Combination of Trabectedin and Gemcitabine for Advanced Soft Tissue Sarcomas: Results of a Phase I Dose Escalating Trial of the German Interdisciplinary Sarcoma Group (GISG)

Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin’s introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01426633","term_id":"NCT01426633"}}NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m² on day 1 and gemcitabine 700 mg/m² on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level −1 with trabectedin 0.7 mg/m² plus gemcitabine 700 mg/m². Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.     

Rice spikelet rot disease in China - 1. Characterization of fungi associated with the disease

Rice spikelet rot disease (SRD) is an emerging disease of rice panicle in China, which affects both rice yield and grain quality. Four fungal pathogens were isolated from diseased rice grains. Morphological observation, biological testing and molecular characterization led to identify these fungi as Fusarium proliferatum, Bipolaris australiensis, Curvularia lunata and Alternaria tenuis. The four fungi can grow from 10 °C to 40 °C, and from pH 5 to pH 10. The most suitable temperature range is 25 °C-30 °C, however the optimal pH for sporulation of these fungi varies greatly. The four fungi can grow on media supplemented with different carbon and nitrogen sources. These differences in carbon and nitrogen requirements suggest differences in trophism, and have large effects on hyphal growth and spore production. The results suggest that rice SRD is caused by various fungi with diverse physiological characteristics.     

Tetraploid induction in tropical oysters,Crassostrea belcheri (Sowerby) and Crassostrea iredalei (Faustino)

Tetraploid induction has been conducted on temperate oysters but not on tropical oysters. In this study, different heat shocks (32, 35 and 38°C) and cold shocks (1, 4 and 7°C) were used to induce tetraploidy in two tropical oyster species, Crassostrea belcheri and Crassostrea iredalei, through meiosis I inhibition. Temperature shocks were applied on the newly fertilized eggs at 8–10 min post fertilization and terminated when second polar bodies began to form in the control eggs. The ploidy of the larvae and spat was determined via direct chromosome count. The percentage of larval survival until Day 20 was low (between 0.4% and 42.9%) for both temperature shocks and oyster species. No surviving larva was recorded for induction at 1, 4 and 38°C. Tetraploid spat was only recorded in C. iredalei but the percentage is low through heat shock induction of 32 and 35°C. This study shows that the tetraploid induction success rate was slightly higher in C. iredalei compared to C. belcheri. No surviving tetraploid spat were recorded for both oyster species through the cold shock method. This study shows that heat shock can be used to inhibit meiosis for the production of tetraploids but more experiments need to be conducted to determine the optimum temperature when dealing with tropical oysters.     

Monovalent salt-induced gelation of enzymatically deesterified pectin

Pectin gels were induced by monovalent salts (0.2 M) concurrently with deesterification of high methoxy pectin using a salt-independent orange pectin methylesterase (PME). Constant pH was maintained during deesterification and gelation. If salt or PME was absent, the pectin did not form a gel. The gel strength was influenced by both pH and species of monovalent cation. At pH 5.0, the pectin gel induced by KCl was significantly stronger than the NaCl-induced gel. In contrast, a much stronger gel was produced in the presence of NaCl as compared to KCl at pH 7.0. LiCl did not induce pectin gelation at either pH. Molecular weights of pectins increased from 1.38 x 10(5) to 2.26 x 10(5) during NaCl-induced gelation at pH 7. One proposal to explain these pectin molecular weight changes is a hypothetical PME transacylation mechanism. However, these pectin molecular weight changes can also be explained by metastable aggregation of the enzymatically deesterified low methoxy pectin. We postulate that gelation was induced by a slow deesterification of pectin under conditions that would normally salt out (precipitate) low methoxy pectin in the absence of PME.     

Assessing Spatial Uncertainty Associated with Forest Fire Boundary Delineation

Uncertainty in managing forested landscapes arises from many sources, including complexities inherent in forest ecosystems and their disturbance processes. However, gaining knowledge about forested ecosystems at the landscape level is often impeded by limitations in collecting comprehensive, representative, as well as accurate data sets. Historical reference data sets about past disturbances are also mostly lacking. In the case of ground fires, however, records of past fires can be obtained by analyzing fire scars using dendrochronology. While the temporal series of disturbance can be determined, there is still uncertainty about the spatial limits of individual forest surface fires. Here, we investigate how a patch-based method (fuzzy set membership) and a boundary-based uncertainty method (boundary membership) can help determine the spatial uncertainty related to forest fire events and their boundary locations. We compare these methods using fire scar data from ponderosa pine (Pinus ponderosa) and Douglas-fir (Pseudotsuga menziesii) sampled at 33 1-ha plots in a 1500-ha study area within the Stein River watershed (British Columbia). Patch-based fire maps, using multiple constraints, were derived for years 1785–1937. We compared the resulting total fire event maps with the boundary-based method, finding that depending on values chosen for the patch-based method, negative correlation was present (though very modest: r = − 0.1, p ≤ 0.05) between some maps. However, significant positive correlation between maps (though again modest: r = 0.22, p ≤ 0.05) was found under the least constrained patch-based methods, suggesting that fire patches are counted more than once in riparian zones. Our results suggest that these two methods provide complementary information about historical fire size and spatial limits. Quantifying spatial uncertainty about fire size and fire boundary location using a boundary membership method can contribute to not only understanding past fire regimes but also to providing better estimates of area burned.     

Interleukin-2 corrects defective NK activity of patients with leukemia

NK cells of patients with leukemia display low cytotoxic potential. Since the NK cells have been suggested to play a role in natural resistance to leukemia, we considered it of importance to investigate the approaches leading to the correction of NK defect of leukemic patients. Our studies demonstrate that culture of effector cells with interleukin-2 (IL-2) resulted in restoration of cytotoxic defect. This was indicated by normalization of tumor-binding as well as lytic NK activity, by normal frequency of cytotoxic cells and their ability to recycle. The NK cell nature of cytotoxic cells was shown by abrogation or depletion of cytotoxicity by antibody directed against NK cell-associated, but not T cell-associated antigen. The generation of NK cell activity against fresh leukemic cells suggests that adoptive transfer of IL-2 activated NK cells may be a new approach to leukemic treatment.