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ABSTRACT Objectives Methods Results Conclusion The role of glycogen synthase kinase (GSK)‐3β in adult T‐cell leukemia (ATL) caused by human T‐cell leukemia virus type 1 (HTLV‐1) is paradoxical and enigmatic. Here, we investigated the role of GSK‐3β and its potential as a therapeutic target for ATL.Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST‐8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK‐3β and cell cycle/death‐related proteins, and survival signals was analyzed using RT‐PCR, immunofluorescence staining, and immunoblotting.HTLV‐1‐infected T‐cell lines showed nuclear accumulation of GSK‐3β. GSK‐3β knockdown and its inhibition with 9‐ING‐41 and LY2090314 suppressed cell proliferation/survival. 9‐ING‐41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c‐Myc. It induced caspase‐mediated apoptosis by decreasing the expression of Bcl‐xL, Mcl‐1, XIAP, c‐IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9‐ING‐41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis‐derived lactate levels.GSK‐3β functions as an oncogene in ATL and could be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T‐cell leukemia (ATL) caused by human T‐cell leukemia virus type 1 (HTLV‐1) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway. Methods: Cell proliferation, viability, cycle, and apoptosis were analyzed using WST‐8 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti‐ATL effects of DHODH knockdown and inhibition, RT‐PCR and immunoblotting were conducted. Results: HTLV‐1‐infected T‐cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV‐1‐infected T‐cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti‐proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c‐Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase‐mediated apoptosis by the upregulation of pro‐apoptotic and downregulation of anti‐apoptotic proteins. Furthermore, BAY2402234 induced caspase‐independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, IκBα, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF‐κB and Akt signaling is involved in its anti‐ATL action. Conclusion: These findings highlight DHODH as a potential therapeutic target for treating ATL. [ABSTRACT FROM AUTHOR]

We developed an oxidative synthetic method for α‐nitroketones from α‐substituted malononitriles and nitromethane under molecular oxygen. Only base and molecular oxygen are necessary without condensation reagents; this is an environmentally benign synthesis. [ABSTRACT FROM AUTHOR]

A case of cytoplasmic anaplastic lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma (ALCL) initially involving the skin in a 44‐year‐old Japanese female is reported. The patient had a hemorrhagic erythematous tumor on the right thigh without any systemic symptoms. Pathology showed diffuse infiltration of CD30‐positive anaplastic large cells positive for epithelial membrane antigen and cytoplasmic ALK. The right inguinal lymph node showed infiltration of tumor cells in the marginal sinus. Only 2 weeks after radiation therapy, the patient developed multiple subcutaneous nodules and lung involvement. Even after subsequent multichemotherapy sessions, cutaneous recurrence occurred. Literature review of cytoplasmic ALK‐positive ALCL initially involving in the skin revealed that skin lesions were mostly seen in the extremities and that half of the cases developed extracutaneous lesions. Radiation and chemotherapy were effective for most cases. Inverse RT‐PCR identified a tumor necrosis factor receptor‐associated factor (TRAF)1‐ALK fusion in our case. Most reported cases with this translocation experienced repeated changes in chemotherapy, suggesting poorer prognosis. Although ALK‐positive ALCL generally responds well to chemotherapy, the presence of a TRAF1‐ALK fusion may suggest resistance to treatment. Detection of fusion partners of ALK is important for predicting clinical courses and deciding treatment options. [ABSTRACT FROM AUTHOR]

Substituted quinolines, tricyclic and tetracyclic molecules with a quinoline moiety are synthesized by a domino reaction from dicyanoalkenes and 3‐aryl‐pent‐2‐en‐4‐ynals in one pot. We established two methods: one is catalyzed by chiral diphenylprolinol silyl ether, and the other is catalyzed by di(2‐ethyl)hexylamine, in combination with p‐nitrophenol. A wide variety of dicyanoalkenes can be employed. As the catalysts are secondary amines, and water is the only by‐product, this is an environmentally benign synthetic method for the preparation of substituted quinolines. [ABSTRACT FROM AUTHOR]

The asymmetric cross‐aldol reaction of two different aldehydes is a synthetically relevant reaction. Diarylprolinol catalyst with trifluoromethyl substituents and sulfonamide catalyst derived from diphenylprolinol are organocatalysts for the cross‐aldol reaction. The reactivity and stereoselectivity of these two catalysts were compared in the asymmetric cross‐aldol reactions of propanal and acetaldehyde as nucleophilic aldehydes and several electrophilic aldehydes. Depending on the electrophilic aldehydes, the preferable catalyst differs. By the proper selection of these two catalysts, potentially synthetically useful chiral building blocks can be synthesized with diastereoselectivities of anti:syn=2.6:1∼>20:1 and enantioselectivities of 60∼>98% ee. [ABSTRACT FROM AUTHOR]

Enantioselective formal carbo [3+3] cycloaddition reaction of isopropylidenemalononitrile (1) and α,β‐unsaturated aldehyde, catalyzed by diphenylprolinol silyl ether, was developed. The reaction is a domino Michael/aldol‐type reaction, followed by Al2O3‐mediated dehydration to afford 5‐substituted cyclohexene derivatives possessing a methylene‐malononitrile moiety, with excellent enantioselectivity. [ABSTRACT FROM AUTHOR]

An asymmetric domino Michael/Michael reaction of α,β‐unsaturated aldehydes 1 and α‐acetyl‐β‐substituted‐α,β‐unsaturated esters 2 catalyzed by diphenylprolinol silyl ether was developed. This is a formal carbo [4+2] cycloaddition reaction affording penta‐substituted cyclohexanes having the three continuous chiral centers with excellent diastereo‐ and enantioselectivity. [ABSTRACT FROM AUTHOR]

