DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancerfree smokers, 15% (3 of 18) of patients with stage I non-smallcell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancerfree individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease. (Cancer Res 2006; 66(12): 6210-8)

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Background: MUC1 plays a role in mediation of signaling initiated by growth factors. Results: Siglec-9-positive cells are associated with MUC1-positive tumor cells in tumor tissues, and Siglec-9 binds to MUC1. Conclusion: MUC1-mediated signaling occurs by direct binding of Siglec-9 to MUC1. Significance: Multiple signaling pathway through MUC1 can be advantageous to adjust to various conditions of tumor microenvironments.

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Alternative one-pot synthesis of 3-(trifluoromethyl)-3-phenyldiazirine derivatives from corresponding tosyloximes is developed. The deprotonation of intermediate diaziridine by NH2(-) is a new approach for construction of diazirine. Moreover, a novel synthesis of optically pure (trifluoromethyl)diazirinylphenylalanine derivatives was attempted involving these methods.

A novel strategy for the dehydrogenation of the NH-NH bond is disclosed using potassium tert-butoxide (tBuOK) in liquid ammonia (NH ) under air at room temperature. Its synthetic value is well demonstrated by the highly efficient synthesis of aromatic azo compounds (up to 100 % yield, 3 min), heterocyclic azo compounds, and dehydrazination of phenylhydrazine. The broad application of this strategy and its benefit to chemical biology is proved by a novel, convenient, one-pot synthesis of aliphatic diazirines, which are important photoreactive agents for photoaffinity labeling.

Transient receptor potential vanilloid (TRPV)1 is a ligand-gated cation channel expressed by primary sensory neurons, including those in the dorsal root ganglia (DRG). TRPV1 plays an essential role in development of inflammatory thermal hyperalgesia after tissue injury and its expression in rat lumbar DRG is increased after hindpaw inflammation. However, the identity of factors mediating forepaw inflammatory hyperalgesia has remained elusive. Here, we examined behavioral responses to noxious thermal stimuli after forepaw inflammation in rats and found that inflammation induced by intraplantar injection of complete Freund's adjuvant significantly reduced hot-plate latency (HPL) at 50 degrees C. TRPV1 expression levels in the ipsilateral cervical DRG were also elevated after forepaw inflammation. By contrast, HPL at 56 degrees C was not shortened after forepaw inflammation and expression of TRPV2, a TRPV1 homolog, in the DRG was not increased. Paratracheal injection of short interfering RNA targeting TRPV1 blocked TRPV1 up-regulation in cervical DRG and abolished inflammation-mediated HPL reductions seen at 50 degrees C. However, thermal hyperalgesia previously established by inflammation was not reversed by short interfering RNA injection. These results indicate that: (i) enhanced TRPV1 expression in cervical DRG is closely associated with development of inflammatory thermal hyperalgesia in the forepaw after tissue injury and (ii) RNA interference targeting TRPV1 prevents inflammatory thermal hyperalgesia after forepaw injuries but does not ameliorate it when already established in a rat model of nociceptive pain representing upper limb injury in humans.

Miyoshi, Michio, Katsumi Nagata, Toshiaki Imoto, Osamu Goto, Akiko Ishida, and Tatsuo Watanabe. ANG II is involved in the LPS-induced production of proinflammatory cytokines in dehydrated rats. Am J Physiol Regul Integr Comp Physiol 284: R1092-R1097, 2003 10.1152/ajpregu.00700.2002We have previously reported results that led us to speculate that ANG II is involved in the LPSinduced production of proinflammatory cytokines, especially under dehydrated conditions. To test this possibility, in this study we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and an antagonist of the type-1 ANG II receptor (AT1 receptor) on the LPS-induced production of the proinflammatory cytokines IL-1 and IL-6 in dehydrated rats. A single intravenous injection of LPS induced a marked increase in the expression of IL-1␤ mRNA in the liver, an effect that was significantly attenuated by pretreatment with the ACE inhibitor. Furthermore, the ACE inhibitor reduced the LPS-induced increase in the hepatic concentration of IL-1␤ protein. When the AT 1-receptor antagonist was given intravenously before the LPS, the increase in the hepatic concentration of IL-1␤ was significantly reduced. Finally, the ACE inhibitor reduced the LPS-induced increase in the plasma concentration of IL-6. These results represent the first in vivo evidence that ANG II and its AT 1 receptor play important roles in the production of proinflammatory cytokines that is induced by LPS under dehydrated conditions. interleukin-1; interleukin-6; fever PROINFLAMMATORY CYTOKINES such as IL-1 or IL-6 are members of a family of endogenous pyrogens (EP), production of which is powerfully stimulated by LPS (6). Occasionally, we experience a high fever in bacteria-infected patients under dehydrated conditions. In 1986, Morimoto et al. (14) showed that intravenous injection of LPS induced a fever that was significantly greater in dehydrated rats than in euhydrated rats. However, dehydration had no effect on the fever induced by intravenous injection of their "homemade" crude EP. Accordingly, the fever enhancement caused by dehydration may be due to increased production of EP in response to LPS. Because the secretion of ANG II increases under dehydrated conditions, we recently tested the possibility that ANG II is involved in this fever enhancement. In fact, the LPS-induced fever seen by us in dehydrated rats was significantly attenuated by an angiotensin-converting enzyme (ACE) inhibitor given intravenously, whereas the IL-1-induced fever underwent no alterations with this inhibitor (27). Taken together, the above evidence makes it likely that ANG II contributes to the LPS-induced production of EP, or of a proinflammatory cytokine such as IL-1, and that this leads to an enhancement of the LPS-induced fever seen under dehydrated conditions. Recent evidence suggests that ANG II may itself be a proinflammatory peptide. For example, ANG II induces an inflammatory response, involving increases in the expressions of such proinflammatory enzymes as phospholipase (23...