survival. In both cancer cell lines, GDC-0980 simultaneously activated apoptosis and autophagy, the latter was detected by p62 degradation, Beclin-1 upregulation and light chain 3B (LC3B) conversion from a cytosolic (LC3B-I) to a membrane-bound (LC3B-II) form. Autophagy inhibitors including 3-methyladenine, hydroxychloroquine, NH4Cl and bafilomycin A1 enhanced apoptosis and cytotoxicity by GDC-0980, such an effect was reversed by caspase inhibitors (z-VAD-FMK and z-ITED-FMK). Furthermore, knockdown of LC3B or Beclin-1 through siRNA increased GDC-0980-induced anti-pancreatic cancer cell activity. Thus, inhibition of autophagy sensitizes GDC-0980-induced anti-pancreatic cancer activity, suggesting a novel therapeutic strategy for GDC-0980 sensitization.

Surgical treatment of hepatocellular carcinoma with inferior vena cava tumor thrombus: a new classification for surgical guidance.

BACKGROUND: Hepatic resection is the main treatment modality for hepatic tumors. Advances in diagnostic technique, preoperative preparation, surgical technique, and postoperative management increased the success rate. The present study aimed to evaluate hepatectomy and resection of inferior vena cava tumor thrombus (IVCTT) in patients with hepatocellular carcinoma, and the relationship between IVCTT classification and selection of surgical technique. METHODS: We retrospectively reviewed 13 patients with hepatocellular carcinoma who had undergone hepatectomy with IVCTT resection between May 1997 and August 2009. Age, gender, diagnosis, findings of physical examination, results of preoperative laboratory investigations, radiological examination, criteria for resection, postoperative pathological results, incisions, operative technique, intraoperative transfusion, drains, and intraoperative and postoperative complications were evaluated for all patients. RESULTS: Type I IVCTT (10 patients) was posterior to the liver and below the diaphragm; type II IVCTT (2 patients) was above the diaphragm but still outside the atrium; and type III IVCTT (1 patient) was above the diaphragm and in the right atrium. Type I was treated by radical hepatectomy and removal of IVCTT with total hepatic vascular exclusion. Type II was treated by radical hepatectomy and removal of IVCTT by incision of the diaphragm. Type III was treated by hepatectomy and resection of the thrombus from the right atrium under cardiopulmonary bypass. There were no surgical complications and one patient has been survived for 4 years with cancer-free status. The median survival time was 18.2 months, and the 1- and 2-year survival rates were 53.8% and 15.4%, respectively. CONCLUSION: Surgical treatment is safe and feasible for treatment of IVCTT in patients with hepatocellular carcinoma, and surgical resectability can be judged according to the classification of tumor thrombus.

Surgical resection versus conformal radiotherapy combined with TACE for resectable hepatocellular carcinoma with portal vein tumor thrombus: a comparative study.

BACKGROUND: The aim of this study was to compare the results of surgical resection with three-dimensional conformal radiotherapy (3D-CRT) in the treatment of resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Transarterial chemoembolization (TACE) was given to both groups of patients when possible. METHODS: A retrospective study of 371 patients with resectable HCC with PVTT was conducted in two tertiary referral centers. The treatment of choice for these patients in one center was surgical resection. In the other center it was 3D-CRT. In the radiotherapy group (RG, n = 185), patients received 3D-CRT to the tumor and PVTT for a total radiation dose of 30-52 Gy (median 40 Gy). In the surgical group (SG, n = 186), patients underwent surgical resection. TACE was applied after surgery or 3D-CRT and then was repeated every 4-6 weeks if the patient tolerated the treatment. RESULTS: The median survival was 12.3 months for RG and 10.0 months for SG. The 1-, 2-, and 3-year overall survivals were 51.6, 28.4, and 19.9 %, respectively, for RG and 40.1, 17.0, and 13.6 %, respectively, for SG (p = 0.029). Stepwise multivariate analysis showed that the extent of PVTT and mode of treatment were independent risk factors of overall survival. The most common cause of death after treatment was liver failure as a consequence of progressive intrahepatic disease. CONCLUSIONS: 3D-CRT gave better survival than surgical resection for HCC with PVTT.