Plants produce a broad variety of defensive metabolites to protect themselves against herbivorous insects. Although polyamines have been implicated in various responses to abiotic and biotic stress, there have been no studies focused on amines in response to insect herbivory. By screening for bioactive amines, we identified isopentylamine as a novel type of herbivory‐induced compound in rice leaves, which was derived from the amino acid leucine in stable isotope labelling experiments. Accumulation of isopentylamine increased during herbivory by the brown planthopper (Nilaparvata lugens, BPH) and the rice‐feeding armyworm (Mythimna loreyi), as well as in response to treatment with the plant hormone, jasmonic acid. Likewise, isopentylamine accumulation was compromised in rice jasmonate biosynthesis mutants, hebiba and Osjar1. In bio‐assays, BPH insects feeding on rice seedlings submerged in 50 mg/L isopentylamine solution had a higher mortality compared with BPH feeding on seedlings submerged in water. Notably, the rice leaves submerged in 50 mg/L solution showed the endogenous concentrations of isopentylamine similar to that induced by BPHs. These results suggest that isopentylamine functions as a new type of plant defence metabolite that is rapidly induced by herbivore attack and deters insect herbivores in rice. We identified isopentylamine as a novel type of herbivory‐induced compound in rice leave. The bioassay results using the brown planthopper suggest that isopentylamine functions as a new type of plant defence metabolite that deters insect herbivores in rice. [ABSTRACT FROM AUTHOR]

Common wheat (Triticum aestivum L., AABBDD genome) is thought to have emerged through natural hybridization between Triticum turgidum L. (AABB genome) and Aegilops tauschii Coss. (DD genome). Hybridization barriers and doubling of the trihaploid F1 hybrids' genome (ABD) via unreduced gamete fusion had key roles in the process. However, how T. turgidum, the maternal progenitor, was involved in these mechanisms remains unknown. An artificial cross‐experiment using 46 cultivated and 31 wild T. turgidum accessions and a single Ae. tauschii tester with a very short genetic distance to the common wheat D genome was conducted. Cytological and quantitative trait locus analyses of F1 hybrid genome doubling were performed. The crossability and ability to cause hybrid inviability did not greatly differ between the cultivars and wild accessions. The ability to cause hybrid genome doubling was higher in the cultivars. Three novel T. turgidum loci for hybrid genome doubling, which influenced unreduced gamete production in F1 hybrids, were identified. Cultivated T. turgidum might have increased the probability of the emergence of common wheat through its enhanced ability to cause genome doubling in F1 hybrids with Ae. tauschii. The ability enhancement might have involved alterations at a relatively small number of loci. [ABSTRACT FROM AUTHOR]

Objectives: New effective therapeutic strategies for human T‐cell leukemia virus type 1 (HTLV‐1)‐driven adult T‐cell leukemia (ATL) are required because of resistance to chemotherapeutic agents. Here, we aimed to determine the therapeutic efficacy of a dual phosphoinositide 3 kinase (PI3K)/histone deacetylase (HDAC) inhibitor, CUDC‐907. Methods: Cell viability, cell cycle progression, and apoptotic events were examined by WST‐8 assay, flow cytometry, and Hoechst 33342 staining. Caspase activity was determined using Calorimetric Caspase Assay kits. Immunoblotting and electrophoretic mobility shift assay were used to assess the intracellular signaling cascades. Results: The combination of PI3K inhibitor BKM120 and HDAC inhibitor LBH589 resulted in a synergistic cytotoxic effect in HTLV‐1‐infected T cells. CUDC‐907 was more efficacious than BKM120 and LBH589. It induced G1 cell cycle arrest with downregulation of cyclin D1/D2, CDK4/6, c‐Myc, and phosphorylated retinoblastoma protein expression. Apoptosis was induced via caspase‐3/8/9 activation along with downregulation of Bcl‐XL, Bcl‐2, XIAP, survivin, and cIAP1/2, and upregulation of Bax and Bak. Histone H3 acetylation, H2AX activation, Hsp27 phosphorylation, and Hsp70 and Hsp27 upregulation were observed after treatment. CUDC‐907 suppressed Akt, NF‐κB, and AP‐1 by downregulating phosphorylated and/or total Akt, IKKα/β, RelA, JunB, and JunD. Conclusion: CUDC‐907 may be a potential therapeutic agent for ATL. [ABSTRACT FROM AUTHOR]

Although chemical volatiles emitted from host and non‐host trees have been suggested as important cues for bark and ambrosia beetles, their responses to leaf volatiles is poorly understood. The oak ambrosia beetle, Platypus quercivorus (Murayama) (Coleoptera: Curculionidae), is a vector for the fungus that causes Japanese oak wilt. Using a Y‐tube olfactometer, we tested the behavioral response of P. quercivorus to leaf volatiles emitted from four host trees – Quercus crispula Blume, Quercus serrata Murray, Quercus salicina Blume, and Castanea crenata Sieb. & Zucc. (all Fagaceae) – and two non‐host trees, Fagus crenata Blume (Fagaceae) and Cryptomeria japonica D. Don (Cupressaceae). A flight mill was used to evaluate the effect of flight on the behavioral response to leaf volatiles. The bioassays were repeated 10× before and 10× after flight in the flight mill for each of the 54 individual beetles. Leaf volatile components were analyzed using gas chromatography–mass spectrometry. The bioassay results supported our hypothesis: P. quercivorus was attracted by the leaf volatiles of hosts and was deterred by the leaf volatiles of non‐hosts. The behavioral response of P. quercivorus to the leaf volatiles was stronger after flight. Males had a stronger behavioral response than females to leaf volatiles. The leaf volatile chemical profile of the non‐host C. japonica differed from the profile of the host plants. However, the chemical profile of the non‐host F. crenata was similar to the profile of the hosts. Our findings provide insight into the functions of leaf chemical volatiles in the interaction of P. quercivorus with its hosts and non‐hosts and may help improve the control of P. quercivorus and Japanese oak wilt. [ABSTRACT FROM AUTHOR]

