No description available.

No description available.

No description available.

No description available.

No description available.

<p>The cancer stem cell hypothesis claims that only a small subpopulation of cells within a tumor is responsible for tumor growth, recurrence after treatment and metastasis. These cells have been termed tumor-initiating cells or cancer stem cells and are functionally defined by their capacity to elicit the growth of tumors in immune-compromised animals that recapitulate the cellularity of the tumor from which they were isolated. Several reports demonstrate that tumor-initiating cells are resistant to most current treatments. Hence, novel therapies for breast cancer should be developed that specifically target these tumorigenic cells. The Notch signaling pathway is hyperactive in human breast cancer as well as in mouse mammary tumor-initiating cells. In this study, I have found that inhibitors of the pathway target breast tumor-initiating cells from various breast cancer subtypes and may provide a novel therapy for breast cancer. MRK-003, a gamma-secretase inhibitor that blocks Notch signaling, inhibited the self-renewal of breast tumor-initiating cells <em>in vitro</em> and reduced tumor growth in xenograft models. MRK-003 inhibited proliferation of tumor cells within xenografts and induced their apoptosis and differentiation towards the myoepithelial lineage. Expression of the Notch pathway antagonists led to similar outcome in human breast tumor cell lines. Notably, tumors in MRK-003 treated mice were devoid of tumor initiating cells, suggesting that inhibitors of Notch signaling may lead to durable cancer cures. These findings suggest that GSIs target breast tumor-initiating cells and may prove to be effective novel anti breast cancer drugs. <strong> </strong></p> <p><strong> </strong></p> / Doctor of Philosophy (PhD)

Among PWM power conversion topologies, the single-switch forward topology is the one that has been most widely used for decades. Its popularity has been based on many factors, including its low cost, circuit simplicity and high efficiency. However, several issues need to be addressed when using the forward converter such as the core reset, the voltage spikes caused by the transformer leakage inductance, and the pulsating input current waveform. The transformer is driven in a unidirectional fashion in the forward converter; a tertiary forward converter (TFC) is an example of this. Therefore, the third winding and reset diode must be provided with an adequate period of reset time so that the flux can be fully reset by the end of each switching cycle to prevent core saturation. Also, due to the utilization of a transformer, leakage inductances cannot be avoided. The energy stored in the leakage inductance during current ramp-up is not transferred to the load, and is not recovered during its discharge phase. As a result, the VDS waveform has a voltage spike and undesirable high-frequency oscillation. Therefore, a higher voltage-rating switch should be used to reduce the risk of high-voltage breakdown. Although a switch with amply high voltage ratings is available, it would tend to have a higher on-resistance, RDS(ON), resulting in increased conduction losses. Moreover, selection of a switch with higher voltage ratings than necessary may needlessly increase the cost of the design. Usually an additional circuit such as a snubber circuit or a clamp circuit or the soft-switching technique is used to absorb these voltage spikes. Consequently, the leakage inductance is intentionally minimized in the PWM power conversion technique so that it will not degrade the circuit performance. In contrast, the leakage inductance of the transformer may enhance rather than detract from circuit performance with a resonant power conversion technique. To date, however, no single-switch forward converter has been claimed to be able to enhance the converter performance with the PWM power conversion technique by utilizing the leakage inductance. Therefore, research on the utilization of the transformer leakage inductance in the PWM forward converter is needed. Two techniques, input current ripple reduction and an embedded filter, are proposed to enhance the performance of forward converter using the PWM technique. By inserting a capacitor between two primary windings of the TFC, an input current ripple reduction technique is proposed and a forward converter with ripple reduction (FRR) is presented in this research work. Because the voltage of the capacitor is clamped to input voltage, the capacitor becomes a second voltage source to share part of the load current. As a result, the input current ripple is reduced. Moreover, the capacitor voltage is clamped both at the static and dynamic states; thus the excessive voltage stress on the main switch S1 of the FAC during low-line to high-line step transient is eliminated. Furthermore, without an external LC filter, the EMI noise levels can be further reduced as a result of the embedded notch filter formed by the transformer leakage inductance and clamp capacitor if the notch frequency is designed to be the same as the switching frequency. With the help of the clamp capacitor, therefore, the leakage inductance can enhance rather than detract from the converter performance. The input current ripple can be reduced further by employing the proposed techniques. Two sets of the clamp capacitors and the leakage inductances are utilized, and the current ripple can even be cancelled if the condition is met. Consequently, the input current becomes a non-pulsating waveform and a forward converter with ripple cancellation (FRC) is presented. Moreover, without an external LC filter, the EMI noise levels can be further attenuated as a result of the embedded low-pass filter formed by the transformer leakage inductances and clamp capacitors. Again, the leakage inductance can enhance the converter performance just as the resonant converter does. In addition to providing the analysis and design procedure, this work verifies the performance of the presented converters, the FRR and the FRC, by the experimental results. By employing the proposed techniques, eight new topologies have been extended for different power conversion applications. Each member of the FRR and the FRC families is able to enhance the converter performance, in ways such as the elimination of the voltage spikes on the main switch without a snubber circuit and the improvement of the EMI performance with small filter components. Consequently, the cost can be reduced and the space of the converter can be saved. / Ph. D.

The primary objective of this study was to investigate the notch sensitivity of ARALL 2 and ARALL 3 laminates subjected to uniaxial tensile loading. An experimental program was designed to test notched 0° and 90° ARALL specimens with three different hole diameters, 0.125 in, 0.250 in, and 0.500 inches. Unnotched specimens were tested to determine the elastic properties, including the shear modulus of of the ARALL laminates. Comparison of ARALL 2 and ARALL 3 laminates has shown that ARALL 3 laminates exhibit higher strength than the corresponding ARALL 2 specimens. Based on the experimental observations, a failure mechanism has been proposed for notched ARALL laminates. The failure of 0° ARALL laminates is governed by fiber failure in the aramid/epoxy layer. Experimental results for the off-axis elastic properties are compared with the predictions from transformation equations. Finite element analysis of notched laminates was performed in order to gain a better understanding of the experimental results. A linear analysis was found to be unsuitable for predicting the complete response of ARALL laminates. A Successive Yielding Model was used for modelling the behavior of the ARALL laminates. Predictions of this Successive Yielding Model are in excellent agreement with experimental results. Finite element analysis was also used to study the end effects and for establishing the specimen geometry. / M.S.

Five angle-ply laminates ([0₄₈], [(±10)₁₂]_s, [(±20)₁₂]_s, [(±30)₁₂]_s, and [(±45)₁₂]_s with central circular holes were tested under uniaxial compressive loading. The results from these tests show that the [(±45)₁₂]_s laminate exhibited plastic deformation, with ultimate applied strains exceeding -1%. All other laminates failed in a brittle manner with ultimate strains of less than -0.5%. A three-dimensional finite element stress analysis was performed for the same laminates. A failure analysis based on the three-dimensional stress tensor polynomial predicted that failure will initiate at the intersection of the ply interface with hole edge for all laminates, and be due to a combination of the out-of-plane and in-plane shear stresses. Use of the state of stress directly on the hole edge in the prediction of laminate failure resulted in predictions of laminate ultimate strengths which were less than experimentally observed values by as much as a factor of ten. In addition, symmetry considerations for three-dimensional finite element modelling of composite laminates are discussed, and a two-dimensional finite element model based on shear-deformable plate theory is predicted. / M.S.

No / Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA–FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA-FFA is an excellent candidate for CRC chemoprevention in CAC.