The Chesapeake Bay: A Study of Present and Furture Water Quality and Its Ecological Effects Volume I: Analysis and Projection of Water Quality

This study, prepared for the National Commission on Water Quality, is an analysis of the present and future water quality in the Chesapeake Bay from the Susquehanna River at Conowingo, Md. to the Atlantic Ocean. The objectives addressed in this volume of the study are 1.) Description of the present conditions of water quality and water quantity with respect to temperature, salinity, nutrients and dissolved oxygen. and 2.) Projection of future water quality conditions associated with the achievement of require ments and goals of the Federal Water Pollution Control Act Amendments of 1972, P.L. 92-500, 86 Stat. 816. The assessment of present and future biological and ecol ogical conditions is addressed in Volume II

Three Dimensional Hydrodynamic-Sedimentation Modeling Study : Hampton Roads Crossing, Lower James River, Virginia

A three-dimensional hydrodynamic-sedimentation computer model, HYSED-3D, was used to evaluate the effect of bridge-tunnel infrastructure for a proposed highway crossing of Hampton Roads on the physical characteristics (tides, currents, circulation, salinity, and sedimentation) of the James River estuary in Virginia. Model-represented infrastructure included tunnel islands and bridges on pilings connecting the islands to interstate highways in Newport News, Hampton, Norfolk, and Portsmouth, Virginia. Combinations of these elements occur in each of three proposed crossing routes designated Alternative 1 (Hampton-Norfolk), Alternative 2 (Hampton-Norfolk, Norfolk-Portsmouth), and Alternative 9 (Newport News-Portsmouth-Norfolk). Simulation comparisons were made between the existing waterways and infrastructure in Hampton Roads (Base Case) and the proposed construction in a series of model test runs representing both normal and extreme hydrologic conditions. Variations in tidal range were simulated using a three constituent tide model. Three levels of freshwater inflow into the headwaters of the James River were represented using historical stream gauge data. The simulation of sedimentation was designed based on the existence of a \u27turbidity maximum\u27 upstream from the area of concern

Evaluation of Cancer Stem Cell Migration Using Compartmentalizing Microfluidic Devices and Live Cell Imaging

In the last 40 years, the United States invested over 200 billion dollars on cancer research, resulting in only a 5% decrease in death rate. A major obstacle for improving patient outcomes is the poor understanding of mechanisms underlying cellular migration associated with aggressive cancer cell invasion, metastasis and therapeutic resistance1. Glioblastoma Multiforme (GBM), the most prevalent primary malignant adult brain tumor2, exemplifies this difficulty. Despite standard surgery, radiation and chemotherapies, patient median survival is only fifteen months, due to aggressive GBM infiltration into adjacent brain and rapid cancer recurrence2. The interactions of aberrant cell migratory mechanisms and the tumor microenvironment likely differentiate cancer from normal cells3. Therefore, improving therapeutic approaches for GBM require a better understanding of cancer cell migration mechanisms. Recent work suggests that a small subpopulation of cells within GBM, the brain tumor stem cell (BTSC), may be responsible for therapeutic resistance and recurrence. Mechanisms underlying BTSC migratory capacity are only starting to be characterized1,4

The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells

AbstractA recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a ⩾10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160μM; 22GSCs: IC50=44μM) compared to MGMT non-expressing (33GSCs: IC50=1.5μM; 114GSCs: IC50=5.2μM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50–500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74±2.9% and 38±3.2%, respectively; 22GSC: 61±11% and 38±2.6%, respectively; 33GSC: 56±9.5% and 60±7.1%, respectively; 114 GSC: 79±3.5% and 41±4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., ± MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications

Solar Neutrinos: Radiative Corrections in Neutrino-Electron Scattering Experiments

Radiative corrections to the electron recoil-energy spectra and to total cross sections are computed for neutrino-electron scattering by solar neutrinos. Radiative corrections change monotonically the electron recoil spectrum for incident \b8 neutrinos, with the relative probability of observing recoil electrons being reduced by about 4 \% at the highest electron energies. For $p-p$ and \be7 neutrinos, the recoil spectra are not affected significantly. Total cross sections for solar neutrino-electron scattering are reduced by about 2 \% compared to previously computed values. We also calculate the recoil spectra from $^{13}$N and $^{15}$O neutrinos including radiative corrections.Comment: 40 pages, uuencoded, Z-compress file

WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration

Background: The bumetanide (BMT)-sensitive Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) maintains cell volume homeostasis by increasing intracellular K+ and Cl- content via regulatory volume increase (RVI). Expression levels of NKCC1 positively correlate with the histological grade and severity of gliomas, the most common primary adult brain tumors, and up-regulated NKCC1 activity facilitates glioma cell migration and apoptotic resistance to the chemotherapeutic drug temozolomide (TMZ). However, the cellular mechanisms underlying NKCC1 functional up-regulation in glioma and in response to TMZ administration remain unknown. Methods: Expression of NKCC1 and its upstream kinases With-No-K (Lysine) kinase 1 (WNK1) and oxidative stress-responsive kinase-1 (OSR1) in different human glioma cell lines and glioma specimens were detected by western blotting and immunostaining. Live cell imaging and microchemotaxis assay were applied to record glioma cell movements under different treatment conditions. Fluorescence indicators were utilized to measure cell volume, intracellular K+ and Cl- content to reflect the activity of NKCC1 on ion transportation. Small interfering RNA (siRNA)-mediated knockdown of WNK1 or OSR1 was used to explore their roles in regulation of NKCC1 activity in glioma cells. Results of different treatment groups were compared by one-way ANOVA using the Bonferroni post-hoc test in the case of multiple comparisons. Results: We show that compared to human neural stem cells and astrocytes, human glioma cells exhibit robust increases in the activation and phosphorylation of NKCC1 and its two upstream regulatory kinases, WNK1 and OSR1. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content and RVI in glioma cells by abolishing NKCC1 regulatory phospho-activation. Unexpectedly, TMZ activates the WNK1/OSR1/NKCC1 signaling pathway and enhances glioma migration. Pharmacological inhibition of NKCC1 with its potent inhibitor BMT or siRNA knockdown of WNK1 or OSR1 significantly decreases glioma cell migration after TMZ treatment. Conclusion: Together, our data show a novel role for the WNK1/OSR1/NKCC1 pathway in basal and TMZ-induced glioma migration, and suggest that glioma treatment with TMZ might be improved by drugs that inhibit elements of the WNK1/OSR1/NKCC1 signaling pathway

Three Dimensional Hydrodynamic Modeling Study, Craney Island eastward expansion, lower James River and Elizabeth River, Virginia

The Craney Island Eastward Expansion Hydrodynamic Model Study was conducted in three phases: 1) model calibration and verification for the Elizabeth River, 2) model testing of four Craney Island expansion options using single variable runs (using a single variable, tidal range, for model input), 3) model testing of two expansion options using historical runs (using multiple variables in real time for model input). The expansion option designs were evaluated for both global and local hydrodynamic change through simulation comparisons with the Base Case condition