Hydrologic Modeling of the Fox River Watershed

published or submitted for publicationis peer reviewedOpe

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) to drive production of an intracellular photosensitiser, protoporphyrin IX (PpIX), is a promising cancer treatment. However, ALA-PDT is still suboptimal for thick or refractory tumours. Searching for new approaches, we tested a known inducer of cellular differentiation, methotrexate (MTX), in combination with ALA-PDT in LNCaP cells. Methotrexate alone promoted growth arrest, differentiation, and apoptosis. Methotrexate pretreatment (1 mg l−1, 72 h) followed by ALA (0.3 mM, 4 h) resulted in a three-fold increase in intracellular PpIX, by biochemical and confocal analyses. After exposure to 512 nm light, killing was significantly enhanced in MTX-preconditioned cells. The reverse order of treatments, ALA-PDT followed by MTX, yielded no enhancement. Methotrexate caused a similar relative increase in PpIX, whether cells were incubated with ALA, methyl-ALA, or hexyl-ALA, arguing against a major effect upon ALA transport. Searching for an effect among porphyrin synthetic enzymes, we found that coproporphyrinogen oxidase (CPO) was increased three-fold by MTX at the mRNA and protein levels. Transfection of LNCaP cells with a CPO-expressing vector stimulated the accumulation of PpIX. Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers

Characterisation of nanoparticles by means of high-resolution SEM/EDS in transmission mode

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Seismic Constraints on Helium Abundances from the TESS Southern CVZ

Poster for Cool Stars 21 Stellar helium abundances strongly determine their structure and evolution. However, since helium cannot be detected directly in the photospheres of cool stars, helium abundances are one of the most poorly-constrained inputs to stellar models. It is therefore typical to assume a relationship with the initial abundances of other heavy elements, typically of linear form described by a gradient ΔY/ΔZ. Attempts to determine from globular-cluster stellar populations and Galactic H-II regions have so far not yielded any consensus about empirically reasonable values of ΔY/ΔZ, or, for that matter, even whether such a linear relation is observationally justifiable. Separately, asteroseismology permits the inference of stellar helium abundances, either directly through acoustic-glitch measurements, or indirectly through the forward modelling of stellar oscillation mode frequencies. Using constraints on the initial helium abundance derived from ensemble asteroseismology and stellar forward modelling against individual mode frequencies of a collection of field stars in the TESS, Kepler, and K2 fields, we characterise the helium-metallicity relation of the brightest cool stars in the solar neighbourhood. We find a large spread of seismic initial helium abundances for any given metallicity, rather than a single well-defined linear enrichment law

Differentiation enhances aminolevulinic acid-dependent photodynamic treatment of LNCaP prostate cancer cells

Photodynamic therapy using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) may be applied to the treatment of neoplasms in a variety of organs. In order to enhance existing regimens of photodynamic therapy, we investigated the effects of adding differentiation therapy to photodynamic therapy in human prostate cancer cells in vitro. The objective of differentiation therapy per se is to reverse the lack of differentiation in cancer cells using pharmacological agents. The motivation for this study was to exploit the differentiation-dependent expression of some heme enzymes to enhance tumour cell toxicity of ALA-photodynamic therapy. A short course of differentiation therapy was applied to increase PpIX formation during subsequent ALA exposure. Using the synthetic androgen R1881, isomers of retinoic acid, and analogues of vitamin D for 3 to 4 days, exogenous ALA-dependent PpIX formation in LNCaP cells was increased, along with markers for growth arrest and for differentiation. As a consequence of higher PpIX levels, cytotoxic effects of visible light exposure were also enhanced. Short-term differentiation therapy increased not only the overall PpIX production but also reduced that fraction of cells that contained low PpIX levels as demonstrated by flow cytometry and fluorescence microscopy. This study suggests that it will be feasible to develop protocols combining short-term differentiation therapy with photodynamic therapy for enhanced photosensitisation

Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

BACKGROUND: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding. METHODS: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority). CONCLUSIONS: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.)

Cleavage Requirements for Activation of Factor V by Factor Xa

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65728/1/j.1432-1033.1997.00012.x.pd

Characteristics and Risk Factors of Cancer Associated Venous Thromboembolism

The objective of this study was to examine the differences in commonly associated characteristics and risk factors of venous thromboembolism (VTE) between patients with and without cancer in a VTE population