A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

BackgroundNeuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.ConclusionsDFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.

Trial Registration

Clinicaltrials.gov NCT#01059071     

Decrease in bacterial production over the past three decades in the north basin of Lake Biwa,Japan

Limnology - In Lake Biwa, the largest lake in Japan, external pollutant loads have decreased since the 1980s, leading to improved water quality, such as reduction in biochemical oxygen demand (BOD)...     

Direct and indirect impacts of predation by fish on the zooplankton community: an experimental analysis using tanks

The impact of Pseudorasbora parva, a common zooplanktivorous fish species in Japan, on a zooplankton community was analyzed in experimental tanks, half of which were stocked with the fish. Different zooplankton species showed different responses to the introduction of the fish. In the presence of the fish, the populations of the large cladoceran Ceriodaphnia and the predatory copepod Mesocyclops were reduced, but the population of the herbivorous copepod Eodiaptomus and the small cladocerans Bosmina fatalis and Bosminopsis deitersi increased relative to the controls. The increase of Mesocyclops seen in the control tanks might have suppressed the populations of the small cladocerans, which are vulnerable to invertebrate predation. The results suggest that the population densities of the large prey items preferred by the fish, Ceriodaphnia and Mesocyclops, were controlled directly by fish predation, but the population densities of the smaller and less preferred zooplankton were controlled indirectly through the food-web cascade.     

Egg viability of the rotifer Brachionus urceolaris after ingestion by the predatory cladoceran Leptodora kindtii

Egg resistance against the digestive process of a predator is an effective strategy for zooplankton to compensate population loss due to predation. Parthenogenetic eggs of the rotiferan Brachionus urceolaris, which were ingested by the predatory cladoceran Leptodora kindtii, were expelled from the feeding basket of the predator without digestion. We found a negative correlation between the unconsumed ratio of eggs after ingestion and body length of the predator. As high as 75% of the unconsumed eggs successfully hatched and the hatch ratio was independent of body length of L. kindtii. Our results indicate that the rotifer has an effective strategy to maintain its population in the environment with abundant invertebrate predators.     

Different Predation Impacts of Two Cyclopoid Species on a Small-sized Zooplankton Community: An Experimental Analysis with Mesocosms

We used mesocosms to analyze predation impacts on the prey populations and prey community structures by two cyclopoid copepod species, the larger Mesocyclops pehpeiensis and the smaller Thermocyclops taihokuensis, who coexist with small-sized herbivorous zooplankton species in a fish-abundant lake. The overall predation impact on the prey populations was stronger for Mesocyclops than for Thermocyclops. Mesocyclops had a strong and less selective impact on the rotifer community but a selective impact on the crustaceans. In contrast, Thermocyclops had a selective predation impact on rotifers but a weak and less selective impact on the crustacean community. As a result, the former predator reduced the diversity of the crustacean community but not the rotifer community, while the latter had an opposite impact on the diversities of the two communities. It has been suggested that fish induce development of a zooplankton community dominated by the small-sized zooplankton species in fish-abundant lakes. Our results demonstrated that cyclopoid copepods altered species composition and diversity of the small-sized zooplankton community in such lakes. Thus, the results have given an important suggestion on the role of the invertebrate predator cyclopoid copepods, which often coexist with fish, that they determine population dynamics and community structures of small-sized zooplankton in fish-abundant lakes.     

Horizontal variability and regulation of bacterial production in Lake Biwa,Japan

Limnology - To clarify horizontal variability and regulation of bacterial production (BP), we investigated BP and environmental variables along three east–west transects (lines 12, 15, and...     

The Role of Metabotropic Glutamate Receptor 5 on the Stromal Cell-Derived Factor-1/CXCR4 System in Oral Cancer

We have demonstrated that blocking CXCR4 may be a potent anti-metastatic therapy for CXCR4-related oral cancer. However, as CXCR4 antagonists are currently in clinical use to induce the mobilization of hematopoietic stem cells, continuous administration as an inhibitor for the metastasis may lead to persistent leukocytosis. In this study, we investigated the novel therapeutic downstream target(s) of the SDF-1/CXCR4 system, using B88-SDF-1 cells, which have an autocrine SDF-1/CXCR4 system and exhibit distant metastatic potential in vivo. Microarray analysis revealed that 418 genes were upregulated in B88-SDF-1 cells. We identified a gene that is highly upregulated in B88-SDF-1 cells, metabotropic glutamate receptor 5 (mGluR5), which was downregulated following treatment with 1,1’ -[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist. The upregulation of mGluR5 mRNA in the SDF-1/CXCR4 system was predominately regulated by the Ras-extracellular signal-regulated kinase (ERK)1/2 pathway. Additionally, the growth of B88-SDF-1 cells was not affected by the mGluR5 agonist (S)-3,5-DHPG (DHPG) or the mGluR5 antagonists 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP). However, we observed that DHPG promoted B88-SDF-1 cell migration, whereas both MPEP and MTEP inhibited B88-SDF-1 cell migration. To assess drug toxicity, the antagonists were intraperitoneally injected into immunocompetent mice for 4 weeks. Mice injected with MPEP (5 mg/kg) and MTEP (5 mg/kg) did not exhibit any side effects, such as hematotoxicity, allergic reactions or weight loss. The administration of antagonists significantly inhibited the metastasis of B88-SDF-1 cells to the lungs of nude mice. These results suggest that blocking mGluR5 with antagonists such as MPEP and MTEP could prevent metastasis in CXCR4-related oral cancer without causing side effects.