Yuichi Iino

PURPOSE: To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer. PATIENTS AND METHODS: Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis. RESULTS: The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase. CONCLUSION: Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.

Schizosaccharomyces pombe ste11 encodes a member of the family of HMG-box proteins. Its transcript is induced in response to nitrogen starvation and a concomitant decrease of the intracellular cAMP level. Expression of ste11 is essential for induction of sexual development, and its ectopic expression stimulates uncontrolled mating and sporulation. Ste11 protein regulates positively transcription of the following genes required for sexual development: the mating type genes, matP and matM, and the mei2 gene, which is essential for commitment to meiosis. Ste11 protein synthesized in vitro binds specifically to a DNA fragment carrying a 10-base motif TTCTTTGTTY that is an essential cis-acting element for the induction of mei2 and is commonly seen in the upstream regions of the genes inducible by nitrogen starvation. These observations strongly suggest that Ste11 serves as a key transcription factor for sexual development.

Caenorhabditis elegans shows chemotaxis to various odorants and water-soluble chemoattractants such as NaCl. Previous studies described the pirouette mechanism for chemotaxis, in which C. elegans quickly changes the direction of locomotion by using a set of stereotyped behaviors, a pirouette, in response to a decrease in the concentration of the chemical. Here, we report the discovery of a second mechanism for chemotaxis, called the weathervane mechanism. In this strategy animals respond to a spatial gradient of chemoattractant and gradually curve toward higher concentration of the chemical. By computer simulation, we find that both of these mechanisms contribute to chemotaxis and both mechanisms need to act in parallel for efficient chemotaxis. Using laser ablation of individual neurons to examine the underlying neural circuit, we find the ASE sensory neurons and AIZ interneurons are essential for both the pirouette and weathervane mechanisms in chemotaxis to NaCl. Salt-conditioned animals show reversed responses in both of these behaviors, leading to avoidance of NaCl. These results provide a platform for detailed molecular and cellular analyses of chemotaxis and its plasticity in this model organism.

While the basic functioning of the nervous system of Caenorhabditis elegans has been extensively studied, its behavioural plasticities have not been fully explored because of the limited availability of assay systems. We report here a simple form of chemotaxis plasticity in this organism: when worms are starved on plates that contain NaCl, their chemotaxis towards NaCl falls dramatically. This conditioning requires both the presence of NaCl and the absence of a bacterial food source, indicating that it is not merely adaptation or habituation, but that it is likely to be a form of associative learning. While chemotaxis towards volatile chemoattractants does not change significantly after conditioning with NaCl, chemotaxis towards other water-soluble attractants does decrease. This suggests that an altered response of a cell or a group of cells specifically involved in chemotaxis towards water-soluble chemoattractants is responsible for the behavioural alteration. The decrease in chemotaxis occurred slowly over 3-4 h of conditioning and returned quickly to the original level when either of the conditioning stimuli, NaCl or starvation, was removed. The application of serotonin partially blocked this reduction in chemotaxis, consistent with the proposed function of this neurotransmitter in food signalling. Using this assay, we have isolated three mutants with reduced plasticity. This assay system expands the opportunities for studying the molecular and cellular mechanisms of behavioural plasticity in C. elegans.