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Purpose: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models.Experimental Design: Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results.Results: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation.Conclusion: Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy. Clin Cancer Res; 16(22); 5469–80. ©2010 AACR.

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Supplementary Figure 4 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Figure 1 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Figure 3 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Table 1 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Table 2 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Figure 5 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

Supplementary Figure 6 from Atu027, a Liposomal Small Interfering RNA Formulation Targeting Protein Kinase N3, Inhibits Cancer Progression

We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788–98]

Voluntary wheel running (VWR) behaviour is a sensitive indicator of disturbed wellbeing and used for the assessment of individual experimental severity levels in laboratory mice. However, monitoring individual VWR performance usually requires single housing, which itself might have a negative effect on wellbeing. In consideration of the 3Rs principle, VWR behaviour was evaluated under group-housing conditions. To test the applicability for severity assessment, this readout was evaluated in a dextran sodium sulphate (DSS) induced colitis model. For continuous monitoring, an automated system with integrated radio-frequency identification technology was used, enabling detection of individual VWR. After a 14-day adaptation period mice demonstrated a stable running performance. Analysis during DSS treatment in combination with repeated facial vein phlebotomy and faecal sampling procedure resulted in significantly reduced VWR behaviour during the course of colitis and increased VWR during disease recovery. Mice submitted to phlebotomy and faecal sampling but no DSS treatment showed less reduced VWR but a longer-lasting recovery. Application of a cluster model discriminating individual severity levels based on VWR and body weight data revealed the highest severity level in most of the DSS-treated mice on day 7, but a considerable number of control mice also showed elevated severity levels due to sampling procedures alone. In summary, VWR sensitively indicated the course of DSS colitis severity and the impact of sample collection. Therefore, monitoring of VWR is a suitable method for the detection of disturbed wellbeing due to DSS colitis and sampling procedure in group-housed female laboratory mice. Federal Ministry of Economics and Energy, "Zentrales Innovationsprogramm Mittelstand (ZIM) Deutsche Forschungsgemeinschaft https://doi.org/https://dx.doi.org/10.13039/501100001659

In this article, we consider an optimization problem of expected utility maximization of continuous-time trading in a financial market. This trading is constrained by a benchmark for a utility-based shortfall risk measure. The market consists of one asset whose price process is modelled by a Geometric Brownian motion where the market parameters change at a random time. The information flow is modelled by initially and progressively enlarged filtrations which represent the knowledge about the price process, the Brownian motion and the random time. We solve the maximization problem and give the optimal terminal wealth depending on these different filtrations for general utility functions by using martingale representation results for the corresponding filtration.

This paper solves a utility maximization problem under utility-based shortfall risk constraint, by proposing an approach using Lagrange multiplier and convex duality. Under mild conditions on the asymptotic elasticity of the utility function and the loss function, we find an optimal wealth process for the constrained problem and characterize the bi-dual relation between the respective value functions of the constrained problem and its dual. This approach applies to both complete and incomplete markets. Moreover, the extension to more complicated cases is illustrated by solving the problem with a consumption process added. Finally, we give an example of utility and loss functions in the Black-Scholes market where the solutions have explicit forms., Comment: 25 pages, Optimization, 2016

Objectives In recent years, cochlear implants have been applied successfully for the treatment of unilateral hearing loss with quite surprising benefit. One reason for this successful treatment, including the relief from tinnitus, could be the normalization of spontaneous activity in the central auditory pathway because of the electrical stimulation. The present study, therefore, investigated at a cellular level, the effect of a unilateral chronic intracochlear stimulation on key structures of the central auditory pathway. Design Normal-hearing guinea pigs were mechanically single-sided deafened through a standard HiFocus1j electrode array (on a HiRes 90k cochlear implant) being inserted into the first turn of the cochlea. Four to five electrode contacts could be used for the stimulation. Six weeks after surgery, the speech processor (Auria) was fitted, based on tNRI values and mounted on the animal's back. The two experimental groups were stimulated 16 hours per day for 90 days, using a HiRes strategy based on different stimulation rates (low rate (275 pps/ch), high rate (5000 pps/ch)). The results were compared with those of unilateral deafened controls (implanted but not stimulated), as well as between the treatment groups. All animals experienced a standardized free field auditory environment. Results The low-rate group showed a significantly lower average spontaneous activity bilaterally in the dorsal cochlear nucleus and the medial geniculate body than the controls. However, there was no difference in the inferior colliculus and the primary auditory cortex. Spontaneous activity of the high-rate group was also reduced bilaterally in the dorsal cochlear nucleus and in the primary auditory cortex. No differences could be observed between the high-rate group and the controls in the contra-lateral inferior colliculus and medial geniculate body. The high-rate group showed bilaterally a higher activity in the CN and the MGB compared with the low-rate group, whereas in the IC and in the AC a trend for an opposite effect could be determined. Conclusions Unilateral intracochlear electrical stimulation seems to facilitate the homeostasis of the network activity, since it decreases the spontaneous activity that is usually elevated upon deafferentiation. The electrical stimulation per se seems to be responsible for the bilateral changes described above, rather than the particular nature of the electrical stimulation (e.g., rate). The normalization effects of electrical stimulation found in the present study are of particular importance in cochlear implant recipients with single-sided deafness.

