Serum S100A6 Concentration Predicts Peritoneal Tumor Burden in Mice with Epithelial Ovarian Cancer and Is Associated with Advanced Stage in Patients

BACKGROUND:Ovarian cancer is the 5th leading cause of cancer related deaths in women. Five-year survival rates for early stage disease are greater than 94%, however most women are diagnosed in advanced stage with 5 year survival less than 28%. Improved means for early detection and reliable patient monitoring are needed to increase survival. METHODOLOGY AND PRINCIPAL FINDINGS:Applying mass spectrometry-based proteomics, we sought to elucidate an unanswered biomarker research question regarding ability to determine tumor burden detectable by an ovarian cancer biomarker protein emanating directly from the tumor cells. Since aggressive serous epithelial ovarian cancers account for most mortality, a xenograft model using human SKOV-3 serous ovarian cancer cells was established to model progression to disseminated carcinomatosis. Using a method for low molecular weight protein enrichment, followed by liquid chromatography and mass spectrometry analysis, a human-specific peptide sequence of S100A6 was identified in sera from mice with advanced-stage experimental ovarian carcinoma. S100A6 expression was documented in cancer xenografts as well as from ovarian cancer patient tissues. Longitudinal study revealed that serum S100A6 concentration is directly related to tumor burden predictions from an inverse regression calibration analysis of data obtained from a detergent-supplemented antigen capture immunoassay and whole-animal bioluminescent optical imaging. The result from the animal model was confirmed in human clinical material as S100A6 was found to be significantly elevated in the sera from women with advanced stage ovarian cancer compared to those with early stage disease. CONCLUSIONS:S100A6 is expressed in ovarian and other cancer tissues, but has not been documented previously in ovarian cancer disease sera. S100A6 is found in serum in concentrations that correlate with experimental tumor burden and with clinical disease stage. The data signify that S100A6 may prove useful in detecting and/or monitoring ovarian cancer, when used in concert with other biomarkers

Co-regulation of a large and rapidly evolving repertoire of odorant receptor genes

The olfactory system meets niche- and species-specific demands by an accelerated evolution of its odorant receptor repertoires. In this review, we describe evolutionary processes that have shaped olfactory and vomeronasal receptor gene families in vertebrate genomes. We emphasize three important periods in the evolution of the olfactory system evident by comparative genomics: the adaptation to land in amphibian ancestors, the decline of olfaction in primates, and the delineation of putative pheromone receptors concurrent with rodent speciation. The rapid evolution of odorant receptor genes, the sheer size of the repertoire, as well as their wide distribution in the genome, presents a developmental challenge: how are these ever-changing odorant receptor repertoires coordinated within the olfactory system? A central organizing principle in olfaction is the specialization of sensory neurons resulting from each sensory neuron expressing only ~one odorant receptor allele. In this review, we also discuss this mutually exclusive expression of odorant receptor genes. We have considered several models to account for co-regulation of odorant receptor repertoires, as well as discussed a new hypothesis that invokes important epigenetic properties of the system

瞬时受体电位通道TRPV1、 TRPA1 和TRPM8拮抗剂在小鼠神经源性和神经病理性疼痛模型中的镇痛作用

The aim of this research was to assess the antinociceptive activity of the transient receptor potential (TRP) channel TRPV1, TRPM8, and TRPA1 antagonists in neurogenic, tonic, and neuropathic pain models in mice. For this purpose, TRP channel antagonists were administered into the dorsal surface of a hind paw 15 min before capsaicin, allyl isothiocyanate (AITC), or formalin. Their antiallodynic and antihyperalgesic efficacies after intraperitoneal administration were also assessed in a paclitaxel-induced neuropathic pain model. Motor coordination of paclitaxel-treated mice that received these TRP channel antagonists was investigated using the rotarod test. TRPV1 antagonists, capsazepine and SB-366791, attenuated capsaicin-induced nociceptive reaction in a concentration-dependent manner. At 8 μg/20 μl, this effect was 51% (P<0.001) for capsazepine and 37% (P<0.05) for SB-366791. A TRPA1 antagonist, A-967079, reduced pain reaction by 48% (P<0.05) in the AITC test and by 54% (P<0.001) in the early phase of the formalin test. The test compounds had no influence on the late phase of the formalin test. In paclitaxel-treated mice, they did not attenuate heat hyperalgesia but N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl) benzamide hydrochloride salt (AMTB), a TRPM8 antagonist, reduced cold hyperalgesia and tactile allodynia by 31% (P<0.05) and 51% (P<0.01), respectively. HC-030031, a TRPA1 channel antagonist, attenuated tactile allodynia in the von Frey test (62%; P<0.001). In conclusion, distinct members of TRP channel family are involved in different pain models in mice. Antagonists of TRP channels attenuate nocifensive responses of neurogenic, tonic, and neuropathic pain, but their efficacies strongly depend on the pain model used