Breast cancer is the most prevalent cancer type among Canadian women. Breast cancers originate from the malignant transformation of mammary epithelial cells, which causes them to adopt an uncontrolled cell proliferation phenotype. My research suggests that the activity of specific ion channels (KV10.1, KCa3.1 and TRPM8) contribute to the proliferation of MCF-7 cells, a cell line commonly used to study breast cancer in vitro. Pharmacologically inhibiting the activities of KV10.1 or KCa3.1 channels decreased basal, but not estrogen-stimulated [3H]-thymidine incorporation, demonstrating that these channels contribute to MCF-7 cell proliferation. One way K+ channel activity is hypothesized to control cell proliferation is via regulation of membrane potential-dependent Ca2+ influx. Inhibition of KCa3.1 but not KV10.1 channel activity resulted in a membrane potential-dependent decrease in basal Ca2+ influx, suggesting that the way in which KCa3.1 channels contribute to cell proliferation is via regulating Ca2+ influx. In addition, my research also demonstrated that TRAM-34 increased or decreased cell proliferation depending on the concentration used and mitogenesis by TRAM-34 was blocked by estrogen receptor antagonists. TRAM-34 increased progesterone receptor mRNA expression, decreased estrogen receptor-alpha mRNA expression and reduced the binding of radiolabelled estrogen to estrogen receptor protein, in each case mimicking the effects of estrogen. Our finding that TRAM-34 is able to activate the estrogen receptor suggests a novel action of this supposedly specific K+ channel inhibitor and raises concerns of interpretation in its use. TRPM8 channels were also identified in MCF-7 cells, where they appeared to be important Ca2+ entry pathways. Inhibiting the activity of TRPM8 pharmacologically, as well as knocking down TRPM8 mRNA expression decreased cell proliferation, indicating that TRPM8 also contributed to MCF-7 cell proliferation. In conclusion, my research demonstrates that the activities of KV10.1, KCa3.1 and TRPM8 channels contribute to basal breast cancer cell proliferation. These findings suggest that the activity of specific ion channels may be potential targets for future therapeutic agents to treat breast cancer.

No description available.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

No description available.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24637号 / 工博第5143号 / 新制||工||1982(附属図書館) / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 森 泰生, 教授 浜地 格, 教授 跡見 晴幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Common behavioral trends and characteristics of alluvial channels including rivers are extensively discussed in the literature. However, little is known about the hydrodynamic effects of seepage on alluvial channels. Factors like sand bed resistance, stream power of the channel, incipient motion of bed particles, and geometry of the channel cross section are significantly affected by seepage. This thesis presents the experimental investigations that are aimed to find out the quantitative effect of seepage, through a sand bed in downward (suction) direction, on the above mentioned factors. The problem in the sediment transport analysis is that the knowledge of complex interaction of several parameters with seepage cannot be fully obtained. In order to generalize the results, experiments are conducted in four rectangular smooth walled sand bed flumes under steady and fairly uniform flow conditions. Among the four, one is the Large Tilting Flume (LTF), which is 25 m long, 1.80 m wide and 1.00 m deep and with a seepage length of up to 20 m. This LTF is specially built at hydraulic laboratory, Indian Institute of Science exclusively for the present research work especially on alluvial channel regime. The experimental channels are designed to apply controlled amounts of uniform seepage flow in either direction in one flume (Flume-2), and only in downward direction to other three flumes (Flumes 1, 3 and 4). The application of seepage is perpendicular to the sand bed thickness over a sufficient length of the main channel. Appropriate instruments are used to accurately measure the basic experimental variables such as discharge in the main channel, seepage discharge, flow depth, water surface and bed slope, seepage gradients and cross sectional profiles. Experiments are carried out at different conditions (plane beds and curved shape channels) as explained below: Plane sediment beds Series – 1: Experiments to determine incipient motion of bed particles under no-seepage condition. Series – 2: Experiments on the non-transporting condition of the bed particles under both no-seepage and seepage condition. Series – 3: Experiments on the transporting condition of the bed particles under both no-seepage and seepage condition. Curved shape channels Series – A: Experiments to verify Lane’s (1953) geometric profile against higher discharge than prescribed by Lane (1953). Series – B: Experiments to verify the Lane’s (1953) geometric profile by allowing the discharge prescribed by Lane (1953). Series – C: Experiments to predict the final geometric profile by applying suction to Series – B experiments. A wide range of sediment particles are tested. Five different sized uniform sands (d50 = 1 mm, 0.56 mm, 0.65 mm, 1.00 mm and 1.77 mm) and gravel of size d50 = 8.00 mm are used for experimentation. Among the six sizes, three sizes (d50 = 0.56 mm, 0.65 mm, 2 mm) are used for seepage experimentation. The experimental data from the present experiments along with the available data from other sources on more sizes of sand are analyzed, thus covering a wide range of sand sizes. The following important results are obtained from the analysis. A new resistance equation has been developed for plane sediment beds (with little or no-transport) such that the average velocity in the channel depends on the shear velocity Reynolds number. A careful study has been done on incipient motion and concluded that incipient motion is better explained by critical stream power criterion for plane sediment beds. With the help of critical stream power criterion, a straightforward design procedure using design tables/design curves and analytical methods are presented to solve six possible design problems. For plane and non-transporting beds, in general, the stream power in the channel increases with suction and decreases with injection. The increase and decrease depend on the seepage power intensity parameter (NP), initial value of stream power (Ωbo), and critical stream power of the particles under no-seepage condition (Ωco). An expression relating all the influencing parameters is established to quantitatively estimate the stream power (Ωbs) variation with both the types of seepages, i.e., with suction and injection. It is found that the seepage has a significant influence in changing critical stream power for incipient motion of the bed material and the value is significantly different from the no-seepage critical value. An expression is established to quantitatively estimate the critical stream power with seepage (upward and downward) for a given critical stream power (Ωco) of the bed material under no-seepage conditions and initial stream power (Ωbo). It has been established that critical stream power curve used to define incipient motion is valid only for no-seepage condition of the bed and it cannot be used for sand beds under seepage condition, as seepage effects significantly alters the stream power. From the wide range of experimental data (including the observations from LTF) it is found that suction (downward seepage through the sand bed) enhances the transport or aids the incipient motion of bed particles which are initially at rest. Thus, suction reduces the stability and increases the erosion of bed particles when compared to no-seepage conditions. However, it is found that injection (upward seepage) affects in an opposite way, i.e., it can reduce the transport rate or even inhibit the incipient motion. Thus, injection increases the stability and reduces the erosion of bed particles when compared to no-seepage conditions. Therefore, it is concluded that suction increases the mobility of sand particles where as injection decreases their mobility. An expression to find the incipient motion with seepage (both suction and injection) is established in terms of stream power’s (Ωco, Ωbo and Ωbs) based on the present experimental data along with others' data. With the help of these expressions design procedure is developed for ten types of possible problems. A numerical model for spatially varied flow has been developed with the help of the seepage governing equations, developed in this thesis, to compute flow profiles along the channel length. A methodology of predicting the location of incipient motion section in sand bed channels affected by seepage is also presented. Channel geometry affected by seepage (suction) is established in the form of regression relationships for perimeter, flow depth and slope of the channel. Different combinations (bi-variate and tri-variate) of dimensional and non-dimensional regression relationships are developed. An approach to channel design has been developed based on the application of functional analysis of the salient variables that control the channel behavior. And also, it has been established that, Lane’s (1953) profile almost matches with experimental profile for no-seepage condition. The present investigation clearly shows the significance of seepage in altering the hydraulic and sediment transport behavior of sand bed channels. From the practicing engineer’s point of view it is hoped that present design procedures will be helpful in safe guarding the seepage affected channels.