A prospective randomized controlled trial to compare Pringle maneuver, hemihepatic vascular inflow occlusion, and main portal vein inflow occlusion in partial hepatectomy.

BACKGROUND: blood loss during liver resection and the need for perioperative blood transfusions have negative impact on perioperative morbidity, mortality, and long-term outcomes. METHODS: a randomized controlled trial was performed on patients undergoing liver resection comparing hemihepatic vascular inflow occlusion, main portal vein inflow occlusion, and Pringle maneuver. The primary endpoints were intraoperative blood loss and postoperative liver injury. The secondary outcomes were operating time, morbidity, and mortality. RESULTS: a total of 180 patients were randomized into 3 groups according to the technique used for inflow occlusion during hepatectomy: the hemihepatic vascular inflow occlusion group (n = 60), the main portal vein inflow occlusion group (n = 60), and the Pringle maneuver group (n = 60). Only 1 patient in the hemihepatic vascular occlusion group required conversion to the Pringle maneuver because of technical difficulty. The Pringle maneuver group showed a significantly shorter operating time. There were no significant differences between the 3 groups in intraoperative blood loss and perioperative mortality. The degree of postoperative liver injury and complication rates were significantly higher in the Pringle maneuver group, resulting in a significantly longer hospital stay. CONCLUSIONS: all 3 vascular inflow occlusion techniques were safe and efficacious in reducing blood loss. Patients subjected to hemihepatic vascular inflow occlusion, or main portal vein inflow occlusion responded better than those with Pringle maneuver in terms of earlier recovery of postoperative liver function. As hemihepatic vascular inflow occlusion was technically easier than main portal vein inflow occlusion, it is recommended.

Distribution and ecological effect of mercury in Laogang landfill, Shanghai, China.

Laogang landfill near Shanghai is the largest landfill in China, and receives about 10000 t of daily garbage per day. Samples of topsoil and plants were analyzed to evaluate mercury pollution from the landfill. For topsoil samples, there were significant correlations among total mercury (HgT), combinative mercury (HgC) and gaseous mercury (HgG), and content of total organic carbon (TOC), but, no significantly relationship was found between Hg content and filling time. Hg content changes in vertical profiles with time showed that the average HgT of profiles 1992, 1996, and 2000 was similar, but their average HgG was quite different. HgT was significantly correlated with HgC in profile 1992 and 2000, and HgT was significantly correlated with HgG in profile 1996. HgG/HgT ratio in profile samples decreased in the order of (HgG/HgT)1992 > (HgG/Hg)1996 >> (Hg/HgT)2000. A simple outline of Hg release in landfill could be drawn: with increasing of filling time, degradation undergoes different biodegradation, accordingly, gaseous mercury goes through small, more, and small proportion to total mercury. Distribution of Hg in plants was inhomogeneous, following the order of leaf > root > stem. The highest value of leaf may be associated with higher atmospheric Hg from landfill. Ligneous plants (e.g. Phyllostachys glanca, Prunus salicina and Ligustrum lucidum) are capable of enriching more Hg than herbaceous plants.

[Relationship between oxidized lipoprotein, angiogenesis and human coronary atherosclerotic plaque stabilization].

