Nuclear oncogene products have the potential to induce alterations in gene regulation leading to the genesis of cancer. The biochemical mechanisms by which nuclear oncoproteins act remain unknown. Recently, an oncogene, v-jun, was found to share homology with the DNA binding domain of a yeast transcription factor, GCN4. Furthermore, GCN4 and the phorbol ester-inducible enhancer binding protein, AP-1, recognize very similar DNA sequences. The human proto-oncogene c-jun has now been isolated, and the deduced amino acid sequence indicates more than 80 percent identity with v-jun. Expression of cloned c-jun in bacteria produced a protein with sequence-specific DNA binding properties identical to AP-1. Antibodies raised against two distinct peptides derived from v-jun reacted specifically with human AP-1. In addition, partial amino acid sequence of purified AP-1 revealed tryptic peptides in common with the c-jun protein. The structural and functional similarities between the c-jun product and the enhancer binding protein suggest that AP-1 may be encoded by c-jun. These findings demonstrate that the proto-oncogene product of c-jun interacts directly with specific target DNA sequences to regulate gene expression, and therefore it may now be possible to identify genes under the control of c-jun that affect cell growth and neoplasia.

-Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rodshaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/ carcinogenic properties, especially of their long-term biodurability, are fully assessed.

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To assess the transforming capability of the c-Jun protein, we introduced the chicken c-jun proto-oncogene into a replication competent avian retroviral expression vector (RCAS). Viral Jun efficiently transformed chicken embryo fibroblasts (CEFs) when expressed from this vector. Overexpression of c-Jun leads to transformation of CEFs with an efficiency that is 15-to 25-fold less than that seen for v-Jun, suggesting that v-Jun contains structural features that increase its oncogenic potential relative to c-Jun. There are four structural differences between v-Jun and c-Jun. To determine the relative contribution that each of these structural differences between v-Jun and c-Jun has on oncogenic activity, several deletion and substitution mutants were constructed. Each of these mutants was expressed in CEF and assayed for transformation by focus formation. Analysis of the results reveals that deletion of a region of 27 amino acids near the amino terminus of c-Jun and deletion of 3'-untranslated sequences are critical in activating the full oncogenic potential of Jun.

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We evaluated the efficacy and safety of stereotactic body radiation therapy (SBRT) for patients with head and neck tumors. From April 2005 through April 2008, 34 patients with head and neck tumors were treated with CyberKnife SBRT. Twenty-one of them had prior radiotherapy. Treatment sites were orbit (n = 7), cervical lymph nodes (n = 6), nasopharynx (n = 5), oropharynx (n = 4) and others (n = 12). The prescribed dose ranged from 19.5 to 42 Gy (median, 30 Gy) in 3-8 fractions for consecutive days. The target volume ranged from 0.7 to 78.1 cm(3) (median, 11.6 cm(3)). The median follow-up was 16 months. Treatment was well tolerated without significant acute complications in any cases. Complete response rate and partial response rate were 32.4% and 38.6%, respectively. The overall survival rates were 70.6% and 58.3% at 12 and 24 months, respectively. The overall survival was better in patients without prior radiotherapy within the previous 24 months or in case of smaller target volume. Six patients suffered severe late complications. All these patients had prior radiotherapy, and 2 of them developed massive hemorrhage in the pharynx and both died of this complication 5 and 28 months, respectively, after SBRT. Our preliminary results suggest that SBRT is an effective treatment modality for head and neck tumors. However, re-irradiation has significant risk of severe and even fatal late complications in the form of necrosis and hemorrhage in re-irradiated areas.

This article is available online at http://dmd.aspetjournals.org ABSTRACT:7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of antitumor agent irinotecan (CPT-11), is conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT) 1A1. Genetic polymorphisms in UGT1A1 are thought to contribute to severe diarrhea and/or leukopenia caused by CPT-11. In this regard, it has been reported that polymorphisms in the promoter region could affect the CPT-11 pharmacokinetics and interindividual variation of toxicity. However, little information is available on the influence of UGT1A1 polymorphisms in the coding region on the SN-38 glucuronidation activity. In the present study, wild-type (WT) and three variant (G71R, P229Q, and Y486D) cDNAs of human UGT1A1s were transiently expressed in COS-1 cells, and the kinetic parameters of these UGT1A1s were determined for SN-38 glucuronidation. A partially reduced UGT1A1 protein expression was observed in COS-1 cells for G71R and Y486D. WT UGT1A1 catalyzed SN-38 glucuronidation with an apparent K m value of 11.5 M, whereas those of G71R, P229Q, and Y486D were 14.0, 18.0, and 63.5 M, respectively. The SN-38 glucuronidation efficiency ratio (V max /K m ) normalized for the level of expression was 1.4, 0.66 (47% of WT), 0.73 (52%), and 0.07 (5%) l/min/mg of protein for WT, G71R, P229Q, and Y486D, respectively. Thus, the SN-38 glucuronidation activity of Y486D was drastically reduced, whereas the reduction in the G71R and P229Q activities was fractional. The decreased SN-38 glucuronidation efficiency ratio of G71R and P229Q could be critical in combination with other polymorphisms in the UGT1A1 gene.