Objectives: T‐cell receptor (TCR) signaling‐induced activation of NF‐κB requires assembly of the CARD11‐BCL10‐MALT‐1 complex and IκB kinase (IKK). Gain‐of‐function alterations in this component of the TCR/NF‐κB pathway are associated with the development of HTLV‐1‐driven adult T‐cell leukemia (ATL). We aimed to determine whether inhibition of MALT‐1‐mediated NF‐κB activation could have anti‐ATL activity. Methods: RT‐PCR, immunoblotting, and electrophoretic mobility shift assays were performed to assess expression levels of MALT‐1 and the intracellular signaling cascades. Cell proliferation, cell cycle progression, and apoptotic events were examined using WST‐8 assays, flow cytometry, and Hoechst 33342 staining. Results: MALT‐1 expression was upregulated in ATL‐derived T‐cell lines compared to that in normal PBMCs and uninfected or HTLV‐1‐transformed T‐cell lines. Targeting MALT‐1 with siRNA decreased cell proliferation. A MALT‐1 inhibitor (MI‐2) suppressed cleavage of the MALT‐1‐target protein, CYLD, and inhibited proliferation via G1 phase arrest. MI‐2 induced apoptosis through caspase‐3/8/9 activation and inhibited the phosphorylation of IKKα/β and IκBα, resulting in the accumulation of IκBα and suppression of NF‐κB‐DNA binding. Additionally, MI‐2 inhibited the expression of apoptosis‐ and cell cycle‐related proteins regulated by NF‐κB. Conclusions: MALT‐1 plays an important regulatory role in NF‐κB signaling during ATL‐genesis, and targeting MALT‐1 is a promising therapeutic strategy for this disease. [ABSTRACT FROM AUTHOR]

Summary: Phytoalexins play a pivotal role in plant–pathogen interactions. Whereas leaves of rice (Oryza sativa) cultivar Nipponbare predominantly accumulated the phytoalexin sakuranetin after jasmonic acid induction, only very low amounts accumulated in the Kasalath cultivar. Sakuranetin is synthesized from naringenin by naringenin 7‐O‐methyltransferase (NOMT). Analysis of chromosome segment substitution lines and backcrossed inbred lines suggested that NOMT is the underlying cause of differential phytoalexin accumulation between Nipponbare and Kasalath. Indeed, both NOMT expression and NOMT enzymatic activity are lower in Kasalath than in Nipponbare. We identified a proline to threonine substitution in Kasalath relative to Nipponbare NOMT as the main cause of the lower enzymatic activity. Expanding this analysis to rice cultivars with varying amounts of sakuranetin collected from around the world showed that NOMT induction is correlated with sakuranetin accumulation. In bioassays with Pyricularia oryzae, Gibberella fujikuroi, Bipolaris oryzae, Burkholderia glumae, Xanthomonas oryzae, Erwinia chrysanthemi, Pseudomonas syringae, and Acidovorax avenae, naringenin was more effective against bacterial pathogens and sakuranetin was more effective against fungal pathogens. Therefore, the relative amounts of naringenin and sakuranetin may provide protection against specific pathogen profiles in different rice‐growing environments. In a dendrogram of NOMT genes, those from low‐sakuranetin‐accumulating cultivars formed at least two clusters, only one of which involves the proline to threonine mutation, suggesting that the low sakuranetin chemotype was acquired more than once in cultivated rice. Strains of the wild rice species Oryza rufipogon also exhibited differential sakuranetin accumulation, indicating that this metabolic diversity predates rice domestication. Significance Statement: Although phytoalexin accumulation plays an important role in plant–pathogen interactions, there has been insufficient investigation of within‐species chemodiversity. We found that variation in naringenin O‐methyltransferase, a sakuranetin biosynthetic enzyme, strongly influences the relative abundance of two flavonoid phytoalexins, sakuranetin and its precursor naringenin, in rice. This phytochemical diversity, which is present in both cultivated and wild rice, provides insight into the evolution of plant defenses and may influence susceptibility to bacterial and fungal pathogens. [ABSTRACT FROM AUTHOR]

The PLCG1 gene, which encodes the phospholipase C γ1 isoform, is located within the commonly deleted region of the long arm of chromosome 20 (del(20q)) observed in myelodysplastic syndromes (MDS). Phospholipase C is involved in diverse physiological and pathological cellular processes through inositide signaling. We hypothesized that reduced PLCG1 expression because of haploinsufficiency by del(20q) plays a role in the molecular pathogenesis of MDS. Therefore, we analyzed PLCG1 expression in bone marrow mononuclear cells at diagnosis in 116 MDS patients with or without del(20q) by quantitative RT‐PCR to evaluate its clinical significance. The expression level of PLCG1 was significantly lower not only in MDS patients with del(20q) but also in those without del(20q) compared to that of the controls, which suggests that reduced PLCG1 expression is a common molecular event in MDS. Patients in the lowest quartile (Q4) group for PLCG1 expression had lower overall survival (OS) compared to that of other patients (Q1‐Q3) (log‐rank test, P =.0004) with estimated median OS times of 22 in the Q4 group and 106 months in the Q1‐3 group. Univariate and multivariate analysis indicated reduced PLCG1 expression (Q4) was associated with lower OS (hazard ratio 2.58, 95% CI 1.35‐4.84, P =.0049), which suggests that reduced PLCG1 expression is an independent prognostic factor for OS. In addition, patients were well‐stratified for OS by combining PLCG1 expression level (Q4 vs Q1‐3) and bone marrow blast percentage (5% or more vs less than 5%). Thus, the level of PLCG1 expression at time of diagnosis is a prognostic biomarker for MDS. [ABSTRACT FROM AUTHOR]

To elucidate the mechanism of acyl chain remodeling at the sn‐1 position of phosphatidylcholine (PC), we investigated acyl chain introduction using a newly synthesized 1‐hydroxy‐2‐hexadecyl‐sn‐glycero‐3‐phosphocholine (HHPC) in Saccharomyces cerevisiae. HHPC is incorporated into yeast cells and converted to a PC species containing acyl residues of 16 or 18 carbons. The efficiency of palmitoleic acid introduction to HHPCin vitro is lower in the reaction with the extract from the deletion mutant of ALE1, which encodes a membrane‐bound O‐acyltransferase, than in that with extracts from the wild‐type strain. In addition, deletion of ALE1 causes reductions in the molecular species containing acyl residues in HHPC. These results reveal that ALE1 is involved in acyl chain transfer to the sn‐1 position of HHPC in yeast. [ABSTRACT FROM AUTHOR]

