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1.
Curr Opin Psychol ; 49: 101474, 2023 02.
Article in English | MEDLINE | ID: mdl-36469962

ABSTRACT

The online sex industry expanded in the 21st Century with 'webcamming' (explicit video content for money) first categorised in 2016 [1] as sex work. Research shows sexual interactions more attractive to clients, online and offline, if conversation/dialogue facilitates perceived or real intimacy. Considering this alongside the success of social media influencers commoditising services, goods, and their intimate attention [2], the birth of fan sites became inevitable. This article proposes that experiences of fan site explicit content creators and those of individuals in entrepreneurial businesses overlap. The online sex solopreneur as a concept, therefore, opens new avenues for examination of online sex work within an entrepreneurial framework. The experiences of one should illuminate the other and further investigation is warranted.


Subject(s)
Communications Media , Social Media , Humans , Sexual Behavior , Sexual Partners , Communication
2.
Carcinogenesis ; 33(12): 2558-67, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23027626

ABSTRACT

Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.


Subject(s)
Prostatic Neoplasms/pathology , Protein Serine-Threonine Kinases/physiology , Trans-Activators/physiology , Animals , Azo Compounds/pharmacology , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Humans , Lymphoid Enhancer-Binding Factor 1/physiology , Male , Mice , Neoplasm Invasiveness , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Snail Family Transcription Factors , Transcription Factors/physiology , Transcriptional Regulator ERG
3.
Cancer Res ; 69(7): 2912-8, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19339269

ABSTRACT

Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti-epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4',6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n=31). We then used quantitative reverse transcription-PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n=48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC.


Subject(s)
Neoplastic Cells, Circulating , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/genetics , Receptors, Androgen/genetics , Trans-Activators/genetics , Androstenes , Androstenols/therapeutic use , Antigens, Neoplasm/biosynthesis , Cell Adhesion Molecules/biosynthesis , Epithelial Cell Adhesion Molecule , Gene Order , Humans , Immunomagnetic Separation , In Situ Hybridization, Fluorescence , Keratins/biosynthesis , Male , Neoplasms, Hormone-Dependent/blood , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/pathology , Oncogene Proteins, Fusion/genetics , Prostatic Neoplasms/blood , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Transcriptional Regulator ERG
4.
Prostate ; 69(1): 33-40, 2009 Jan 01.
Article in English | MEDLINE | ID: mdl-18785179

ABSTRACT

BACKGROUND: Although recent laboratory and population studies suggest that prostate cancer may be responsive to insulin, there is a gap in knowledge concerning the expression of insulin receptors on benign or malignant prostate tissue. METHODS: We immunostained 644 cores on tissue microarrays prepared from 29 prostate tissue samples without malignancies, 78 Gleason grade 3 cancers, 21 Gleason grade 4 cancers and 33 Gleason grade 5 cancers with antibodies against the insulin-like growth factor I receptor and the insulin receptor. RESULTS: We observed immunoreactivity with both antibodies, which implies the presence of hybrid receptors as well as IGF-I receptors and insulin receptors. Insulin receptor staining intensity was significantly (P < 0.001) higher on malignant than benign prostate epithelial cells. Analysis of information from public gene expression databases confirmed that co-expression of insulin receptor mRNA and IGF-I receptor mRNA is common in prostate cancer specimens. RT-PCR methods provided evidence for the presence of mRNA for both IR-A and IR-B insulin receptor isoforms. CONCLUSION: These observations document the presence of insulin receptors on primary human prostate cancers. The findings are relevant not only to ongoing clinical trials of drug candidates that target IGF-I and/or insulin receptors, but also to the hypothesis that obesity-associated hyperinsulinemia mediates the adverse effect of obesity on prostate cancer prognosis.


Subject(s)
Obesity/physiopathology , Prostatic Neoplasms/physiopathology , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Antibody Specificity , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Hyperinsulinism/metabolism , Hyperinsulinism/pathology , Hyperinsulinism/physiopathology , Immunohistochemistry , Liver Neoplasms , Male , Metabolic Syndrome/metabolism , Metabolic Syndrome/pathology , Metabolic Syndrome/physiopathology , Obesity/metabolism , Obesity/pathology , Oligonucleotide Array Sequence Analysis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/immunology , Receptor, IGF Type 1/metabolism , Receptor, Insulin/immunology , Signal Transduction/physiology
5.
Mol Cell Biol ; 24(23): 10340-51, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15542842

ABSTRACT

Members of the ternary complex factor (TCF) subfamily of the ETS-domain transcription factors are activated through phosphorylation by mitogen-activated protein kinases (MAPKs) in response to a variety of mitogenic and stress stimuli. The TCFs bind and activate serum response elements (SREs) in the promoters of target genes in a ternary complex with a second transcription factor, serum response factor (SRF). The association of TCFs with SREs within immediate-early gene promoters is suggestive of a role for the ternary TCF-SRF complex in promoting cell cycle entry and proliferation in response to mitogenic signaling. Here we have investigated the downstream gene regulatory and phenotypic effects of inhibiting the activity of genes regulated by TCFs by expressing a dominantly acting repressive form of the TCF, Elk-1. Inhibition of ternary complex activity leads to the downregulation of several immediate-early genes. Furthermore, blocking TCF-mediated gene expression leads to growth arrest and triggers apoptosis. By using mutant Elk-1 alleles, we demonstrated that these effects are via an SRF-dependent mechanism. The antiapoptotic gene Mcl-1 is identified as a key target for the TCF-SRF complex in this system. Thus, our data confirm a role for TCF-SRF-regulated gene activity in regulating proliferation and provide further evidence to indicate a role in protecting cells from apoptotic cell death.