OBJECTIVES: To analyze the relationship between oxidized low density lipoprotein (oxLDL), angiogenesis and stabilization of atherosclerotic plaques in human coronary arteries; and to investigate the role of oxLDL in creating vulnerable sites in atherosclerotic plaques. METHODS: Samples of coronary arteries were obtained at autopsies of 42 patients with acute coronary syndrome. Eighty randomly selected blocks were studied by immunohistochemistry using antibodies against oxLDL and endothelial cells (factor VIII). Computer-aided planimeter was used for quantitative analysis. RESULTS: In unstable plaques, percentage of immunoreactive areas for oxLDL was significantly higher than that in stable plaques. Most of the oxLDL were located in shoulder region of these plaques, as compared to the fibrous cap and basal regions. The details of distribution of oxLDL were as follows: shoulder region (20.43 +/- 3.12 for unstable plaques and 17.65 +/- 4.22 for stable plaques), fibrous cap (4.77 +/- 2.03 for unstable plaque and 2.80 +/- 0.22 for stable plaques) and basal region (5.65 +/- 1.65 for unstable plaques and 3.22 +/- 1.02 for unstable plaques). OxLDL was also a main component in the lipid core. In the shoulder region, there was a significant positive correlation between neovascularization and oxLDL (r = 0.8247, P = 0.000). CONCLUSIONS: The amount of oxLDL is significantly higher in unstable atherosclerotic plaques, especially over the shoulder region. OxLDL in coronary atherosclerotic plaques is thus an important factor in determining stabilization of the plaques. OxLDL may induce influx of inflammatory cells which subsequently leads to decreased plaque stabilization.

[Distribution and species of mercury in water and sediments from Huangpu River].

Levels of total mercury, soluble mercury and particle mercury in water of Huangpu River change greatly, their average values are (0.4 +/- 0.44) ng/mL, (0.27 +/- 0.42)ng/mL, (0.13 +/- 0.10) ng/mL respectively. Mercury in water is mainly in the form of soluble mercury. Average mercury content in sediment of Huangpu River is relative high and up to (204.03 +/- 97.41) ng/g, with a range of 70.52 ng/g - 387.30 ng/g. Mercury content is high in the middle reach of Huangpu River, especially in section of Xidu-Nanpu Bridge, and low in upstream and downstream. Distribution of mercury is hightly related with distribution of industry plants and farming. Locations with high mercury content in sediment are in the downstream of locations with high mercury content in water. Mercury (in sediments) is mainly in the form of residue, exchangeable ions, and humics-bound, seldom is in the form of carbonate-bound. Contrary to residue-bound mercury, exchangeable mercury is low in the middle reach, and high in upstream and downstream. There mainly are residue-bound mercury and little humics-bound mercury, exchangeable mercury, and carbonate-bound mercury in sediment in profile, and the residue-bound mercury increases irregularly with depth. Nearing the Mouth of Yangtze River, mercury in sediment becomes more active.

[Environmental effects of mercury around a large scale MSW incineration plant].

Samples of soil, vegetables, crops and air collected from Yuqiao Incineration Paint, Pudong Shanghai, were analyzed with an AMA-254 liquid/solid mercury analyzer. It is shown that background levels(BLs,2001) of mercury in surface soil is a little higher, mercury content in soils one year after operation(2002) and two year(2003) were both higher than BLs. The levels of mercury in vegetables is higher than Standard levels (GB 2762-94), the content of mercury in Soya and broomcorn sampled in 2003 was 2.3 and 2.7 times than that in 2002. Atmospheric mercury levels were 10.1, 5.0 and 10.6 ng/m3 in up-site,site and down-site.

[Mercury pollution and its ecosystem effects in Wanshan mercury miner area, Guizhou].

Samples of water, soil, plants, crops and animals collected from Wanshan mercury miner area, Guzhou Province, were analyzed with an AMA-254 liquid/solid mercury analyzer. It was shown that mercury pollution is mainly in soil and air; except water from a pool, no anomaly mercury is found in waters. Mercury content in soil is 24.31-347.52 mg.kg-1, two or three magnitude higher than the average value of Chinese soils; mercury content in plants is 0.47-331.4 mg.kg-1, and moss can enrich much mercury. Due to the long time of exploration and smelting, abundant mercury are accumulated in the local ecosystem, and healthy of local people are threatened seriously.