Background Human T-cell leukemia virus type 1 ( HTLV-1) causes adult T-cell leukemia ( ATL). Viral Tax protein plays a major role in ATL development. Pim family of serine/threonine kinases is composed of Pim-1, -2, and -3. The potential of Pim family as a target in ATL was analyzed. Methods RT- PCR and Western blotting were used to determine the expression of Pim kinases, Tax, and intracellular signal molecules. Knockdown of Pim-3 and RelA was performed using small interfering RNA. The effects on cell proliferation, viability, cell cycle, and apoptosis were analyzed by WST-8, propidium iodide, and APO2.7 assay. NF-κB DNA binding activity was investigated by electrophoretic mobility shift assay. Results Pim-3 expression was restricted to HTLV-1-infected T-cell lines. Tax induced Pim-3 expression through NF-κB. Knockdown of Pim-3 showed growth inhibition of HTLV-1-infected T cells. NJC97- NH, a novel inhibitor of the Pim-1/3 kinases, inhibited cell viability. NJC97- NH induced G2/M cell cycle arrest associated with downregulation of cyclin A and cyclin B1 expression, as well as apoptosis accompanied with downregulation of XIAP and Mcl-1 expression through inhibition of NF-κB pathway, mediated through decrease in IκBα and RelA phosphorylation. Conclusion Pim-3 is a potentially suitable target for the development of novel therapeutic agents against ATL. [ABSTRACT FROM AUTHOR]

Objectives We previously reported loss of heterozygosity on 1p in chronic myelogenous leukemia ( CML). We analyzed promoter methylation and mutation of tumor suppressor genes on 1p36 in CML. Methods We performed methylation-specific PCR ( MS- PCR) analysis of the PRDM2, RUNX3, and TP73 genes in 61 patients with CML (43 chronic phase, CP; two accelerated phase; and 16 blast crisis, BC). Oxidative MS- PCR, PCR-single-strand conformation polymorphism, and real-time reverse transcriptase PCR were also analyzed. K-562 cells were grown in the presence of 5-Aza- dC and trichostatin A. Results Methylation of the PRDM2, RUNX3, and TP73 genes was detected in 24/60 (40%), 21/61 (34%), and 28/60 (47%) patients, respectively. Methylation of all three genes was detected in 19/59 (32%) patients. Methylation was more frequent in BC than in CP. Oxidative MS- PCR analysis detected 5- mC in the PRDM2, RUNX3, and TP73 genes in 10/22 (45%), 15/21 (71%), and 16/26 (62%) samples with methylation detected by MS- PCR, respectively. Decreased expression was observed in several samples with methylation, while no mutations were found in the genes. Treatment of K-562 cells induced growth suppression, demethylation, and reexpression of the PRDM2 and RUNX3 genes. Conclusion Multiple tumor suppressor genes on 1p were inactivated in CML by methylation. [ABSTRACT FROM AUTHOR]

An asymmetric formal synthesis of azadirachtin, a potent insect antifeedant, was accomplished in 30 steps to Ley's synthetic intermediate (longest linear sequence). The synthesis features: 1) rapid access to the optically active right-hand segment starting from the known 5-hydroxymethyl-2-cyclopentenone scaffold; 2) construction of the B and E rings by a key intramolecular tandem radical cyclization; 3) formation of the hemiacetal moiety in the C ring through the a-oxidation of the six-membered lactone followed by methanolysis. [ABSTRACT FROM AUTHOR]

Understanding the factors affecting stress tolerance in phytoseiid mites is critical for their integration into biological control programs. In the present study, the effects of diet (varying in prey species, physiological status and phenotype) are examined on the future starvation tolerance of the predatorymite Neoseiulus californicus McGregor (Acari: Phytoseiidae). The predators are fed from egg to adulthood on diapausing or nondiapausing Tetranychus urticae, Tetranychus kanzawai (wild and albino strains) or the nondiapausing species Panonychus citri (wild and albino strains). Thereafter, 3-day-old mated adult females are held without food at 25±1 °C and a relative humidity of 98±2%. The survival of these starved females is observed daily until all females have died. The survival curves and mean survival times of N. californicus are found to vary among prey types and are significantly longer when the predator is fed with diapausing prey. This enhanced survival is consistent with high concentrations of glycogen and triacylglyceride in the body of the predator at the onset of starvation. The predators fed nondiapausing prey have shorter survival times, and the glycogen and triacylglyceride contents in their bodies are low or undetectable. The protein contents of the predator's body are similar after consuming different prey types, except for a high concentration when fed the albino strain of P. citri. Protein content is unlikely to play a direct role in starvation tolerance, although it may affect the response to varying glycogen and triacylglyceride levels. These findings indicate that nutritional value of prey has a strong impact on the starvation tolerance of N. californicus. [ABSTRACT FROM AUTHOR]

Objective To analyze the role of adjuvant chemotherapy in lymph node-positive patients with upper tract urothelial carcinoma undergoing radical nephroureterectomy, and identified the prognostic adjuvant chemotherapy parameters. Methods The clinicopathological records of 74 lymph node-positive upper tract urothelial carcinoma patients who underwent radical nephroureterectomy at multiple institutions were retrospectively reviewed. A total of 45 patients (60.8%) received adjuvant chemotherapy, and 29 (39.2%) underwent radical nephroureterectomy only. Kaplan-Meier analyses and Cox proportional hazard modeling were used to study the association between adjuvant chemotherapy status and both recurrence-free survival and cancer-specific survival. Results Estimated 5-year recurrence-free survival was 33.6% in patients undergoing radical nephroureterectomy plus adjuvant chemotherapy compared with 13.5% in patients undergoing radical nephroureterectomy only (hazard ratio 0.52; P = 0.014, log-rank test). Estimated 5-year cancer-specific survival was 42.5% in patients undergoing radical nephroureterectomy plus adjuvant chemotherapy, compared with 12.0% in patients undergoing radical nephroureterectomy only (hazard ratio 0.36; P = 0.0003, log-rank test). Multivariate analysis showed that adjuvant chemotherapy was a significant prognostic factor for cancer-specific survival ( P = 0.001), but not for recurrence-free survival ( P = 0.076). When patients undergoing radical nephroureterectomy plus adjuvant chemotherapy were dichotomized, based on preoperative C-reactive protein levels above or below the normal value, higher C-reactive protein levels were significantly associated with poor survival ( P = 0.012). Conclusion Adjuvant chemotherapy seems to improve cancer-specific survival in lymph node-positive patients with upper tract urothelial carcinoma. Preoperative C-reactive protein levels could carry a prognostic value in this setting, and lymph node-positive patients with low preoperative CRP values should be considered for adjuvant chemotherapy. Further studies are necessary to validate these observations. [ABSTRACT FROM AUTHOR]