Thrombotic microangiopathy (TMA) is a rare but increasingly recognized complication of interferon-beta therapy, which can be associated with serious sequelae. We report on a 53-year-old woman with a longstanding history of relapsing-remitting multiple sclerosis, who developed TMA after 15 years of high-dose treatment with subcutaneous interferon-beta-1a. The patient presented with headaches, an epileptic seizure, confusion, and arterial hypertension. Laboratory findings included thrombocytopenia and hemolytic anemia. Despite of severe clinical manifestations and pronounced laboratory abnormalities, therapy with corticosteroids, plasma exchange and rituximab was associated with a favorable outcome and return to her premorbid level of functioning.

In birds, during prenatal 'critical periods' the thermoregulatory system can be life-long imprinted by the actual incubation temperature. The aim of the present study is to elucidate long-term effects of prenatal temperature experiences, applied at the end of incubation, on central thermoregulatory mechanisms by detection of neuronal hypothalamic c-Fos expression as a consequence of acute heat stress in growing and adult chickens using immunohistochemistry. From day 18 of incubation chicken embryos were incubated in three temperature groups: 37.5°C (regular incubated), 34.5°C (cold incubated) or 38.5°C (warm incubated). C-Fos expression was detected in 29 4-weeks old and 61 8-weeks old chickens after acute heat stress (42°C for 90 min). The results show, that prenatal temperature experiences can induce long-lasting changes in the heat induced neuronal hypothalamic c-Fos expression. But significant alterations could be only found in 8 weeks old chickens and these changes were in opposite as expected. It means that after acute heat stress cold incubated chickens have a significantly lower neuronal c-Fos expression compared with the warm incubated ones. This effect could be caused by cross adaptation to the actual ambient temperature during the growing period. Further, the developmental pattern of the hypothalamic neuronal network in different incubated birds, which is demonstrated by neuronal c-Fos expression in the actual study, is similar to the pattern, which we found after recordings of single neurons activity, to a higher extent. Correlations between both parameters, which are involved in neuronal plasticity, can be accepted.

We have previously described a small interfering RNA (siRNA) delivery system (AtuPLEX) for RNA interference (RNAi) in the vasculature of mice. Here we report preclinical data for Atu027, a siRNA-lipoplex directed against protein kinase N3 (PKN3), currently under development for the treatment of advanced solid cancer. In vitro studies revealed that Atu027-mediated inhibition of PKN3 function in primary endothelial cells impaired tube formation on extracellular matrix and cell migration, but is not essential for proliferation. Systemic administration of Atu027 by repeated bolus injections or infusions in mice, rats, and nonhuman primates results in specific, RNAi-mediated silencing of PKN3 expression. We show the efficacy of Atu027 in orthotopic mouse models for prostate and pancreatic cancers with significant inhibition of tumor growth and lymph node metastasis formation. The tumor vasculature of Atu027-treated animals showed a specific reduction in lymph vessel density but no significant changes in microvascular density. [Cancer Res 2008;68(23):9788–98]

