Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers

Effective action in a higher-spin background

We consider a free massless scalar field coupled to an infinite tower of background higher-spin gauge fields via minimal coupling to the traceless conserved currents. The set of Abelian gauge transformations is deformed to the non-Abelian group of unitary operators acting on the scalar field. The gauge invariant effective action is computed perturbatively in the external fields. The structure of the various (divergent or finite) terms is determined. In particular, the quadratic part of the logarithmically divergent (or of the finite) term is expressed in terms of curvatures and related to conformal higher-spin gravity. The generalized higher-spin Weyl anomalies are also determined. The relation with the theory of interacting higher-spin gauge fields on anti de Sitter spacetime via the holographic correspondence is discussed.Comment: 40 pages, Some errors and typos corrected, Version published in JHE

Role of Cyclin B1/Cdc2 Up-Regulation in the Development of Mitotic Prometaphase Arrest in Human Breast Cancer Cells Treated with Nocodazole

Background: During a normal cell cycle, the transition from G 2 phase to mitotic phase is triggered by the activation of the cyclin B1-dependent Cdc2 kinase. Here we report our finding that treatment of MCF-7 human breast cancer cells with nocodazole, a prototypic microtubule inhibitor, results in strong up-regulation of cyclin B1 and Cdc2 levels, and their increases are required for the development of mitotic prometaphase arrest and characteristic phenotypes. Methodology/Principal Findings: It was observed that there was a time-dependent early increase in cyclin B1 and Cdc2 protein levels (peaking between 12 and 24 h post treatment), and their levels started to decline after the initial increase. This early up-regulation of cyclin B1 and Cdc2 closely matched in timing the nocodazole-induced mitotic prometaphase arrest. Selective knockdown of cyclin B1or Cdc2 each abrogated nocodazole-induced accumulation of prometaphase cells. The nocodazole-induced prometaphase arrest was also abrogated by pre-treatment of cells with roscovitine, an inhibitor of cyclin-dependent kinases, or with cycloheximide, a protein synthesis inhibitor that was found to suppress cyclin B1 and Cdc2 up-regulation. In addition, we found that MAD2 knockdown abrogated nocodazole-induced accumulation of cyclin B1 and Cdc2 proteins, which was accompanied by an attenuation of nocodazole-induced prometaphase arrest. Conclusions/Significance: These observations demonstrate that the strong early up-regulation of cyclin B1 and Cdc2 contributes critically to the rapid and selective accumulation of prometaphase-arrested cells, a phenomenon associate

Computational identification of condition-specific miRNA targets based on gene expression profiles and sequence information

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are small and noncoding RNAs that play important roles in various biological processes. They regulate target mRNAs post-transcriptionally through complementary base pairing. Since the changes of miRNAs affect the expression of target genes, the expression levels of target genes in specific biological processes could be different from those of non-target genes. Here we demonstrate that gene expression profiles contain useful information in separating miRNA targets from non-targets.</p> <p>Results</p> <p>The gene expression profiles related to various developmental processes and stresses, as well as the sequences of miRNAs and mRNAs in <it>Arabidopsis</it>, were used to determine whether a given gene is a miRNA target. It is based on the model combining the support vector machine (SVM) classifier and the scoring method based on complementary base pairing between miRNAs and mRNAs. The proposed model yielded low false positive rate and retrieved condition-specific candidate targets through a genome-wide screening.</p> <p>Conclusion</p> <p>Our approach provides a novel framework into screening target genes by considering the gene regulation of miRNAs. It can be broadly applied to identify condition-specific targets computationally by embedding information of gene expression profiles.</p