1. Herbivory often induces systemic plant responses that affect the host choice of subsequent herbivores, either deterring or attracting them, with implications for the performance of both herbivore and host plant. Combining measures of herbivore movement and consumption can efficiently provide insights into the induced plant responses that are most important for determining choice behaviour. 2. The preferences of two frugivorous stink bug species, Nezara viridula and Euschistus servus between cotton plants left undamaged or damaged by Helicoverpa zea and Heliothis virescens larvae were investigated. A novel consumer movement model was used to investigate if attraction rates or leaving rates determined preferences. Stink bug consumption rates were measured using salivary sheath flanges. Finally, the systemic induction of selected phenolic-based and terpenoid secondary metabolites were measured from heliothine herbivory on developing cotton bolls, to investigate if they explained stink bug feeding responses. 3. Heliothine herbivory did not affect the N. viridula feeding preference. However, we found opposing effects of H. zea and H. virescens herbivory on the behaviour of E. servus. Avoidance of H. zea-damaged plants is not obviously related to phenolic or terpenoid induction in cotton bolls; whereas a preference for H. virescens-damaged plants may be related to reductions in chlorogenic acid in boll carpel walls. 4. The present results highlight the inferential power of measuring both consumer movement and consumption in preference experiments and combining behavioural responses with phytochemical responses. Furthermore, while plant-mediated interactions among herbivorous insects are well studied, interactions among frugivorous species specifically have been poorly documented. [ABSTRACT FROM AUTHOR]

SUMMARY Improving the reusability of models and increasing automatic code generation efficiency are problems in model-driven development. In order to solve these problems, we apply component-based development technologies that have mainly been developed at the software implementation level to the modeling level. In the proposed approach, functionally relevant model elements are packaged as a component, and the modeling of software is performed by associating them with the model components. The role of a model becomes clear by introducing the concept of a component, and the reusability of model components is improved by externalizing the dependencies between the components. In addition, flexible model transformation rules united with the roles of models can be designed. As a result, the proposed method is able to generate more source code automatically. The validity of the proposed approach is verified through application experiments. [ABSTRACT FROM AUTHOR]

Left ventricular (LV) twist can be evaluated using two-dimensional speckle tracking echocardiography (2DSTE) by analyzing difference between apical and basal rotation. However, it is unable to evaluate global rotational dyssynchrony because it cannot assess mid-wall rotation. Recently developed three-dimensional STE (3DSTE) can investigate LV global rotational dyssynchrony. In this study, we investigated the role of torsion on the long-term effects of cardiac resynchronization therapy ( CRT) using 3DSTE. We evaluated 43 patients by 3DSTE: 12 CRT responders, 14 CRT nonresponders, and 17 healthy normal controls. Regional torsion and rotation were assessed using 3DSTE across 16 segments during CRT-off (native conduction) and CRT-on. The following parameters were calculated: global peak twist, Δ global peak twist (difference between CRT-on and CRT-off), and torsion delay index. The torsion delay index was considered to be the rotational energy lost by rotational dyssynchrony. Global peak twist did not show significant differences between the responders and nonresponders during CRT-off (4.0 ± 3.4° vs. 2.8 ± 2.3°, P = 0.295), but it significantly improved in responders compared to nonresponders after CRT-on (5.4 ± 3.5° vs. 2.6 ± 2.6°, P = 0.029). The torsion delay index during CRT-off was significantly higher in responders compared to nonresponders and normal controls (18.5 ± 11.3 vs. 8.6 ± 3.8 and 7.8 ± 5.5, P = 0.010 and P = 0.004, respectively). The torsion delay index during CRT-off significantly correlated with the Δ global peak twist (r = 0.503, P = 0.009). Improvement in LV global peak twist, which is one of the mechanisms for the long-term effects of CRT correlated with the torsion delay index during native conduction that can only be calculated by 3DSTE. [ABSTRACT FROM AUTHOR]

Traditionally, Management Information Systems (MIS) have been developed without using formal methods. By informal methods, MIS are developed over their lifecycle without having any models. This causes many problems, such as lack of reliability of the system design specifications. In order to overcome these problems, a model theory approach has been proposed. The approach is based on the idea that a system can be modeled by automata and set theory. However, it is very difficult to generate automata of the system to be developed right from the start. On the other hand, there is a model-driven development method that can flexibly adapt to changes of business logics or implementing technologies. In model-driven development, a system is modeled using a modeling language such as UML. This paper proposes a new development method for management information systems, applying the model-driven development method to a component of the model theory approach. Experiments have shown that the reduction in the amount of efforts is more than 30%. © 2013 Wiley Periodicals, Inc. Electron Comm Jpn, 96(2): 16-24, 2013; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.11445 [ABSTRACT FROM AUTHOR]

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography-tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival ( OS) and event-free survival ( EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270-359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib. ( Cancer Sci 2012; 103: 1071-1078) [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL), which is an aggressive and fatal CD4+ T cell malignancy. MicroRNA (miRNA), a novel class of RNA that regulates gene expression, is involved in many cellular processes such as growth, development and apoptosis. It has recently been linked to several cancer phenotypes. However, aberrant miRNA expression and its pathologic significance in ATL are not well documented. Here, we investigated the role of miRNAs in HTLV-1-related leukemogenesis. The results showed that miR-146a was upregulated in HTLV-1-infected T-cell lines compared to uninfected T-cell lines. Tax-induced miR-146a expression in a NF-κB-dependent manner and inhibited the expression of gene harboring the target sequence of miR-146a on its 3′UTR. Inhibition of miR-146a function by anti-miRNA inhibitor reduced the proliferation of HTLV-1-infected T-cell lines but not that of uninfected T-cell lines. Moreover, overexpression of miR-146a enhanced the growth of an HTLV-1-infected T-cell line. Our findings suggest that miR-146a is a potentially suitable therapeutic target of ATL. [ABSTRACT FROM AUTHOR]

