BackgroundBevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol.Materials and MethodsWe have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. In both cases, three groups were compared in the experiments. The first group did not receive therapy, the second group received one 200 μg bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 μg bevacizumab every day (quasi-continuous therapy). Tumor volume measurement was performed by digital caliper and small animal MRI. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The effectiveness of bevacizumab administration was examined by statistical analysis.ResultsIn the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model.ConclusionOur results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration.

Heart rate (HR) measurements have been used to determine stress in livestock species since the beginning of the 1970s. However, according to the latest studies in veterinary and behaviour-physiological sciences, heart rate variability (HRV) proved to be more precise for studying the activity of the autonomic nervous system. In dairy cattle, HR and HRV indices have been used to detect stress caused by routine management practices, pain or milking. This review provides the significance of HR and HRV measurements in dairy cattle by summarising current knowledge and research results in this area. First, the biological background and the interrelation of the autonomic regulation of cardiovascular function, stress, HR and HRV are discussed. Equipment and methodological approaches developed to measure interbeat intervals and estimate HRV in dairy cattle are described. The methods of HRV analysis in time, frequency and non-linear domains are also explained in detail emphasising their physiological background. Finally, the most important scientific results and potential possibilities for future research are presented.Keywords: heart rate, heart rate variability, stress, welfare, dairy cattle ImplicationsHousing and milking technology, health status and way of handling of animals influence the well-being of animals in intensive dairy farming. Non-invasive methods of assessing stress include heart rate and heart rate variability measurements that involve the monitoring of the autonomic nervous function by digital, high frequency, 24 h multi-channel electrocardiographic recorders. As high-producing cattle breeds are very sensitive to environmental factors, monitoring and decreasing stress is of major importance in terms of both animal welfare and production. IntroductionIn intensive dairy farming, housing and milking systems are main factors in determining the welfare of animals, as adaptation to environmental changes can be challenging for high-producing breeds.Important aspects in the improvement of dairy cattle management systems in respect of animal welfare are the recognition and evaluation of stress. The stressfulness of the technological environment has been examined in many different contexts. Certain welfare studies proved that for intensively farmed cattle, the milking technology (Rushen et al., 2001;Wenzel et al., 2003), fear from given routine treatments (Holst, 1998) and pain (Broom, 1991;Mellor et al., 2000) mean such load that may cause stress (Dantzer and Mormède, 1983;von Borell, 2001) having a negative impact also on milk production (Rushen et al., 2001). Effects of technology and of social interactions can be described not only by classical descriptive behavioural observations (e.g. Milmann, 2013;Theurer et al., 2013), but with physiological measures as well (Hopster and Blokhuis, 1994;Rietmann et al., 2004). Most dairy cattle studies have focused on the stress reactions of animals expressed in neuroendocrine changes that are considered to be reliable indicators of stress and pain in livestock species (...

Most experimental studies on animal stress physiology have focused on acute stress, while chronic stress, which is also encountered in intensive dairy cattle farming–e.g. in case of lameness–, has received little attention. We investigated heart rate (HR) and heart rate variability (HRV) as indicators of the autonomic nervous system activity and fecal glucocorticoid concentrations as the indicator of the hypothalamic–pituitary–adrenal axis activity in lame (with locomotion scores 4 and 5; n = 51) and non-lame (with locomotion scores 1 and 2; n = 52) Holstein-Friesian cows. Data recorded during the periods of undisturbed lying–representing baseline cardiac activity–were involved in the analysis. Besides linear analysis methods of the cardiac inter-beat interval (time-domain geometric, frequency domain and Poincaré analyses) non-linear HRV parameters were also evaluated. With the exception of standard deviation 1 (SD1), all HRV indices were affected by lameness. Heart rate was lower in lame cows than in non-lame ones. Vagal tone parameters were higher in lame cows than in non-lame animals, while indices of the sympathovagal balance reflected on a decreased sympathetic activity in lame cows. All geometric and non-linear HRV measures were lower in lame cows compared to non-lame ones suggesting that chronic stress influenced linear and non-linear characteristics of cardiac function. Lameness had no effect on fecal glucocorticoid concentrations. Our results demonstrate that HRV analysis is a reliable method in the assessment of chronic stress, however, it requires further studies to fully understand the elevated parasympathetic and decreased sympathetic tone in lame animals.

