680 research outputs found
Translational perspectives on MSMB and CRISP3 expression and regulation in prostate cancer
Prostate cancer is currently the most common form of cancer in Sweden. Currently, the only biomarker used in the clinic is serum PSA, and there is a great need for new biomarkers that may increase the diagnostic and prognostic information so that better predictions can be made, and treatment may be tailored. Here, we have investigated two proposed biomarkers microseminoprotein-β (MSMB) and cysteine-rich secretory protein-3 (CRISP3). Firstly, we wanted to validate previous findings, that MSMB and CRISP3 are predictors of recurrence in patients undergoing radical prostatectomy for localized prostate cancer. Using a novel automated image analysis tool, IHC-MARK, we found that MSMB was an independent predictor of recurrence in a large patient cohort. Further, we showed that expression of both MSMB and CRISP3 was induced by androgen in vitro, and MSMB was decreased in patients receiving androgen deprivation therapy prior to radical prostatectomy. MSMB was virtually lost in advanced prostate cancer, in contrast to CRISP3 which was highly expressed. Inflammation has been suggested to be a primary aetiological event in prostate cancer and the presence of putative binding elements for inflammatory transcription factors in the promoter region of CRISP3 led us to hypothesise that CRISP3 may be regulated by inflammatory stimuli. Instead, stimulation of prostate cancer cells with interleukin (IL)-6 strongly induced MSMB expression but had no effect on CRISP3 expression. A long-term IL-6 stimulated cell line, however, had no MSMB expression, probably due to DNA methylation. Finally, expression of MSMB in cell lines without endogenous MSMB resulted in decreased cyclin D1 expression and reduced proliferation. In conclusion, MSMB is an independent predictor of recurrence, whereas the value of CRISP3 as a biomarker remains to be elucidated. In vitro studies show that MSMB may be important for prostate cancer proliferation, but more studies on MSMB and CRISP3 functions are warranted
Pesticidal Diphenylaziridines
Substituted 1,2-diphenylaziridines, particularly those which are substituted by halogen, are useful as pesticidal compositions. . . .
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Adipose tissue pathways involved in weight loss of cancer cachexia
White adipose tissue (WAT) constitutes our most expandable tissue and largest
endocrine organ secreting hundreds of polypeptides collectively termed adipokines.
Changes in WAT mass induce alterations in adipocyte secretion and function, which
are linked to disturbed whole-body metabolism. Although the mechanisms controlling
this are not clear they are dependent on changes in gene expression, a complex process
which is regulated at several levels. Results in recent years have highlighted the role of
small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene
expression via post-transcriptional mechanisms. The aim of this thesis was to
characterize global gene expression levels and describe novel miRNAs and adipokines
controlling the function of human WAT in conditions with pathological increases or
decreases in WAT mass. Obesity and cancer cachexia were selected as two models
since they are both clinically relevant and characterized by involuntary changes in
WAT mass.
In Study I, expressional analyses were performed in subcutaneous WAT from cancer
patients with or without cachexia and obese versus non-obese subjects. In total, 425
transcripts were found to be regulated in cancer cachexia. Pathway analyses based on
this set of genes revealed that processes involving extracellular matrix, actin
cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid
metabolism was upregulated comparing cachectic with weight-stable cancer subjects.
Furthermore, by overlapping these results with microarray data from an obesity study,
many transcripts were found to be reciprocally regulated comparing the two conditions.
This suggests that WAT gene expression in cancer cachexia and obesity are regulated
by similar, albeit opposing, mechanisms.
In Study II, the focus was on the family of
fibroblast growth factors (FGFs), members of which have recently been implicated in
the development of obesity and insulin resistance. A retrospective analysis of global
gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in
WAT. However, only one, FGF1, was actively secreted from WAT and predominantly
so from the adipocyte fraction. Moreover, FGF1 release was increased in obese
compared to non-obese subjects, but was not normalized by weight loss. Although the
clinical significance of these findings is not yet clear, it can be hypothesized that FGF1
may play a role in WAT growth, possibly by promoting fat cell proliferation and/or
differentiation.
In Study III, we identified adipose miRNAs regulated in obesity. Out
of eleven miRNAs regulated by changes in body fat mass, ten controlled the production
of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2)
when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits
were defined.
In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was
identified by combining transcriptome and secretome data. Detailed studies focusing on
SEMA3C revealed that this factor was secreted from adipocytes and induced the
expression of extracellular matrix and matricellular genes in preadipocytes.
Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin
resistance in WAT derived from subjects with a wide range in BMI.
In summary, the results presented in this thesis have delineated transcriptional
alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia.