This article has been retracted at the request of Editor-in-Chief & Author. The following article from Cancer Science: Mariko Tomita, Zahidunnabi Dewan, Naoki Yamamoto, Akira Kikuchi and Naoki Mori. Epstein-Barr virus-encoded latent membrane protein 1 activates β-catenin signaling in B lymphocytes, Cancer Science 2009; : 807-812, (doi: ), published online on 20 March 2009 on Wiley Interscience (), now Wiley Online Library (), has been retracted by agreement between the authors, the journal Editor-in-Chief, Yusuke Nakamura, and Blackwell Publishing Asia Pty Ltd. All authors wish to retract this paper due to repeated use of images in the same gel in two figures within the article. Yusuke Nakamura Editor-in-Chief Cancer Science [ABSTRACT FROM AUTHOR]

Aurora kinases play an essential role in regulating mitosis and cell division. Inhibition of Aurora kinases results in suppression of cell division, phosphorylation of histone H3 and induction of apoptosis in many cell types. These characteristics have prompted the testing of Aurora kinase inhibitors as chemotherapeutic agents. In our study, we report the in vitro activities of AZD1152, a selective inhibitor of Aurora B kinase in human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia (ATL), -infected T-cell lines. Overexpression of Aurora B was noted in HTLV-1-infected T-cell lines compared to HTLV-1-uninfected T-cell lines. AZD1152 reduced the viability of HTLV-1-infected T-cell lines within 24 hr but did not affect that of -uninfected T-cell lines. Although AZD1152 inhibited phosphorylation of histone H3 on Ser10 in both HTLV-1-infected and -uninfected T-cell lines, it induced polyploidy only in HTLV-1-uninfected T-cell lines. AZD1152 induced early apoptosis of HTLV-1-infected T-cells without induction of polyploidy. We have reported previously that a pan-Aurora kinase inhibitor induced apoptosis through inhibition of NF-κB signaling activity in HTLV-1-infected T-cell lines. In contrast, AZD1152 did not affect NF-κB activity in these cells. It induced p53 and p21 expression in HTLV-1-infected but not in HTLV-1-uninfected T-cell lines, suggesting that activation of p53-dependent postmitotic checkpoint might prevent polyploidy in HTLV-1-infected T-cells. Our results suggest that specific inhibition of Aurora B kinase is a potentially useful therapeutic strategy in the treatment of ATL and that further in vivo exploration is warranted. [ABSTRACT FROM AUTHOR]

Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle. We have shown previously that Aurora A expression is increased aberrantly in human T-cell leukemia virus type 1 (HTLV-1)-infected T-cell lines and primary adult T-cell leukemia cells, and a pan-Aurora kinase inhibitor, which inhibits both Aurora A and Aurora B kinases, reduces viability and induces apoptosis in these cells. However, the specific effects of Aurora A inhibition on HTLV-1-infected T-cells are poorly understood. In this study, we addressed this question by comparing the effects of MLN8237, a selective inhibitor of Aurora A, on cell viability, cell cycle progression, and induction of apoptosis in HTLV-1-infected and -uninfected T-cell lines. MLN8237 reduced the viability of HTLV-1-infected T-cell lines within 24 h, but its effects on that of HTLV-1-uninfected T-cell lines were moderate. MLN8237 induced early apoptosis of HTLV-1-infected T-cell lines without induction of polyploidy. It induced p53 and p21 expression in HTLV-1-infected but not in -uninfected T-cell lines, suggesting that MLN8237-treated HTLV-1-infected T-cell lines exit from mitosis and activate a p53-dependent postmitotic G1 checkpoint, leading to G1 arrest followed by the induction of apoptosis. Our results suggest that specific inhibition of Aurora A kinase is a potentially useful therapeutic strategy in the treatment of adult T-cell leukemia and that further in vivo exploration is warranted. ( Cancer Sci 2010; 101: 1204–1211) [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori secretes vacuolating cytotoxin (VacA) that damages the gastric epithelium by erosion and loosening of tight junctions. VacA has also immunosuppressive effects, inhibiting interleukin (IL)-2 secretion by interference with the T cell receptor/IL-2 signaling pathway. This study investigated the effect of VacA on gene expression of T cells. Materials and methods: Gene expression profile of a T cell line, Jurkat, was analyzed by the cDNA microarray technique after VacA challenge. The expression of specific mRNAs was assessed by reverse transcription-polymerase chain reaction. Interleukin (IL)-8 concentrations in culture supernatants and cell surface expression of CD69 were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. We evaluated nuclear factor-κB (NF-κB) activation in Jurkat cells challenged with VacA by luciferase assay, electrophoretic mobility shift assay, and Western blot analysis. Results: VacA produced two or greater fold up-regulation of expression of 60 genes. Most of these genes were associated with signal transduction, regulation of gene expression, apoptosis, and inflammation. Up-regulation of four genes ( IL8, IL2RA, ICAM1, and CD69) was confirmed. The supernatants of cells incubated with VacA showed significantly higher secretion levels of IL-8 than those incubated without VacA. VacA also induced the cell surface expression of CD69. Since microarray analysis indicated NF-κB was involved in the transcriptional activation of the above genes, we examined NF-κB signaling pathway. VacA activated NF-κB via classical but not alternative pathway. Conclusions: VacA has two paradoxical effects on T cells, immunosuppression, and proinflammatory effects. The latter is mediated by NF-κB activation. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus-encoded latent membrane protein 1 is considered the Epstein–Barr virus oncogene based on its importance in Epstein–Barr virus-induced B-lymphocyte transformation. β-Catenin is a potential oncogene, and its accumulation has been implicated in a variety of human cancers. Here, we found that β-catenin protein was highly expressed in Epstein–Barr virus-immortalized B-cell lines compared with peripheral blood mononuclear cells from healthy donors. β-Catenin expression in Epstein–Barr virus-immortalized B-cell line decreased following treatment with LY294002, an inhibitor of phosphatidylinositol 3-kinase. Treatment with LY294002 or knockdown of β-catenin by small interfering RNA reduced the growth of Epstein–Barr virus-immortalized B-cell line. Transient transfection of latent membrane protein 1 expression plasmid increased β-catenin protein expression and β-catenin-dependent transcription. Latent membrane protein 1 deletions mutants lacking the carboxyl-terminal activating region 1 domain failed to enhance β-catenin protein expression and β-catenin-dependent transcriptional activity. They also failed to increase phosphorylated AKT expression. Dominant-negative AKT suppressed latent membrane protein 1-induced β-catenin-dependent transcriptional activity. These results suggest that latent membrane protein 1 activates β-catenin through the phosphatidylinositol 3-kinase/AKT signaling pathway. Activation of the β-catenin pathway by Epstein–Barr virus may contribute to the lymphoproliferation characteristic of Epstein–Barr virus-infected B-cells. ( Cancer Sci 2009; 100: 807–812) [ABSTRACT FROM AUTHOR]

