Members of the NAC gene family encode plant-specific transcription factors and are widely distributed in plant species. The OsNAC6 gene is one of many NAC genes in rice and has high similarity to genes in the ATAF subfamily. Here we show that OsNAC6 is induced by cold, salt, drought and abscisic acid (ABA). We found that OsNAC6 is also induced by wounding. The response of OsNAC6 to wounding is very rapid and strong. OsNAC6 was also induced by jasmonic acid (JA), a plant hormone that activates defense responses against herbivores and pathogens. Our results imply that OsNAC6 , besides having a role in plant adaptation to abiotic stresses, also integrates signals derived from both abiotic and biotic stresses.

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In healthy tissue, the tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 epitopes. Moreover, CLDN18.2 is aberrantly expressed in malignancies of several other organs, such as pancreatic cancer (PC). A monoclonal antibody, zolbetuximab (formerly known as IMAB362), has been generated against CLDN18.2. In a phase 2 clinical trial (FAST: NCT01630083), zolbetuximab in conjunction with chemotherapy prolonged overall and progression-free survival over chemotherapy alone and improved quality of life. In this study, the mechanism of action and antitumor activity of zolbetuximab were investigated using nonclinical PC models. Zolbetuximab bound specifically and with strong affinity to human PC cells that expressed CLDN18.2 on the cell surface. In ex vivo systems using immune effector cells and serum from healthy donors, zolbetuximab induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), resulting in the lysis of cultured human PC cells. The amplitude of ADCC and CDC directly correlated with cell surface CLDN18.2 levels. The chemotherapeutic agent gemcitabine upregulated CLDN18.2 expression in cultured human PC cells and enhanced zolbetuximab-induced ADCC. In mouse xenograft tumors derived from human PC cell lines, including gemcitabine-refractory ones, zolbetuximab slowed tumor growth, benefited survival, and attenuated metastases development. The results presented here validate CLDN18.2 as a targetable biomarker in PC and support extension of the clinical development of zolbetuximab to patients with CLDN18.2-expressing PC.

HM-1 killer toxin secreted from Hansenula mrakii inhibits the growth of Saccharomyces cerevisiae cells by interfering with/%l,3-glucan synthesis. We found that HM-1 killer toxin killed intact cells but not nrotoolasts. In addition. cells lacking the functional KRE6 allele (kre6d) became resistant to higher concentration of HM-1 killer toxin. As reported by Xoemer and Bus$ey [(1991) I%oc. Natl. Acad. Sci. 88 112&-l li99], cells lacking functional KRE6 had a reduced level of the cell wall j?-1,6-glucan compared to that in cells harboring the normal KRE6. These results suggest that the cell wall /3-&can is involved in the action of HM-1 killer toxin. Addition of HM-1 killer toxin with several kinds of olieosaccharides revealed that either &l,j-or /3-1,6-glucan blocked the cytocidal action of HM-1 killer toxin whereas a-1,4-glucan and chitin did not. Gannan also interfered with HM-1 killer toxin action, but this inhibitory effect was much weaker than that observed with/L1,3-or B-1,6-glucans. Thus, it appears that the cell wall B-glucan interacts with HM-1 killer toxin, and that this toxin+glucan commitment is required for the action of HM-1 killer toxin.

Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified with their relative prevalence varying among the ethnical backgrounds. Recently, responsible genes, FANCA and FANCC, have been cloned. This report describes mutations of the FANCA gene, which we studied by direct sequencing of cDNA with confirmation on genomic DNA in 15 unclassified Japanese FA patients. A total of 19 sequence alterations were identified, of which 10 (six missense and four silent alterations) were likely to be nonpathogenic polymorphism. The remaining nine alterations, of which eight were novel mutations, were assumed to be pathogenic and consisted of two missense mutations and seven mutations resulting in truncation of gene product, demonstrating a wide allelic heterogeneity. The pathogenic mutations were found in 12 patients (80%); they were either homozygous or compound heterozygous in 10 patients, apparently heterozygous in two patients and none in three patients. We conclude that the sequence variability is intrinsic to the FANCA gene and that the relative prevalence of the FA-A subtype is unusually high in Japanese FA patients.

The novel immunosuppressant AS1387392 has been isolated from Acremonium sp. No. 27082. This compound showed a strong inhibitory effect against mammalian histone deacetylase and T-cell proliferation. Further, AS1387392 showed a good oral absorption, and its plasma concentration was higher than that of FR235222, an analog of AS1387392 that inhibited histone deacetylase previously reported. Given these findings, AS1387392 may represent an important new lead in developing immunosuppressant.

Fanconi anemia (FA), an autosomal recessive disorder characterized by a progressive pancytopenia associated with congenital anomalies and high predisposition to malignancies, is a genetically and clinically heterogeneous disease. At least eight complementation groups (FA-A to FA-H) have been identified. Previously, we studied mutations of the FANCA gene, responsible for FA-A, and found pathogenic mutations in 12 of 15 unclassified Japanese FA patients. Here, we further studied an additional 5 FA patients for sequence alterations of the FANCA gene and found pathogenic mutations in 2 of them. We further analyzed mutations of the FANCC and FANCG genes, responsible for FA-C and FA-G, respectively, in the remaining 6 FA patients. Although there was no alterations in the FANCC gene in these 6 patients, two novel mutations of the FANCG gene, causing aberrant RNA splicing, were detected in 2 FA patients. One was a base substitution from G to C of the invariant GT dinucleotides at the splice donor site of intron 3, resulting in the skipping of exon 3, as well as the skipping of exons 3 and 4. The other was a base substitution from C to T in exon 8, creating a nonsense codon (Q356X). This mutation resulted in the exclusion of a sequence of 18 nucleotides containing the mutation from the mRNA, without affecting the splicing potential of either the authentic or the cryptic splice donor site. Collectively, 14 of the 20 unclassified Japanese FA patients belong to the FA-A group, 2 belong to the FA-G group, and none belongs to the FA-C group.

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