Tumor growth models are important to create an engineering background for cancer treatment either by using the models for simulations and evaluation of treatment protocols or, if combined with control engineering, by designing treatment protocols. A well-defined tumor growth model must describe the physiological processes and the measurements as well. Growing tumors are composed of dead tumor cells (forming the necrotic part) and living, proliferating tumor cells (forming the proliferating part); when tumor volume is measured, these parts are measured together. Most of the known tumor growth models do not consider the modeling of the necrotic part. Starting from a minimal model of the tumor growth under bevacizumab treatment, the aim of the current research is to extend it incorporating the volume and dynamics of the necrotic part and the pharmacodynamics and mixed-order pharmacokinetics of the applied drug. The extended model is validated using measurements with mice as hosts, colon adenocarcinoma as tumor, and bevacizumab as the drug used for treatment. The results show that the extended model can describe the important physiological phenomena and shows a good fit to the average of the measurements.

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Abstract-Modeling the tumor growth under angiogenic inhibition is an important step towards designing tumor treatment therapies based on mathematical tools. Our goal is to create a model for tumor growth that describes the underlying physiological processes adequately while being as simple as possible. We propose a second-order model containing linear terms and one bilinear term modeling the dynamics of tumor volume and inhibitor level, and work out the parametric identification process for the model. The parametric identification of the model is done using measurements from experiments on C57Bl/6 mice with C38 colon adenocarcinoma treated with bevacizumab. The control group of the mice received one injection at the beginning of the experiment, these measurement data are used for parametric identification, while the case group of mice received injection at each day of the treatment, these measurements are used to validate the model. The validation showed that the proposed model is capable of describing the tumor growth dynamics.

Welfare aspects of obstetrical assistance were studied in multiparous Holstein-Friesian cows (n=176) with (1) unassisted calving in an individual pen (UCIP; n=42), (2) unassisted calving in a group pen (UCG; n=48), (3) assisted calving with appropriately timed obstetrical assistance (ACAP; n=50), and (4) assisted calving with inappropriately timed (premature) obstetrical assistance (ACIN; n=36). Duration of the stages of calving, the prevalence and the degree of dystocia, stillbirth ratio, newborn calf vitality, and the occurrence of postpartum health problems (i.e., retained placenta and vulvovaginal laceration) were recorded. The time from amniotic sac and hooves appearance to birth and the total duration of calving (from the onset of calving restlessness to delivery) were shorter for UCG cows than for any other groups. The overall incidence of dystocia was 31.3% in the calvings studied. The prevalence of dystocia was below 10% in cases of unassisted calvings. The proportion of severe dystocia was higher in ACIN cows than in ACAP cows (47.2 vs. 12.0%, respectively). The prevalence of stillbirths was the highest in ACIN calvings (22.2%), followed by ACAP, UCI, and UCG cows (8.0, 4.8, and 0.0%, respectively). The ACIN calves had lower vitality scores than calves born from ACAP, UCG, and UCIP dams immediately after delivery and 24h after birth. Although ACAP calves had lower vitality scores than UCG and UCIP calves at birth, a delayed recovery of vitality was mirrored by satisfactory vitality scores 24h after birth. Retained placenta and vulvovaginal laceration occurred more often with assisted dams (i.e., ACAP and ACIN animals) compared with UCIP cows with the highest prevalence in ACIN cows. In UCG cows, no injuries occurred in the vulva or vagina, and we noted only 4 cases of retained placenta (8.3%), proportions lower than in cows with unassisted calving in the maternity pen. Our results suggest that calving in a group might have benefits over calving in an individual pen in terms of calving ease, duration of the delivery process, and postpartum health of the dam vitality of her offspring. Premature obstetrical assistance leads to a high prevalence of dystocia, impairs postpartum health of the dam, and poses a potential risk to calf survival.

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