Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy

Current systemic treatments for metastatic uveal melanoma (UM) have not improved overall survival (OS). The fully human anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, ipilimumab, improved OS of patients with advanced cutaneous melanoma in a phase 3 trial; however, UM patients were excluded. The aim of this subanalysis, performed by the ipilimumab-ocular melanoma expanded access program (I-OMEAP) study group, was to assess the activity and safety of ipilimumab in patients with UM in a setting similar to daily clinical practice. Patients participating in a multicenter expanded access program (EAP) received induction treatment with ipilimumab 10 mg/kg. Maintenance doses were administered in patients who experienced clinical benefit or at physicians' discretion. Tumor assessment was evaluated per modified World Health Organization criteria at baseline, Week 12, Week 24, and Week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. Thirteen pretreated patients with metastatic UM were treated at 6 European institutions. All patients received at least one dose of ipilimumab. Overall, no objective responses were observed; however, two patients had stable disease (SD), with a third patient achieving SD after initial progressive disease. Median OS as of July 1, 2011, was 36 weeks (range 2-172+?weeks). No grade 3/4 AEs of non-immune origin were reported. Three patients (23%) experienced grade 3 irAEs (1 thrombocytopenia, 1 diarrhea, and 1 alanine/aspartate aminotransferase elevation) that resolved with steroid therapy. The results indicate UM is a potential indication for ipilimumab treatment that should be further investigated in clinical trials.     

Greater impact of extreme drought on photosynthesis of grasslands exposed to a warmer climate in spite of acclimation

In view of the projected increase in the frequency of extreme events during this century, we investigated the impact of a drought extreme on leaf ecophysiological parameters and carbon isotope composition (δ¹³C) of grassland communities with species richness (S) of one, three or nine species. The communities, grown for 3 years at either ambient air temperatures (ambient T_air) or ambient T_air + 3°C (elevated T_air), were additionally subjected to an imposed drought by withholding water for 24 days. During the previous 3 years equal precipitation was applied in both temperature treatments, thus communities at elevated T_air had experienced more frequent, mild droughts. However, it was unknown whether this resulted in a higher resistance for facing extreme droughts. At similar soil matric potentials stomatal conductance (g_s) and transpiration (Tr) were higher at elevated than ambient T_air, indicating acclimation to lower soil water content. Despite the stomatal acclimation observed, plants in elevated T_air showed a lower resistance to the drought extreme as indicated by their lower photosynthetic rate (A_max), g_s and Tr during the entire duration of the drought extreme. Lower values for A_max, Tr and g_s were also recorded in species at S = 3 as compared with species at S = 1 for both temperature treatments, but no further differences with S = 9 suggesting that stress was not alleviated at higher S‐levels. The discrimination of ¹³C was poorly correlated with measurements of instantaneous leaf water‐use efficiency (A_max/Tr) and, with this time scale and sampling method, it was not possible to detect any potential change in plant water‐use efficiency using leaf δ¹³C.     

Clonal propagation of kurrat (Allium ampeloprasum var. kurrat)

Summary Two protocols for clonal propagation of kurrat (Allium ampeloprasum var.kurrat) using explants from the basal plates of mature plants are described. In direct formation, explants were cultured in Murashige and Skoog (MS) medium and supplemented with either benzyladenine at 0.0 or 4.4 μM, or supplemented with 7.0 μM benzyladenine and 0.1 μM naphthaleneacetic acid. Shoots appeared after 4 wk of culture. In the two-step procedure, explants were cultured first on MS medium supplemented with 1.4 μM 2,4-dichlorophenoxyacetic acid and 1.4 μM kinetin, and incubated in the dark for 4 wk. They were then transferred to MS medium supplemented with 4.4 μM benzyladenine for shoot formation. All shoots were rooted on MS medium containing 5 g·liter⁻¹ activated charcoal. Normal viable plants were successfully established in soil.     

Assessing ecosystem health

Evaluating ecosystem health in relation to the ecological, economic and human health spheres requires integrating human values with biophysical processes, an integration that has been explicitly avoided by conventional science. The field is advancing with the articulation of the linkages between human activity, regional and global environmental change, reduction in ecological services and the consequences for human health, economic opportunity and human communities. Increasing our understanding of these interactions will involve more active collaboration between the ecological, social and health sciences. In this, ecologists will have substantive and catalytic roles.     

INCREASE IN LARGE NEUTRAL AMINO ACID TRANSPORT INTO BRAIN BY INSULIN

The administration of oral glucose to fasted rats produced a decline of all large neutral amino acid levels in serum, including that of the free fraction of tryptophan. In addition to this well known effect, it also decreased the brain concentrations of leucine, isoleucine and valine, while increasing those of tryptophan, tyrosine and phenylalanine. The total concentration of large neutral amino acids in serum was decreased by 44%, while it was slightly increased in brain. Analogous results were obtained in 4 rats injected with exogenous insulin. Moreover, the administration of either glucagon or isoproterenol to rats force-fed with glucose produced a decline in total serum tryptophan concentration proportional to that of the rise in FFA, while it increased free serum tryptophan and brain tryptophan levels. It can be concluded that insulin stimulates the transport of large neutral amino acids from blood to brain and that the level of free serum tryptophan also controls the entry of tryptophan into the brain under the influence of insulin.     

Letter to Editor: Carpal tunnel syndrome due to an atypical deep soft tissue leiomyoma: The risk of misdiagnosis and mismanagement

A response to Chalidis et al: Carpal tunnel syndrome due to an atypical deep soft tissue leiomyoma: The risk of misdiagnosis and mismanagement. World J Surg Oncol 2007, 5:92.     

A casein kinase 1 and PAR proteins regulate asymmetry of a PIP(2) synthesis enzyme for asymmetric spindle positioning

Spindle positioning is an essential feature of asymmetric cell division. The conserved PAR proteins together with heterotrimeric G proteins control spindle positioning in animal cells, but how these are linked is not known. In C. elegans, PAR protein activity leads to asymmetric spindle placement through cortical asymmetry of Galpha regulators GPR-1/2. Here, we establish that the casein kinase 1 gamma CSNK-1 and a PIP(2) synthesis enzyme (PPK-1) transduce PAR polarity to asymmetric Galpha regulation. PPK-1 is posteriorly enriched in the one-celled embryo through PAR and CSNK-1 activities. Loss of CSNK-1 causes uniformly high PPK-1 levels, high symmetric cortical levels of GPR-1/2 and LIN-5, and increased spindle pulling forces. In contrast, knockdown of ppk-1 leads to low GPR-1/2 levels and decreased spindle forces. Furthermore, loss of CSNK-1 leads to increased levels of PIP(2). We propose that asymmetric generation of PIP(2) by PPK-1 directs the posterior enrichment of GPR-1/2 and LIN-5, leading to posterior spindle displacement.