Inflation, moduli (de)stabilization and supersymmetry breaking

We study the cosmological inflation from the viewpoint of the moduli stabilization. We study the scenario that the superpotential has a large value during the inflation era enough to stabilize moduli, but it is small in the true vacuum. This scenario is discussed by using a simple model, one type of hybrid models.Comment: 17 pages, 7 figure

Fine Tuning in General Gauge Mediation

We study the fine-tuning problem in the context of general gauge mediation. Numerical analyses toward for relaxing fine-tuning are presented. We analyse the problem in typical three cases of the messenger scale, that is, GUT ($2\times10^{16}$ GeV), intermediate ($10^{10}$ GeV), and relatively low energy ($10^6$ GeV) scales. In each messenger scale, the parameter space reducing the degree of tuning as around 10% is found. Certain ratios among gluino mass, wino mass and soft scalar masses are favorable. It is shown that the favorable region becomes narrow as the messenger scale becomes lower, and tachyonic initial conditions of stop masses at the messenger scale are favored to relax the fine-tuning problem for the relatively low energy messenger scale. Our spectra would also be important from the viewpoint of the $\mu-B$ problem.Comment: 22 pages, 16 figures, comment adde

Allelopathic effects of Ulva pertusa, Corallina pilulifera and Sargassum thunbergii on the growth of the dinoflagellates Heterosigma akashiwo and Alexandrium tamarense

The allelopathic effects of fresh tissue, dry powder and aqueous extracts of three macroalgae, Ulva pertusa, Corallina pilulifera and Sargassum thunbergii, on the growth of the dinoflagellates Heterosigma akashiwo and Alexandrium tamarense were evaluated using coexistence culture systems in which concentrations of the three macroalga were varied. The results of the coexistence assay showed that the growth of the two microalgae was strongly inhibited by using fresh tissue, dry powder and aqueous extracts of the three macroalga; the allelochemicals were lethal to H. akashiwo at relatively higher concentrations of the three macroalga. The macroalgae showing the most allelopathic effect on H. akashiwo and A. tamarense using fresh tissue were U. pertusa and S. thunbergii, using dry powder were S. thunbergii and U. pertusa, and using aqueous extracts were U. pertusa and C. pilulifera. We also examined the potential allelopathic effect on the two microalgae of culture filtrate of the three macroalga; culture medium filtrate initially exhibited no inhibitory effects when first added but inhibitory effects became apparent under semi-continuous addition, which suggested that continuous release of small quantities of rapidly degradable allelochemicals from the fresh macroalgal tissue were essential to effectively inhibit the growth of the two microalgae

The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation

The ataxia telangiectasia mutated (ATM) and the ATM- related (ATR) kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933) or ATM and ATR (CGK733) have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB). Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles

Mu Insertions Are Repaired by the Double-Strand Break Repair Pathway of Escherichia coli

Mu is both a transposable element and a temperate bacteriophage. During lytic growth, it amplifies its genome by replicative transposition. During infection, it integrates into the Escherichia coli chromosome through a mechanism not requiring extensive DNA replication. In the latter pathway, the transposition intermediate is repaired by transposase-mediated resecting of the 5′ flaps attached to the ends of the incoming Mu genome, followed by filling the remaining 5 bp gaps at each end of the Mu insertion. It is widely assumed that the gaps are repaired by a gap-filling host polymerase. Using the E. coli Keio Collection to screen for mutants defective in recovery of stable Mu insertions, we show in this study that the gaps are repaired by the machinery responsible for the repair of double-strand breaks in E. coli—the replication restart proteins PriA-DnaT and homologous recombination proteins RecABC. We discuss alternate models for recombinational repair of the Mu gaps

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

Endometrial cancer

Endometrial cancer is the most common gynecological malignancy in well-developed countries. Biologically and clinicopathologically, endometrial carcinomas are divided into two types: type 1 or estrogen-dependent carcinomas and type 2 or estrogen-independent carcinomas. Type 1 cancers correspond mainly to endometrioid carcinomas and account for approximately 90 % of endometrial cancers, whereas type 2 cancers correspond to the majority of the other histopathological subtypes. The vast majority of endometrial cancers present as abnormal vaginal bleedings in postmenopausal women. Therefore, 75 % of cancers are diagnosed at an early stage, which makes the overall prognosis favorable. The first diagnostic step to evaluate women with an abnormal vaginal bleeding is the measurement of the endometrial thickness with transvaginal ultrasound. If endometrial thickening or heterogeneity is confirmed, a biopsy should be performed to establish a definite histopathological diagnosis. Magnetic resonance imaging is not considered in the International Federation of Gynaecology and Obstetrics staging system. Nonetheless it plays a relevant role in the preoperative staging of endometrial carcinoma, helping to define the best therapeutic management. Moreover, it is important in the diagnosis of treatment complications, in the surveillance of therapy response, and in the assessment of recurrent disease.info:eu-repo/semantics/publishedVersio

Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Mouse Transgenesis Identifies Conserved Functional Enhancers and cis-Regulatory Motif in the Vertebrate LIM Homeobox Gene Lhx2 Locus

The vertebrate Lhx2 is a member of the LIM homeobox family of transcription factors. It is essential for the normal development of the forebrain, eye, olfactory system and liver as well for the differentiation of lymphoid cells. However, despite the highly restricted spatio-temporal expression pattern of Lhx2, nothing is known about its transcriptional regulation. In mammals and chicken, Crb2, Dennd1a and Lhx2 constitute a conserved linkage block, while the intervening Dennd1a is lost in the fugu Lhx2 locus. To identify functional enhancers of Lhx2, we predicted conserved noncoding elements (CNEs) in the human, mouse and fugu Crb2-Lhx2 loci and assayed their function in transgenic mouse at E11.5. Four of the eight CNE constructs tested functioned as tissue-specific enhancers in specific regions of the central nervous system and the dorsal root ganglia (DRG), recapitulating partial and overlapping expression patterns of Lhx2 and Crb2 genes. There was considerable overlap in the expression domains of the CNEs, which suggests that the CNEs are either redundant enhancers or regulating different genes in the locus. Using a large set of CNEs (810 CNEs) associated with transcription factor-encoding genes that express predominantly in the central nervous system, we predicted four over-represented 8-mer motifs that are likely to be associated with expression in the central nervous system. Mutation of one of them in a CNE that drove reporter expression in the neural tube and DRG abolished expression in both domains indicating that this motif is essential for expression in these domains. The failure of the four functional enhancers to recapitulate the complete expression pattern of Lhx2 at E11.5 indicates that there must be other Lhx2 enhancers that are either located outside the region investigated or divergent in mammals and fishes. Other approaches such as sequence comparison between multiple mammals are required to identify and characterize such enhancers