This has allowed the identification of novel adipokines and microRNAs with potential
pathophysiological importance. These findings form the basis for further studies aiming
at understanding the central role of WAT in disorders associated with metabolic
complications
Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability
Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERβ. Aberrant
estrogen signaling is involved in breast cancer development. ERα is one of the key
biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERβ is still not
introduced as a marker for diagnosis and established as a target of therapy. Numerous
studies suggest antiproliferative effects of ERβ, however its role remains to be fully
explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα
function are still unclear. This thesis aims to characterize distinct molecular facets of
ER action relevant for breast cancer and provide valuable information for ER-based
diagnosis and treatment design.
In PAPER I, we analyzed the functionality of two common single
nucleotide polymorphisms in the 3’ untranslated regions of ERβ, rs4986938 and
rs928554, which have been extensively investigated for association with various
diseases. A significant difference in allelic expression was observed for rs4986938 in
breast tumor samples from heterozygous individuals. However, no difference in mRNA
stability or translatability between the alleles was observed.
In PAPER II, we provided a more comprehensive understanding of ERβ
function independent of ERα. A global gene expression analysis in a HEK293/ERβ cell
model identified a set of ERβ-regulated genes. Gene Ontology (GO) analysis showed
that they are involved in cell-cell signaling, morphogenesis and cell proliferation.
Moreover, ERβ expression resulted in a significant decrease in cell proliferation.
In PAPER III, using the human breast cancer MCF-7/ERβ cell model,
we demonstrated, for the first time, the binding of ERα/β heterodimers to various
DNA-binding regions in intact chromatin.
In PAPER IV, we investigated a potential cross-talk between estrogen
signaling and DNA methylation by identifying their common target genes in MCF-7
cells. Gene expression profiling identified around 150 genes regulated by both 17β-
estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine. Based on GO
analysis, CpG island prediction analysis and previously reported ER binding regions,
we selected six genes for further analysis. We identified BTG3 and FHL2 as direct
target genes of both pathways. However, our data did not support a direct molecular
interplay of mediators of estrogen and epigenetic signaling at promoters of regulated
genes.
In PAPER V, we further explored the interactions between estrogen
signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1,
DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated
DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with
ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes,
CDKN1A and FHL2. We proposed that the molecular mechanism underlying
regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and
ERα.
In conclusion, the studies presented in this thesis contribute to the knowledge of ERβ
function, and give additional insight into the cross-talk mechanisms underlying ERα
signaling with ERβ and with DNA methylation pathways
A Transcriptional Enhancer from the Coding Region of ADAMTS5
The revelation that the human genome encodes only approximately 25,000 genes and thus cannot account for phenotypic complexity has been one of the biggest surprises in the post-genomic era. However, accumulating evidence suggests that transcriptional regulation may be in large part responsible for this observed mammalian complexity. Consequently, there has been a strong drive to locate cis-regulatory regions in mammalian genomes in order to understand the unifying principles governing these regions, including their genomic distribution. Although a number of systematic approaches have been developed, these all discount coding sequence.Using the computational tool PRI (Pattern-defined Regulatory Islands), which does not mask coding sequence, we identified a regulatory region associated with the gene ADAMTS5 that encompasses the entirety of the essential coding exon 2. We demonstrate through a combination of chromatin immunoprecipitation and reporter gene studies that this region can not only bind the myogenic transcription factors MYOD and myogenin and the E-protein HEB but can also function as a very strong myogenic transcriptional enhancer.Thus, we report the identification and detailed characterization of an exonic enhancer. Ultimately, this leads to the interesting question of why evolution would be so parsimonious in the functional assignment of sequence
Prototype effect and the persuasiveness of generalizations
An argument that makes use of a generalization activates the prototype for the category used in the generalization. We conducted two experiments that investigated how the activation of the prototype affects the persuasiveness of the argument. The results of the experiments suggest that the features of the prototype overshadow and partly overwrite the actual facts of the case. The case is, to some extent, judged as if it had the features of the prototype instead of the features it actually has. This prototype effect increases the persuasiveness of the argument in situations where the audience finds the judgment more warranted for the prototype than for the actual case (positive prototype effect), but decreases persuasiveness in situations where the audience finds the judgment less warranted for the prototype than for the actual case (negative prototype effect)
A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia
<p>Abstract</p> <p>Background</p> <p>Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the <it>NR1H3 </it>and <it>NR1H2 </it>genes and preeclampsia.</p> <p>Methods</p> <p>We assessed associations between single nucleotide polymorphisms of <it>NR1H3 </it>(rs2279238 and rs7120118) and <it>NR1H2 </it>(rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.</p> <p>Results</p> <p>We found no association between <it>NR1H3 </it>SNPs and the disease, but the <it>NR1H2 </it>polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; <it>p </it>= 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; <it>p </it>= 0.049).</p> <p>Conclusions</p> <p>This study provides the first evidence of an association between the <it>NR1H2 </it>gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.</p
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