Clinical trials for treatment of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) using all- trans-retinoic acid (ATRA) have shown satisfactory therapeutic responses, although efficacies were limited. Recently, many synthetic retinoids have been developed and among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARα- and RARβ-specific retinoid expected to overcome ATRA resistance. The present study examined the inhibitory effects of Am80 on HTLV-I-infected T-cell lines and ATL cells. Am80 had negligible growth inhibition of peripheral blood mononuclear cells but marked growth inhibition of both HTLV-I-infected T-cell lines and ATL cells. Am80 arrested cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. It inhibited also the phosphorylation of IκBα and NF-κB-DNA binding, in conjunction with reduction of expression of proteins involved in the G1/S cell cycle transition and apoptosis. Am80 also inhibited the expression of JunD, resulting in suppression of AP-1-DNA binding. Furthermore, severe combined immunodeficient mice with tumors induced by subcutaneous inoculation of HTLV-I-infected T cells, responded to Am80 treatment with partial regression of tumors and no side-effects. These findings demonstrate that Am80 is a potential inhibitor of NF-κB and AP-1, and is a potentially useful therapeutic agent against ATL. ( Cancer Sci 2008; 99: 2286–2294) [ABSTRACT FROM AUTHOR]

The identification of galectin-9 as a ligand for T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), expressed on T-helper type-1 (Th1) cells, has established the Tim-3-galectin-9 pathway as a regulator of Th1 immunity. Whereas there is compelling evidence for the effects of galectin-9 on T-cell fate, limited information is available on the impact of galectin-9 on B lymphocytes. We found that protease-resistant galectin-9, hG9NC(null), but not galectin-1 or -8, prevented cell growth of malignant B cells, such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL). β-galactoside binding was essential for galectin-9-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, D2, B1, Cdk4, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of the genes that encode these proteins are regulated by nuclear factor-κB (NF-κB), and constitutive activation of NF-κΒ is a common characteristic of both types of malignancies. hG9NC(null) inhibited IκBα phosphorylation, resulting in suppression of NF-κB. AP-1 has also been implicated in the control of cell survival. hG9NC(null) inhibited the expression of JunD, resulting in the suppression of AP-1. Our results suggest that hG9NC(null) is a potentially suitable agent for the management of BL and HL. [ABSTRACT FROM AUTHOR]

A multiagent system (MAS) has recently gained public attention as a technique to solve competition and cooperation in distributed systems. However, MAS's vulnerability due to the propagation of failures prevents its application to a large-scale system. This paper proposes a general composition technique to improve its reliability easily applied to the existent MAS. The proposed system monitors messages between agents to detect undesirable behaviors (failures). Collecting related information, the system generates global information of interdependence between agents and expresses it in a graph. This interdependence graph enables us to detect or predict undesirable behaviors. This paper also shows that the system can optimize performance of MAS and improve adaptively its reliability under complicated and dynamic environment by applying the global information acquired from analysis of the interdependence graph to a replication system. © 2008 Wiley Periodicals, Inc. Electr Eng Jpn, 164(1): 62–68, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20517 [ABSTRACT FROM AUTHOR]

Geraniol dehydrogenase (GeDH), which plays an important role in the biosynthesis of neral, an alarm pheromone, was purified from the astigmatid mite Carpoglyphus lactis. The enzyme was obtained in an apparently homogeneous and active form after 1879-fold purification through seven steps of chromatography. Car. lactis GeDH was determined to be a monomer in its active form with a relative molecular mass of 42 800, which is a unique subunit structure in comparison with already established alcohol dehydrogenases. Car. lactis GeDH oxidized geraniol into geranial in the presence of NAD+. NADP+ was ineffective as a cofactor, suggesting that Car. lactis GeDH is an NAD+-dependent alcohol dehydrogenase. The optimal pH and temperature for geraniol oxidation were determined to be pH 9.0 and 25 °C, respectively. The Km values for geraniol and NAD+ were 51.0 μm and 59.5 μm, respectively. Car. lactis GeDH was shown to selectively oxidize geraniol, whereas its geometrical isomer, nerol, was inert as a substrate. The high specificity for geraniol suggests that Car. lactis GeDH specializes in the alarm pheromone biosynthesis of Car. lactis. Car. lactis GeDH is composed of 378 amino acids. Structurally, Car. lactis GeDH showed homology with zinc-dependent alcohol dehydrogenases found in mammals and a mosquito (36.6–37.6% identical), and the enzyme was considered to be a member of the medium-chain dehydrogenase/reductase family, in view of the highly conserved sequences of zinc-binding and NAD+-binding sites. Phylogenetic analyses indicate that Car. lactis GeDH could be categorized as a new class, different from other established alcohol dehydrogenases. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia (ATL) is an aggressive type of leukemia, originating from T-cells infected with human T-cell leukemia virus type 1. Accumulating evidence suggests the aberrant activation of NF-κB to be a causative factor mediating the abnormal proliferation of leukemic cells, thus resulting in the development of ATL. A rearranged NF-κB2/p100 gene was isolated from an ATL-derived cell line, which was generated by a chromosomal translocation. The isolated NF-κB2 mutant is fused with the with no (lysine) deficient protein kinase 1 gene, coding for a 58 kDa protein that retains the DNA binding Rel homology domain, but it lacks the entire ankyrin repeat inhibitory domain, thus suggesting its constitutive activation. This rearranged NF-κB2 gene product (p58) was localized in the nucleus, and formed a complex with NF-κB p65 or RelB. Moreover, a T-cell line expressing p58 increased the amount of an NF-κB2-inducible gene, NF-κB2/p100 by itself. These results suggest that such NF-κB2 gene rearrangement may therefore be a factor in the constitutive activation of NF-κB in ATL, and thereby playing a role in the ATL pathogenesis. ( Cancer Sci 2008; 99: 792–798) [ABSTRACT FROM AUTHOR]

ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that β-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-κB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IκBα phosphorylation, resulting in suppression of NF-κB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Anti-resorptive bisphosphonates are used for the treatment of hypercalcaemia and bone complications associated with malignancies and osteoporosis, but also have been shown to have anti-tumour effects in various cancers. Adult T-cell leukaemia (ATL) is a fatal T-cell malignancy caused by infection with human T-cell leukaemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcaemia, both of which are major factors in the morbidity of ATL. Thus, the search for anti-ATL agents that have both anti-tumour and anti-resorptive activity is warranted. The bisphosphonate agent, incadronate, prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of non-infected T-cell lines or normal peripheral blood mononuclear cells. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines, and treatment of these cells with substrates of the mevalonate pathway blocked the incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Rap1A protein. These results demonstrated that incadronate-induced growth suppression occurs by interfering with the mevalonate pathway. Importantly, treatment with incadronate reduced tumour formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into severe combined immunodeficient mice. These findings suggest that incadronate could be potentially useful for the treatment of ATL. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are an important component of the innate immune response against microbial infections and tumors. Direct involvement of NK cells in tumor growth and infiltration has not yet been demonstrated clearly. Primary effusion lymphoma (PEL) cells were able to produce tumors and ascites very efficiently with infiltration of cells in various organs of T-, B- and NK-cell knock-out NOD/SCID/γcnull (NOG) mice within 3 weeks. In contrast, PEL cells formed small tumors at inoculated sites in T- and B-cell knock-out NOD/SCID mice with NK-cells while completely failing to infiltrate into various organs. Immunosupression of NOD/SCID by treatment with an antimurine TM-β1 antibody, which transiently abrogates NK cell activity in vivo, resulted in enhanced tumorigenicity and organ infiltration in comparison with non-treated NOD/SCID mice. Activated human NK cells inhibited tumor growth and infiltration in NOG mice. Our results suggest that NK cells play an important role in growth and infiltration of PEL cells, and activated NK cells could be a promising immunotherapeutic tool against tumor or virus-infected cells either alone or in combination with conventional therapy. The rapid and efficient engraftment of PEL cells in NOG mice also suggests that this new animal model could provide a unique opportunity to understand and investigate the mechanism of pathogenesis and malignant cell growth. ( Cancer Sci 2006; 97: 1381–1387) [ABSTRACT FROM AUTHOR]

The Akt signaling pathway is important for survival and growth of cancer cells. In the present paper we show that the Akt signaling pathway is constitutively activated in human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines and in primary adult T-cell leukemia (ATL) cells. Curcumin, a natural compound present in turmeric, has been studied vigorously as a potent chemopreventive agent for cancer therapy because of its inhibitory effect on proliferation and induction of apoptosis in several tumor cell lines. We investigated the effect of curcumin on Akt activity in HTLV-I-infected T-cell lines and primary ATL cells. Phosphorylated PDK1 is an activator of Akt by phosphorylating Akt. Curcumin reduced phosphorylation of PDK1 and inhibited constitutive activation of Akt. Curcumin activated glycogen synthase kinase (GSK)-3β, a downstream target of Akt kinase, by inhibiting phosphorylation of this protein. Curcumin reduced the expression of cell cycle regulators, cyclin D1 and c-Myc proteins, which are both degraded by activated GSK-3β. Our results suggest that activation of the Akt signaling pathway plays an important role in ATL cell survival, and that curcumin may have anti-ATL properties mediated, at least in part, by inhibiting Akt activity. We propose that Akt-targeting agents could be useful for the treatment of ATL. In this regard, curcumin is a potentially promising compound for the treatment of ATL. ( Cancer Sci 2006; 97: 322 – 327) [ABSTRACT FROM AUTHOR]

CCL20 is expected to play a crucial role in the initiation of immune responses and tumour growth. However, expression of CCL20 in Epstein–Barr virus (EBV)-associated diseases has not been studied. We examined the contribution of EBV infection and EBV-encoded latent membrane protein (LMP)-1 to CCL20 expression. EBV infection and LMP-1 induced CCL20 mRNA expression in the EBV-negative Burkitt lymphoma (BL) cell lines and the embryonic kidney cell line. Histone deacetylase inhibitor-stimulated endogenous LMP-1 also induced CCL20 expression in an EBV-positive BL cell line. Analysis of the CCL20 promoter showed that it was activated by LMP-1 C-terminal activation region (CTAR)-1 and CTAR-2. Co-expression of I κB α, I κB β, I κB kinase (IKK) α, IKK β, IKK γ, nuclear factor (NF)- κB-inducing kinase and tumour necrosis factor receptor-associated factor 2 dominant-negative constructs with LMP-1 inhibited the activation of the CCL20 promoter by LMP-1, suggesting that LMP-1 induces CCL20 via NF- κB signalling. The requirement for the NF- κB-binding site in the CCL20 promoter in LMP-1 responsiveness was established. Our results indicate that activation of the NF- κB pathway by LMP-1 is required for the activation of CCL20 expression. [ABSTRACT FROM AUTHOR]