Changes over time in the effect of marital status on cancer survival

<p>Abstract</p> <p>Background</p> <p>Rates of all-cause and cause-specific mortality are higher among unmarried than married individuals. Cancer survival is also poorer in the unmarried population. Recently, some studies have found that the excess all-cause mortality of the unmarried has increased over time, and the same pattern has been shown for some specific causes of death. The objective of this study was to investigate whether there has been a similar change over time in marital status differences in cancer survival.</p> <p>Methods</p> <p>Discrete-time hazard regression models for cancer deaths among more than 440 000 women and men diagnosed with cancer 1970-2007 at age 30-89 were estimated, using register data encompassing the entire Norwegian population. More than 200 000 cancer deaths during over 2 million person-years of exposure were analyzed.</p> <p>Results</p> <p>The excess mortality of the never-married compared to the married has increased steadily for men, in particular the elderly. Among elderly women, the excess mortality of the never-married compared to the married has increased, and there are indications of an increasing excess mortality of the widowed. The excess mortality of divorced men and women, however, has been stable.</p> <p>Conclusions</p> <p>There is no obvious explanation for the increasing disadvantage among the never-married. It could be due to a relatively poorer general health at time of diagnosis, either because of a more protective effect of partnership in a society that may have become less cohesive or because of more positive selection into marriage. Alternatively, it could be related to increasing differentials with respect to treatment. Today's complex cancer therapy regimens may be more difficult for never-married to follow, and health care interventions directed and adapted more specifically to the broad subgroup of never-married patients might be warranted.</p

Modulation of the <i>Neisseria gonorrhoeae </i>drug efflux conduit MtrE

We acknowledge funding through the Wellcome Trust Interdisciplinary Research Funds (grant WT097818MF), the Scottish Universities’ Physics Alliance (SUPA), Tenovus Tayside (grant T16/30) and the Tayside Charitable Trust. O.N.V. has been funded through a BBSRC CASE award (BB/J013072/1).Widespread antibiotic resistance, especially of Gram-negative bacteria, has become a severe concern for human health. Tripartite efflux pumps are one of the major contributors to resistance in Gram-negative pathogens, by efficiently expelling a broad spectrum of antibiotics from the organism. In Neisseria gonorrhoeae, one of the first bacteria for which pan-resistance has been reported, the most expressed efflux complex is MtrCDE. Here we present the electrophysiological characterisation of the outer membrane component MtrE and the membrane fusion protein MtrC, obtained by a combination of planar lipid bilayer recordings and in silico techniques. Our in vitro results show that MtrE can be regulated by periplasmic binding events and that the interaction between MtrE and MtrC is sufficient to stabilize this complex in an open state. In contrast to other efflux conduits, the open complex only displays a slight preference for cations. The maximum conductance we obtain in the in vitro recordings is comparable to that seen in our computational electrophysiology simulations conducted on the MtrE crystal structure, indicating that this state may reflect a physiologically relevant open conformation of MtrE. Our results suggest that the MtrC/E binding interface is an important modulator of MtrE function, which could potentially be targeted by new efflux inhibitors.Publisher PDFPeer reviewe

Underuse of medication for circulatory disorders among unmarried women and men in Norway?

BACKGROUND: It is well established that unmarried people have higher mortality from circulatory diseases and higher all-cause mortality than the married, and these marital status differences seem to be increasing. However, much remains to be known about the underlying mechanisms. Our objective was to examine marital status differences in the purchase of medication for circulatory diseases, and risk factors for them, which may indicate underuse of such medication by some marital status groups. METHODS: Using data from registers covering the entire Norwegian population, we analysed marital status differences in the purchase of medicine for eight circulatory disorders by people aged 50-79 in 2004-2008. These differences were compared with those in circulatory disease mortality during 2004-2007, considered as indicating probable differences in disease burden. RESULTS: The unmarried had 1.4-2.8 times higher mortality from the four types of circulatory diseases considered. However, the never-married in particular purchased less medicine for these diseases, or precursor risk factors of these diseases, primarily because of a low chance of making a first purchase. The picture was more mixed for the divorced and widowed. Both groups purchased less of some of these medicines than the married, but, especially in the case of the widowed, relatively more of other types of medicine. In contrast to the never-married, divorced and widowed people were as least as likely as the married to make a first purchase, but adherence rates thereafter, indicated by continuing purchases, were lower. CONCLUSION: The most plausible interpretation of the findings is that compared with married people, especially the never-married more often have circulatory disorders that are undiagnosed or for which they for other reasons underuse medication. Inadequate use of these potentially very efficient medicines in such a large population group is a serious public health challenge which needs further investigation. It is possible that marital status differences in use of medicines for circulatory disorders combined with an increasing importance of these medicines have contributed to the widening marital status gap in mortality observed in several countries. This also requires further investigation

Characterization of transcriptome dynamics during watermelon fruit development: sequencing, assembly, annotation and gene expression profiles

<p>Abstract</p> <p>Background</p> <p>Cultivated watermelon [<it>Citrullus lanatus </it>(Thunb.) Matsum. & Nakai var. <it>lanatus</it>] is an important agriculture crop world-wide. The fruit of watermelon undergoes distinct stages of development with dramatic changes in its size, color, sweetness, texture and aroma. In order to better understand the genetic and molecular basis of these changes and significantly expand the watermelon transcript catalog, we have selected four critical stages of watermelon fruit development and used Roche/454 next-generation sequencing technology to generate a large expressed sequence tag (EST) dataset and a comprehensive transcriptome profile for watermelon fruit flesh tissues.</p> <p>Results</p> <p>We performed half Roche/454 GS-FLX run for each of the four watermelon fruit developmental stages (immature white, white-pink flesh, red flesh and over-ripe) and obtained 577,023 high quality ESTs with an average length of 302.8 bp. <it>De novo </it>assembly of these ESTs together with 11,786 watermelon ESTs collected from GenBank produced 75,068 unigenes with a total length of approximately 31.8 Mb. Overall 54.9% of the unigenes showed significant similarities to known sequences in GenBank non-redundant (nr) protein database and around two-thirds of them matched proteins of cucumber, the most closely-related species with a sequenced genome. The unigenes were further assigned with gene ontology (GO) terms and mapped to biochemical pathways. More than 5,000 SSRs were identified from the EST collection. Furthermore we carried out digital gene expression analysis of these ESTs and identified 3,023 genes that were differentially expressed during watermelon fruit development and ripening, which provided novel insights into watermelon fruit biology and a comprehensive resource of candidate genes for future functional analysis. We then generated profiles of several interesting metabolites that are important to fruit quality including pigmentation and sweetness. Integrative analysis of metabolite and digital gene expression profiles helped elucidating molecular mechanisms governing these important quality-related traits during watermelon fruit development.</p> <p>Conclusion</p> <p>We have generated a large collection of watermelon ESTs, which represents a significant expansion of the current transcript catalog of watermelon and a valuable resource for future studies on the genomics of watermelon and other closely-related species. Digital expression analysis of this EST collection allowed us to identify a large set of genes that were differentially expressed during watermelon fruit development and ripening, which provide a rich source of candidates for future functional analysis and represent a valuable increase in our knowledge base of watermelon fruit biology.</p

Tilt aftereffect following adaptation to translational Glass patterns

Glass patterns (GPs) consist of randomly distributed dot pairs (dipoles) whose orientations are determined by specific geometric transforms. We assessed whether adaptation to stationary oriented translational GPs suppresses the activity of orientation selective detectors producing a tilt aftereffect (TAE). The results showed that adaptation to GPs produces a TAE similar to that reported in previous studies, though reduced in amplitude. This suggests the involvement of orientation selective mechanisms. We also measured the interocular transfer (IOT) of the GP-induced TAE and found an almost complete IOT, indicating the involvement of orientation selective and binocularly driven units. In additional experiments, we assessed the role of attention in TAE from GPs. The results showed that distraction during adaptation similarly modulates the TAE after adapting to both GPs and gratings. Moreover, in the case of GPs, distraction is likely to interfere with the adaptation process rather than with the spatial summation of local dipoles. We conclude that TAE from GPs possibly relies on visual processing levels in which the global orientation of GPs has been encoded by neurons that are mostly binocularly driven, orientation selective and whose adaptation-related neural activity is strongly modulated by attention