Dynamics of Tumor Hypoxia in Response to Patupilone and Ionizing Radiation

Tumor hypoxia is one of the most important parameters that determines treatment sensitivity and is mainly due to insufficient tumor angiogenesis. However, the local oxygen concentration in a tumor can also be shifted in response to different treatment modalities such as cytotoxic agents or ionizing radiation. Thus, combined treatment modalities including microtubule stabilizing agents could create an additional challenge for an effective treatment response due to treatment-induced shifts in tumor oxygenation. Tumor hypoxia was probed over a prolonged observation period in response to treatment with different cytotoxic agents, using a non-invasive bioluminescent ODD-Luc reporter system, in which part of the oxygen-dependent degradation (ODD) domain of HIF-1α is fused to luciferase. As demonstrated in vitro, this system not only detects hypoxia at an ambient oxygen concentration of 1% O₂, but also discriminates low oxygen concentrations in the range from 0.2 to 1% O₂. Treatment of A549 lung adenocarcinoma-derived tumor xenografts with the microtubule stabilizing agent patupilone resulted in a prolonged increase in tumor hypoxia, which could be used as marker for its antitumoral treatment response, while irradiation did not induce detectable changes in tumor hypoxia. Furthermore, despite patupilone-induced hypoxia, the potency of ionizing radiation (IR) was not reduced as part of a concomitant or adjuvant combined treatment modality.     

NOS Inhibition Enhances Myogenic Tone by Increasing Rho-Kinase Mediated Ca2+ Sensitivity in the Male but Not the Female Gerbil Spiral Modiolar Artery

Cochlear blood flow regulation is important to prevent hearing loss caused by ischemia and oxidative stress. Cochlear blood supply is provided by the spiral modiolar artery (SMA). The myogenic tone of the SMA is enhanced by the nitric oxide synthase (NOS) blocker L-N^G-Nitro-Arginine (LNNA) in males, but not in females. Here, we investigated whether this gender difference is based on differences in the cytosolic Ca²⁺ concentration and/or the Ca²⁺ sensitivity of the myofilaments. Vascular diameter, myogenic tone, cytosolic Ca²⁺, and Ca²⁺ sensitivity were evaluated in pressurized SMA segments isolated from male and female gerbils using laser-scanning microscopy and microfluorometry. The gender difference of the LNNA-induced tone was compared, in the same vessel segments, to tone induced by 150 mM K⁺ and endothelin-1, neither of which showed an apparent gender-difference. Interestingly, LNNA-induced tone in male SMAs was observed in protocols that included changes in intramural pressure, but not when the intramural pressure was held constant. LNNA in male SMAs did not increase the global Ca²⁺ concentration in smooth muscle cells but increased the Ca²⁺ sensitivity. This increase in the Ca²⁺ sensitivity was abolished in the presence of the guanylyl cyclase inhibitor ODQ or by extrinsic application of either the nitric oxide (NO)-donor DEA-NONOate or the cGMP analog 8-pCPT-cGMP. The rho-kinase blocker Y27632 decreased the basal Ca²⁺ sensitivity and abolished the LNNA-induced increase in Ca²⁺ sensitivity in male SMAs. Neither LNNA nor Y27632 changed the Ca²⁺ sensitivity in female SMAs. The data suggest that the gender difference in LNNA-induced tone is based on a gender difference in the regulation of rho-kinase mediated Ca²⁺ sensitivity. Rho-kinase and NO thus emerge as critical factors in the regulation of cochlear blood flow. The larger role of NO-dependent mechanisms in male SMAs predicts greater restrictions on cochlear blood flow under conditions of impaired endothelial cell function.     

Growth factors and gangliosides: A possible new perspective in neuronal growth control

For many permanent cell lines the transition from a growing (P) to a resting (R) state is reversibly controlled by growth factors present in serum. This P-to-R transition was studied in a neuronal cell line (B 104) with respect to the action of serum, dibutyryl cyclic AMP (DBcAMP), gangliosides, and a glioma cell-produced growth factor GGF. In this cell system gangliosides seem to act as differentiation and survival factors. The kinetics of uptake of radioactively labeled gangliosides and survival experiments both support the idea of the stable incorporation of exogenously added gangliosides into the cells. Based on the experimental evidence a new model of cell development is proposed. Thus in addition to the R or G₀ state, which in this cell system is rather unstable and probably regulated by cyclic nucleotides, we postulate a differentiated D state, which is controlled by gangliosides and which is characterized by its stability (survival time). This D compartment seems to be closer to the in vivo differentiated neuron than does the R or P state. The possible mechanisms for the action of gangliosides are discussed.     

Die bodenfauna des greifswalder boddens. Ein beitrag zur ökologie der brackwasserfauna

Ohne Zusammenfassung     

Negative Evaluation Bias for Positive Self-Referential Information in Borderline Personality Disorder

Previous research has suggested that patients meeting criteria for borderline personality disorder (BPD) display altered self-related information processing. However, experimental studies on dysfunctional self-referential information processing in BPD are rare. In this study, BPD patients (N = 30) and healthy control participants (N = 30) judged positive, neutral, and negative words in terms of emotional valence. Referential processing was manipulated by a preceding self-referential pronoun, an other-referential pronoun, or no referential context. Subsequently, patients and participants completed a free recall and recognition task. BPD patients judged positive and neutral words as more negative than healthy control participants when the words had self-reference or no reference. In BPD patients, these biases were significantly correlated with self-reported attributional style, particularly for negative events, but unrelated to measures of depressive mood. However, BPD patients did not differ from healthy control participants in a subsequent free recall task and a recognition task. Our findings point to a negative evaluation bias for positive, self-referential information in BPD. This bias did not affect the storage of information in memory, but may be related to self-attributions of negative events in everyday life in BPD.     

Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates.