Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.     

Occurrence and chirality of oscillaxanthin

The quantitative carotenoid composition of natural blooms of Oscillatoria rubescens and O. agardhii is reported and compared with previous isolations. Chemical or enzymatic conversion of oscillaxanthin to the chiral aglycone failed. CD-correlation of oscillaxanthin hexaacetate with (2S,2′S)-bacterioruberin, (2′R)-plectaniaxanthin and (2′R)-plectaniaxanthin-2′-β-D-glucoside tetraacetate support the 2R,2′R-configuration for oscillaxanthin.     

Filtering structures and particle size selection in coexisting Cladocera

Summary Five commonly co-occurring cladocerans, Holopedium gibberum, Daphnia longispina, Ceriodaphnia quadrangula, Bosmina longispina, Diaphanosoma brachyurum and the calanoid copepod Eudiaptomus gracilis were fed monodisperse fluorescent latex beads (0.5, 1,5 m) to reveal clearance rates and particle size selection. The results were compared to those obtained with labelled bacteria and yeast. All cladoceran species ingested the beads, and particle size selection varied from a strong predominance of the largest particles in Holopedium, to an almost non selective particle retention in Diaphanosoma. The results indicated a strong correlation between morphology of the filtering combs, measured by Scanning electron microscopy, and ability to retain the smallest particles.     

On the mechanisms of the growth-promoting effect of prostaglandins in hepatocytes: The relationship between stimulation of DNA synthesis and signaling mediated by adenylyl cyclase and phosphoinositide-specific phospholipase C

While many observations indicate that prostaglandins may act as positive regulators of hepatocyte proliferation, the underlying mechanisms are not known. We have examined some of the signal pathways in the growth response induced by prostaglandins in hepatocytes, with particular focus on adenylyl cyclase and phosphoinositide-specific phospholipase C. Adult rat hepatocytes were cultured as primary monolayers in serum-free medium in the presence of EGF and insulin. PGE₂ or PGF_2α (added 0-3 h after plating) enhanced the incorporation of [³H]-thymidine into DNA (measured at 50 h); at 100 γM the stimulation was about threefold. PGI₂ and PGD₂ also showed significant but smaller stimulatory effects. No significant increase in the level of cyclic AMP (cAMP) was detected in response to any of the prostaglandins. Low concentrations of glucagon (0.1-10 nM), a potent activator of hepatic adenylyl cyclase, or 8-bromo-cAMP (0.1-10 γM) enhanced the DNA synthesis. When 8-bromo-cAMP was used in maximally effective concentrations, no further stimulation was obtained by combining it with glucagon, whereas the effects of PGE₂ and 8-bromo-cAMP were completely additive. All the prostaglandins also showed additivity with the effect of glucagon on the DNA synthesis. PGE₂, PGF_2α, PGI₂, and PGD₂ increased intracellular inositol-1,4,5-trisphosphate (InsP₃), with a relative order of efficacy roughly corresponding to their activity as stimulators of DNA synthesis. Increases in cytosolic free Ca²⁺, as measured in single cells, were elicited in a majority of the hepatocytes by all these prostaglandins at 1 γM. Supramaximal concentrations of vasopressin, a strong activator of phospholipase C in hepatocytes, acted additively with PGE₂ on the DNA synthesis. Pretreatment of the hepatocytes with a concentration of pertussis toxin that prevented the inhibitory effect of PGE₂ on glucagon-induced cAMP accumulation did not abolish the ability of PGE₂ to stimulate the DNA synthesis. The results do not support a role for adenylyl cyclase activation in the stimulatory effect of prostaglandins on hepatocyte growth. While the data are compatible with an involvement of phosphoinositide-specific phospholipase C in the growth-promoting effect of prostaglandins in cultured rat hepatocytes, they suggest this may not be the sole mechanism. © 1995 Wiley-Liss, Inc.     

Impacts from hydropower production on biodiversity in an LCA framework—review and recommendations

Purpose

Expanding renewable energy production is widely accepted as a promising strategy in climate change mitigation. However, even renewable energy production has some environmental impacts, some of which are not (yet) covered in life cycle impact assessment (LCIA). We aim to identify the most important cause-effect pathways related to hydropower production on biodiversity, as one of the most common renewable energy sources, and to provide recommendations for future characterization factor (CF) development.

Methods

We start with a comprehensive review of cause-effect chains related to hydropower production for both aquatic and terrestrial biodiversity. Next, we explore contemporary coverage of impacts on biodiversity from hydropower production in LCA. Further, we select cause-effect pathways displaying some degree of consistency with existing LCA frameworks for method development recommendations. For this, we compare and contrast different hydrologic models and discuss how existing LCIA methodologies might be modified or combined to improve the assessment of biodiversity impacts from hydropower production.

Results and discussion

Hydropower impacts were categorized into three overarching impact pathways: (1) freshwater habitat alteration, (2) water quality degradation, and (3) land use change. Impacts included within these pathways are flow alteration, geomorphological alteration to habitats, changes in water quality, habitat fragmentation, and land use transformation. For the majority of these impacts, no operational methodology exists currently. Furthermore, the seasonal nature of river dynamics requires a level of temporal resolution currently beyond LCIA modeling capabilities. State-of-the-art LCIA methods covering biodiversity impacts exist for land use and impacts from consumptive water use that can potentially be adapted to cases involving hydropower production, while other impact pathways need novel development.

Conclusions

In the short term, coverage of biodiversity impacts from hydropower could be significantly improved by adding a time step representing seasonal ecological water demands to existing LCIA methods. In the long term, LCIA should focus on ecological response curves based on multiple hydrologic indices to capture the spatiotemporal aspects of river flow, by using models based on the “ecological limits to hydrologic alteration” (ELOHA) approach. This approach is based on hydrologic alteration-ecological response curves, including site-specific environmental impact data. Though data-intensive, ELOHA represents the potential to build a global impact assessment framework covering multiple ecological indicators from local impacts. Further, we recommend LCIA methods based on degree of regulation for geomorphologic alteration and a fragmentation index based on dam density for “freshwater habitat alteration,” which our review identified as significant unquantified threats to aquatic biodiversity.

     

Quantitative Evaluation of Performance in Interventional Neuroradiology: An Integrated Curriculum Featuring Theoretical and Practical Challenges

Purpose

We sought to develop a standardized curriculum capable of assessing key competencies in Interventional Neuroradiology by the use of models and simulators in an objective, quantitative, and efficient way. In this evaluation we analyzed the associations between the practical experience, theoretical knowledge, and the skills lab performance of interventionalists.

Materials and Methods

We evaluated the endovascular skills of 26 participants of the Advanced Course in Endovascular Interventional Neuroradiology of the European Society of Neuroradiology with a set of three tasks (aneurysm coiling and thrombectomy in a virtual simulator and placement of an intra-aneurysmal flow disruptor in a flow model). Practical experience was assessed by a survey. Participants completed a written and oral examination to evaluate theoretical knowledge. Bivariate and multivariate analyses were performed.

Results

In multivariate analysis knowledge of materials and techniques in Interventional Neuroradiology was moderately associated with skills in aneurysm coiling and thrombectomy. Experience in mechanical thrombectomy was moderately associated with thrombectomy skills, while age was negatively associated with thrombectomy skills. We found no significant association between age, sex, or work experience and skills in aneurysm coiling.

Conclusion

Our study gives an example of how an integrated curriculum for reasonable and cost-effective assessment of key competences of an interventional neuroradiologist could look. In addition to traditional assessment of theoretical knowledge practical skills are measured by the use of endovascular simulators yielding objective, quantitative, and constructive data for the evaluation of the current performance status of participants as well as the evolution of their technical competency over time.     

A limnological investigation of the tarn Syslaktjønn, W Norway

An investigation covering hydrography, chemistry, vascular and cryptogamic plants, nitrogen fixation, phytoplankton biomass and production, and zooplankton was carried out from April to November 1976 in tarn in W Norway, The volume of the tarn was 18000 m³ and the turnover time about 30 d. Temperature ranged between 3.6 and 23.4°C and pH between 4.8 and 5.5. Nuphar luteum and Carex rostrata were the two dominating vasculars-with biomasses of 117 and 97 g m⁻², respectively The biomass of the bryophytes ( Sphagnum spp.) was about 510 g m⁻² and the production of the order 0.2–2.1 μg (mg d.w.)⁻¹h⁻¹. Nitrogen fixation in association with Sphagnum spp. was estimated at 25 g yr⁻¹ for the whole tarn. Phytoplankton was dominated by diatoms, green algae and chrysophyceans. The chlorophyll a content ranged from 2 to 20 mg m⁻³ and the carbon assimilation rates from 0.03 to 20 mg C m⁻³h⁻¹ at 0–4 m depths. Production in the period was of the magnitude 22 g C m⁻². The copepod Eudiaptomus gracilis was the most common netzooplankter. Large numbers of rotationrians were found during summer.