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Defne, Z.; Spitz, F.J.; DePaul, V., and Wool, T.A., 2017. Toward a comprehensive water-quality modeling of Barnegat Bay: Development of ROMS to WASP coupler. In: Buchanan, G.A.; Belton, T.J., and Paudel, B. (eds.), A Comprehensive Assessment of Barnegat Bay-Little Egg Harbor, New Jersey. The Regional Ocean Modeling System (ROMS) has been coupled with the Water Quality Analysis Simulation Program (WASP) to be used in a comprehensive analysis of water quality in Barnegat Bay, New Jersey. The coupler can spatially aggregate hydrodynamic information in ROMS cells into larger WASP segments. It can also be used to resample ROMS output at a finer temporal scale to meet WASP time-stepping requirements. The coupler aggregates flow components, temperature, and salinity in ROMS output for input to WASP via a hydrodynamic linkage file. The coupler was tested initially with idealized cases designed to verify the water mass balance and conservation of constituent mass using one-to-one and one-to-many connectivity options between segments. A realistic example from the Toms River embayment, a subdomain of Barnegat Bay, was used to demonstrate the functionality of the coupling. A WASP eutrophication model accounting for dissolved oxygen (DO), nitrogen, and constant phytoplankton concentrations was applied to explore the distribution and trends in DO and nitrogen in the embayment for the period of July–August 2012. Results of DO modeling indicate satisfactory agreement with measurements collected at in-bay stations and also indicate that this coupled approach, despite substantial differences in spatiotemporal discretization between the models, provides adequate predictive capabilities.

This paper discusses a method for overcoming the problem of weak sinks representing wells that result from spatial discretization effects when using MODPATH, the particle‐tracking postprocessor for the ground water low model MODFLQW. Weak sink cells are model cells that represent a well that does not discharge at a sufficiently large rate to capture all of the flow entering the cell; therefore, flowpaths within these cells cannot be uniquely defined because it is impossible to know whether a given water particle discharges to the well or passes through the cell. Creating a submodel of the well cell by using the nested rediscretization method can eliminate this ambiguity by converting the weak sink cell into a strong sink cell. The method is designed to be run manually for each well and for steady‐state conditions. Other advantages, disadvantages, technical considerations, and limitations of the method are presented. Software created for the method consists of five Fortran programs that are operated using a set of instructions. A practical application of the method is presented by using an example wellhead‐protection problem that demonstrates that nested rediscretization can provide more accurate particle‐tracking results than those obtained by using a coarsely discretized model alone.

α-Tocopheryl succinate (α-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of α-TOS has not been identified. Here, we show that α-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q P and Q D , respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of α-TOS compared to that of UbQ for the Q P and Q D sites, respectively. CybL -mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of α-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL -mutant cells susceptible to α-TOS. We propose that α-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

Gastric adenocarcinoma most often presents at an advanced stage and overall five-year survival of ∼30%. Pharmacological ascorbate (high-dose IV ascorbate) has been proposed as a promising nontoxic adjuvant to standard radio-chemotherapies in several cancer types. In the current study, pharmacological ascorbate (0.5–2 mM) caused a dose-dependent decrease (70–85% at 2 mM) in clonogenic survival of gastric adenocarcinoma cells (AGS and MNK-45), but was relatively nontoxic to a small intestinal epithelial nonimmortalized human cell isolate (FHs 74 Int). The addition of pharmacological ascorbate (1 mM) to standard radio-chemotherapies [i.e., 5-FU (5 μM); cisplatin (0.5 μM); irinotecan (2.5 μM); carboplatin (5 μM); paclitaxel (2–4 nM); and X rays (1.8 Gy)] also potentiated gastric cancer clonogenic cell killing [additional decreases were noted with: ascorbate plus 5-FU/radiation (1%); ascorbate plus cisplatin/irinotecan (9–19%); and ascorbate plus paclitaxel/carboplatin (6–7%)]. The gastric cancer cell toxicity and chemosensitization seen with pharmacological ascorbate was dependent on H2O2 and the presence of catalytic metal ions. In addition, pharmacological ascorbate dosing resulted in a concentration-dependent decrease (64% at 20 mM, P ≤ 0.0001) in cancer cell invasion and migration that was inhibited by catalase. Finally, pharmacological ascorbate significantly increased the overall survival of mice with gastric cancer xenografts when used in combination with paclitaxel, carboplatin and radiation (P = 0.019). These results demonstrate that pharmacological ascorbate is selectively cytotoxic to gastric adenocarcinoma cells (relative to normal intestinal epithelial cells) by a mechanism involving H2O2 and redox active metal ions. Furthermore, pharmacological ascorbate significantly enhances gastric cancer xenograft responses to radio-chemotherapy as well as inhibiting tumor cell migration and invasiveness. Overall, these results support the hypothesis that pharmacological ascorbate can be used as an adjuvant with standard-of-care radio-chemotherapies for the treatment of gastric adenocarcinomas.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O 2 availability by mediating crucial homeostatic processes. HIF-1 is composed of an HIF-1 α subunit and an HIF-1 β subunit. HIF-1 α is degraded following enzyme-dependent hydroxylation of prolines of HIF-1 α in the presence of molecular oxygen, Fe 2+ , α -ketoglutarate, and ascorbate. These cofactors contribute to the redox environment of cells. The antioxidant enzyme manganese superoxide dismutase (MnSOD) also modulates the cellular redox environment. Here we show that MnSOD suppressed hypoxic accumulation of HIF-1 α protein in human breast carcinoma MCF-7 cells. This suppression was biphasic depending on MnSOD activity. At low levels of MnSOD activity, HIF-1 α protein accumulated under hypoxic conditions. At moderate levels of MnSOD activity (two- to six-fold increase compared to parent cells), these accumulations were blocked. However, at higher levels of MnSOD activity (>6-fold increase), accumulation of HIF-1 α protein was again observed. This biphasic modulation was observed under both 1 and 4% O 2 . Coexpression of mitochondrial hydrogen peroxide-removing proteins prevented the accumulation of HIF-1 α protein in cells with high levels of MnSOD; this effect demonstrates that the restabilization of HIF-1 α observed in high MnSOD overexpressors is probably due to hydrogen peroxide, most likely produced from MnSOD. Hypoxic induction of vascular endothelial growth factor (VEGF) protein was also suppressed by elevated MnSOD activity and its levels reflected HIF-1 α protein levels. These observations demonstrated that HIF-1 α accumulation and VEGF expression could be modulated by the antioxidant enzyme MnSOD.

Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of 137Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of 137Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3–/–/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice.

It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O2 metabolism lead to persistent heritable increases in steady-state levels of intracellular superoxide (O2•U+2212) and hydrogen peroxide (H2O2) that contribute to the biological effects of radiation. Hamster fibroblasts (B9 cells) expressing a mutation in the gene coding for the mitochondrial electron transport chain protein succinate dehydrogenase subunit C (SDHC) demonstrate increases in steady-state levels of O2•− and H2O2. When B9 cells were exposed to low-dose/low-LET radiation (5–50 cGy), they displayed significantly increased clonogenic cell killing compared with parental cells. Clones derived from B9 cells overexpressing a wild-type human SDHC (T4, T8) demonstrated significantly increased surviving fractions after exposure to 5–50 cGy relative to B9 vector controls. In addition, pretreatment with polyethylene glycol-conjugated CuZn superoxide dismutase and catalase as well as adenoviral-mediated overexpression of MnSOD and/or mitochondria-targeted catalase resulted in significantly increased survival of B9 cells exposed to 10 cGy ionizing radiation relative to vector controls. Adenoviral-mediated overexpression of either MnSOD or mitochondria-targeted catalase alone was equally as effective as when both were combined. These results show that mammalian cells over expressing mutations in SDHC demonstrate low-dose/low-LET radiation sensitization that is mediated by increased levels of O2•− and H2O2. These results also support the hypothesis that mitochondrial O2•− and H2O2 originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O2 availability by mediating crucial homeostatic processes. HIF-1 is composed of an HIF-1alpha subunit and an HIF-1beta subunit. HIF-1alpha is degraded following enzyme-dependent hydroxylation of prolines of HIF-1alpha in the presence of molecular oxygen, Fe2+, alpha-ketoglutarate, and ascorbate. These cofactors contribute to the redox environment of cells. The antioxidant enzyme manganese superoxide dismutase (MnSOD) also modulates the cellular redox environment. Here we show that MnSOD suppressed hypoxic accumulation of HIF-1alpha protein in human breast carcinoma MCF-7 cells. This suppression was biphasic depending on MnSOD activity. At low levels of MnSOD activity, HIF-1alpha protein accumulated under hypoxic conditions. At moderate levels of MnSOD activity (two- to six-fold increase compared to parent cells), these accumulations were blocked. However, at higher levels of MnSOD activity (>6-fold increase), accumulation of HIF-1alpha protein was again observed. This biphasic modulation was observed under both 1 and 4% O2. Coexpression of mitochondrial hydrogen peroxide-removing proteins prevented the accumulation of HIF-1alpha protein in cells with high levels of MnSOD; this effect demonstrates that the restabilization of HIF-1alpha observed in high MnSOD overexpressors is probably due to hydrogen peroxide, most likely produced from MnSOD. Hypoxic induction of vascular endothelial growth factor (VEGF) protein was also suppressed by elevated MnSOD activity and its levels reflected HIF-1alpha protein levels. These observations demonstrated that HIF-1alpha accumulation and VEGF expression could be modulated by the antioxidant enzyme MnSOD.

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O2 availability by mediating crucial homeostatic processes. HIF-1 is composed of an HIF-1alpha subunit and an HIF-1beta subunit. HIF-1alpha is degraded following enzyme-dependent hydroxylation of prolines of HIF-1alpha in the presence of molecular oxygen, Fe2+, alpha-ketoglutarate, and ascorbate. These cofactors contribute to the redox environment of cells. The antioxidant enzyme manganese superoxide dismutase (MnSOD) also modulates the cellular redox environment. Here we show that MnSOD suppressed hypoxic accumulation of HIF-1alpha protein in human breast carcinoma MCF-7 cells. This suppression was biphasic depending on MnSOD activity. At low levels of MnSOD activity, HIF-1alpha protein accumulated under hypoxic conditions. At moderate levels of MnSOD activity (two- to six-fold increase compared to parent cells), these accumulations were blocked. However, at higher levels of MnSOD activity (>6-fold increase), accumulation of HIF-1alpha protein was again observed. This biphasic modulation was observed under both 1 and 4% O2. Coexpression of mitochondrial hydrogen peroxide-removing proteins prevented the accumulation of HIF-1alpha protein in cells with high levels of MnSOD; this effect demonstrates that the restabilization of HIF-1alpha observed in high MnSOD overexpressors is probably due to hydrogen peroxide, most likely produced from MnSOD. Hypoxic induction of vascular endothelial growth factor (VEGF) protein was also suppressed by elevated MnSOD activity and its levels reflected HIF-1alpha protein levels. These observations demonstrated that HIF-1alpha accumulation and VEGF expression could be modulated by the antioxidant enzyme MnSOD.