Immunotherapy of melanoma : toward clinical application

This thesis describes different immunotherapeutic strategies that can be used for the treatment of cancer in general, and of melanoma in particular. Tumor-specific T cell responses can be induced via either active or passive immunization. Active immunization can be used to target tumors for which high affinity T cells are present within the endogenous repertoire. This thesis describes a vaccination method where a tattoo device is used to deliver a DNA vaccine into the skin. The vaccine-induced anti-tumor effect can be further enhanced by combining vaccination with host conditioning and adoptive transfer. Passive immunization via TCR gene transfer is the preferred strategy when targeting tumor self antigens, because this can circumvent limitations of the endogenous T cell repertoire and does not require extensive in vitro culture. This thesis describes several factors that can improve the anti-tumor ac tivity of TCR modified cells. In addition, we describe a procedure for the selection of a human TCR that is well expressed and highly affine, and that is therefore likely to enable more efficient targeting of human melanoma. Implementation of these factors in the design of clinical trials is likely to positively affect the clinical efficacy of TCR gene therapy.UBL - phd migration 201

Effect of voluntary waiting period on metabolism of dairy cows during different phases of the lactation.

An extended calving interval (CInt) by extending the voluntary waiting period (VWP) could be associated with altered metabolism in dairy cows. The aim of this study was first to evaluate the effects of VWP on metabolism and body condition during the first 305 days after the first calving in the experiment (calving 1), around the end of the VWP, and during pregnancy (280 d before calving 2). Second, the effects of the VWP on metabolism were determined from 2 wk before until 6 wk after calving 2. Third, individual cow characteristics were used to predict milk production and body condition of cows after different VWP. Holstein-Friesian cows (N=154, 41 primiparous (PP), 113 multiparous (MP)) were blocked for parity, milk production, and lactation persistency, randomly assigned to a VWP of 50, 125, or 200 days (VWP50, VWP125, or VWP200) and followed from calving 1 until 6 wk after calving 2. In the first 6 wk after calving 1 and from 2 wk before until 6 wk after calving 2, weekly plasma samples were analyzed for non-esterified fatty acids (NEFA), β-hydroxybutyrate, glucose, insulin, and insulin-like growth factor 1 (IGF-1). From wk 7 after calving 1 until 2 wk before calving 2, insulin and IGF-1 were analyzed every 2 wk. Fat- and protein-corrected milk (FPCM) and body weight (BW) gain were measured weekly. Cows were divided in two parity classes based on calving 1 (PP and MP) and remained in these classes after calving 2. During pregnancy, MP cows in VWP200 had greater plasma insulin and IGF-1 concentration and lower FPCM compared with MP cows in VWP125 (insulin: 18.5 vs 13.9 µU/mL, CI 13.0 - 19.7, P<0.01; IGF-1: 198.5 vs 175.3 ng/mL ± 5.3, P=0.04; FPCM: 22.6 vs 30.0 kg/d ± 0.8, P<0.01) or VWP50 (insulin: 15.8 µU/mL, P<0.01; IGF-1: 178.2 ng/mL, P<0.01; FPCM: 26.6 kg/d, P<0.01) and had a greater daily BW gain compared with cows in VWP50 (3.6 vs 2.5 kg/d ± 0.2; P<0.01). After calving 2, MP cows in VWP200 had greater plasma NEFA concentration (0.41 mmol/L) compared with MP cows in VWP125 (0.30 mmol/L, P=0.04) or VWP50 (0.26 mmol/L, P<0.01). For PP cows, the VWP did not affect FPCM or body condition during the first lactation in the experiment, or metabolism after calving 2. Independent of the VWP, higher milk production and lower body condition before insemination were associated with higher milk production and lower body condition at the end of the lactation. Variation in these characteristics among cows could call for an individual approach for an extended VWP

Coarsening Dynamics of Crystalline Thin Films

The formation of pyramid-like structures in thin-film growth on substrates with a quadratic symmetry, e.g., {001} surfaces, is shown to exhibit anisotropic scaling as there exist two length scales with different time dependences. Analytical and numerical results indicate that for most realizations coarsening of mounds is described by an exponent n=0.2357. However, depending on material parameters, n may lie between 0 (logarithmic coarsening) and 1/3. In contrast, growth on substrates with triangular symmetries ({111} surfaces) is dominated by a single length scale and an exponent n=1/3.Comment: RevTeX, 4 pages, 3 figure

Исследование свободных колебаний ортотропных цилиндрических оболочек на основе различных моделей

Досліджуються вільні коливання ортотропних циліндричних оболонок при різних граничних умовах на краях в уточненій постановці з застосуванням теорії Міндліна–Тимошенка та на основі тривимірної теорії пружності. Для розрахунку частот використовується чисельно-аналітичний підхід, який базується на застосуванні сплайн-апроксимації, а також методу колокації, дискретної ортогоналізації разом з методом покрокового пошуку. Проведено порівняння частот циліндричних оболонок з різними граничними умовами на торцях, отриманих в рамках різних моделей.A problem of natural vibrations of orthotropic cylindrical shells under various boundary conditions of its end-faces within the framework of the Mindlin–Timoshenko theory and on the basis of 3-D elasticity theory is considered. Using the method of spline-approximation and collocation, the problems are solved by the steady-state numerical method of discrete orthogonalization with incremental search. The comparison of the frequencies of cylindrical shells with different boundary conditions on their ends within various models is performed