Two marsupial species ( Monodelphis domestica, Macropus eugenii ) and four eutherian species (Mesocricetus auratus, Suncus murinus, Tupaia belangeri and Cavia aperea ) were examined to compare and contrast the timing of lung and metabolic development during the postnatal maturation of the mammalian respiratory apparatus. Using light, scanning and transmission electron microscopy, the lung structural changes were correlated with indirect calorimetry to track the metabolic development. Marsupial and eutherian species followed the same pattern of mammalian lung development, but differed in the developmental pace. In the two newborn marsupial species, the lung parenchyma was at the early terminal sac stage, with large terminal air sacs, and the lung developed slowly. In contrast, the newborn eutherian species had more advanced lungs at the late terminal sac stage in altricial species ( M. auratus, S. murinus ) and at the alveolar stage in precocial species ( T. belangeri, C. aperea ). Postnatal lung development proceeded rapidly in eutherian species. The marsupial species had a low metabolic rate at birth and achieved adult metabolism late in postnatal development. In contrast, newborn eutherian species had high metabolic rates and reached adult metabolism during the first week of life. The time course of the metabolic development is thus tightly linked to the structural differentiation of the lungs and the timing of postnatal lung development. These differences in the neonatal lung structure and the timing of postnatal lung maturation between marsupial and eutherian species reflect their differing reproductive strategies.

Oxygen consumption, heat production (HP) and core temperature ( T af ) were measured over 3 h in 20–34-day-old Muscovy duck and 12–21-day-old chicken embryos at ambient temperature ( T a ) of 37.5 °C and thereafter for 3 h at T a of 39.0 °C. At 37.5 °C T a , HP increased with age in avian embryos of both species, following an exponential function. In muscovy duck embryos, a plateau phase occurred between D29 and D32; in chicken embryos, a similar plateau occurred between D19 and D21. T af rose in accordance with HP, and the relationships between T af and HP could be described by significant linear regressions in both species. Mostly, HP increased in embryos of both species during heat load, but by less than calculated by the van't Hoff rule; however, there was often also a decrease in HP under these conditions. Obviously, in avian embryos high T a causes a down-regulation of HP mediated by active thermoregulatory mechanisms. This is in agreement with data describing the influence of hyperthermia on HP in the postnatal period of birds and mammals. Because of this, the term ‘second chemical thermoregulation’ defined by Gelineo [C. R. Soc. Biol. (1936) 122 337] for birds and mammals should also be used for avian embryos.

Eggs of Muscovy duck and domestic fowl were incubated at 37.5°C and relative air humidity of 70%. After 60 min the influence of lowered (31.5°C, 34.5°C and 28.5°C) T a on heat production (HP) and temperature of the allantoic fluid (T af ) as a measure of core temperature was estimated for 3 h. The Q 10 was calculated using the relationships between T af and HP. HP dropped with decreasing T af . The Q 10 crossed the 2.0 threshold mostly between 34°C and 36°C T af in dependence of T a . Precocial birds are endothermic in the last third of incubation but these reactions have only an ultimate but not a proximate influence on efficiency of thermoregulation.

1. Incubated chicken eggs (D14 to D21) were placed separately in transparent acrylic glass chambers which were immersed in a 37.5°C water bath for 3 h. The chambers were then moved for 3 h to another water bath controlled at 34.5°C. Oxygen consumption and temperature of the allantoic fluid (Taf) were measured at 5-min intervals for the whole experiment using an oxygen analyzer and CrNi–Ni-thermocouples, respectively. Heat production (HP) was calculated, using an assumed RQ of 0.72. 2. At 37.5°C the relationship between HP and embryonic age follows a sigmoid curve. Between D18 (HP 7.25 J g−1 h; 2.01 W kg−1) and D19 (HP 7.21 J g−1 h−1; 2.00 W kg−1) this function had a plateau phase with a duration of about 24 h. 3. During the cooling process, HP decreased continuously and the relationship between Ta and HP could be described by an exponential function. From the results, it was possible to calculate the relationships between Taf, as a measure of body core temperature, and Q10; the lower the Taf the higher the Q10. 4. Because the actual measured HP is the result of the negative effect of Q10 on HP and the stimulating influence of the CNS-generated HP, a Q10 of more than 2.0 demonstrates the absence of endothermy. Chicken embryos aged between 14 and 21 d have a Q10 of less than 2.0 at body temperatures (Taf) between 34 and 30°C. It is postulated that in chicken embryos of this age endothermic reactions may occur. 5. The Q10-method is suitable for investigating the prenatal development of endothermic reactions in avian embryos.

With their increasing number, it is getting important that decentralized and renewable energy sources are supporting the stabilization of the system voltage after short voltage dropouts. Often, in the past, these generators were disconnected during network faults. This is not adequate anymore, as it would lead to a loss of a considerable amount of feed-in power. However, if the generators stay connected, it must be ensured that they are not receiving reactive power, as this would lead to a collapse of the grid.

Purpose: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models. Experimental Design: Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results. Results: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation. Conclusion: Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy. Clin Cancer Res; 16(22); 5469–80. ©2010 AACR.