Thesis (Ph.D.)--University of South Florida, 2005. / Includes vita. Includes bibliographical references (leaves 128-144). Also available online.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Master of Arts / Department of Geography / Melinda Daniels / The US Army Corps of Engineers (USACE) has begun side channel restoration projects on the Missouri River as part of the Missouri River Recovery Program. The USACE acquires land on the Missouri River needed to develop fish and wildlife habitat. There is a need to prioritize which land to purchase on the Missouri River. High priority land would be areas that had side channels and can be constructed to restore ecosystems to a more natural state. Much of the river has since been dammed, straightened, and channelized starting heavily in the mid 1890’s, and historical side channels have been eliminated, leaving little information to guide USACE efforts to restore them. My thesis documents the historical distribution of side channels on the Missouri River between St. Louis and Kansas City and explores the relationships between side channel location and a variety of potential driving variables, including channel sinuosity, valley width, valley slope and the presence of large confluences. This is the first know study to document the historical extent of side channels on a major river system, and it is also the first to quantitatively explore driving variables of side channel formation. The historical analysis revealed abundant side channels in the late 1800’s, with a dramatic decline into the early 1920’s as engineering works on the river began in earnest. Results also show that high channel sinuosity and the presence of a large confluences are the two variables most correlated with side channel formation. Based on documented frequencies and locations of historical side channels, recommendations for specific side channel restoration opportunities are also highlighted.

Published Article / Magnesium is the second most abundant intracellular cation with many control and regulatory functions. It regulates energy production and utilization and modulates activity of membrane ionic channels. Magnesium has direct control effects on cardiac myocyte ion channels making it useful in certain arrhythmias. Calcium is responsible for pacemaker excitation and for excitation-contraction coupling in myocytes but increased intracellular calcium produces early and late afterdepolarisations initiating arrhythmias. Magnesium regulates calcium channel activity preventing raised intracellular levels. Potassium channel activity is enhanced by magnesium hyperpolarizing the cell reducing arrhythmia generation. Magnesium is effective against long QT Torsade de Pointes. In rapid atrial fibrillation magnesium produces rate control slowing AV nodal conduction. Magnesium prevents digitalis toxicity due to associated hypomagnesemia.