Subject(s)
Apoptosis , Serum Response Factor/metabolism , Alleles , Blotting, Northern , Blotting, Western , Bromodeoxyuridine/pharmacology , Cell Cycle , Cell Line , Cell Proliferation , Cell Separation , Cell Survival , Chromatin Immunoprecipitation , DNA-Binding Proteins/metabolism , Down-Regulation , Flow Cytometry , Genes, Reporter , Genetic Vectors , HeLa Cells , Humans , Lymphoid Enhancer-Binding Factor 1 , Microscopy, Fluorescence , Mitogens , Models, Biological , Models, Molecular , Oligonucleotide Array Sequence Analysis , Phosphorylation , Plasmids/metabolism , Promoter Regions, Genetic , Protein Structure, Tertiary , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription Factors/metabolism , Transcription, Genetic , Transfection
6.
Inorg Chem ; 43(20): 6414-20, 2004 Oct 04.
Article in English | MEDLINE | ID: mdl-15446892

ABSTRACT

A new family of molecule-based magnets of general formula V[TCNQR(2)](2).zCH(2)Cl(2) has been synthesized and characterized (TCNQ = 7,7,8,8-tetracyano-p-quinodimethane; R = H, Br, Me, Et, i-Pr, OMe, OEt, and OPh). In addition, solid solutions of V[TCNQ](x)()[TCNQ(OEt)(2)](2)(-)(x)().zCH(2)Cl(2) composition have been prepared. Except R = Br, magnetic ordering was observed for all materials, with T(c) values between 7.5 K (R = Me) and 106 K (R = OEt), with R = H at 52 K. The substitution of electron-donating OMe and OEt groups for H in TCNQ increased T(c), whereas the substitution of less electron-donating alkyl groups (with respect to alkoxy groups) decreased T(c). The results of MO calculations indicate that neither the spin nor charge densities of the disubstituted TCNQs are sufficiently different to explain the wide range of critical temperatures. Although the structures of the amorphous materials are not known, it is proposed that the oxygen atom of the [TCNQR(2)](*)(-) acceptor (R = OMe and OEt) and the V(II) interact to form a seven-membered ring. This interaction could stabilize the structure and enhance the magnetic coupling, leading to an increased T(c). The magnetic properties of V[TCNQ](x)()[TCNQ(OEt)(2)](2)(-)(x)().zCH(2)Cl(2) deviated from the expected linear relationship with respect to x, exhibiting magnetic behavior more characteristic of a step function in a plot of T(c) versus x.


Subject(s)
Magnetics , Nitriles/chemistry , Organometallic Compounds , Organometallic Compounds/chemistry , Vanadium/chemistry , Molecular Structure , Organometallic Compounds/chemical synthesis
7.
J Am Chem Soc ; 126(12): 3716-7, 2004 Mar 31.
Article in English | MEDLINE | ID: mdl-15038716

ABSTRACT

A new organic-based magnet, V[TCNP]2.yCH2Cl2 (TCNP = tetracyanopyrazine), has been synthesized, and its magnetic properties have been examined. The amorphous nature of V[TCNP]2.yCH2Cl2 makes it difficult to determine the structure of the material; however, ac and dc magnetic measurements indicate that it is a ferrimagnet below 200 K with a small coercive field of 8 Oe at 5 K.

8.
Biol Reprod ; 70(4): 1136-46, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14668205

ABSTRACT

Cells containing different GnRH peptides currently are thought to have distinct locations and functions in the brain. Lake whitefish is the first salmonid species to have three forms of GnRH peptide in contrast to later-evolving salmonids (salmon and trout) in which only two forms have been identified. Our objective was to isolate the cDNAs that code for these transcripts and to localize the transcripts for the three forms of GnRH in adult lake whitefish brain. Also, we provide phylogenetic analysis of these three whitefish genes based on their preprohormone sequence. From whitefish we isolated cDNAs encoding chicken (c)GnRH-II, salmon (s)GnRH, and the novel whitefish (wf)GnRH. The three cDNAs each encode only one GnRH and are placed in separate groups with phylogenetic analysis. A combination of in situ hybridization and immunocytochemistry with two antisera revealed neurons that expressed protein and/or mRNA for cGnRH-II in the midbrain and hindbrain; sGnRH in the olfactory nerve and bulb, ventral telencephalon, and preoptic area; and wfGnRH in the same latter two brain regions and the hypothalamus. Thus, in the anterior brain, cells containing sGnRH and wfGnRH were in the same brain areas but not at identical locations in the ventral telencephalon and preoptic area. Based on our results, we speculate that both sGnRH and wfGnRH have gonadotropin-releasing roles in the lake whitefish brain.


Subject(s)
Brain/metabolism , Cloning, Molecular , Gonadotropin-Releasing Hormone/genetics , Gonadotropin-Releasing Hormone/metabolism , Salmonidae/metabolism , Amino Acid Sequence , Animals , Base Sequence , Chickens/genetics , Chickens/metabolism , DNA, Complementary/genetics , In Situ Hybridization , Molecular Sequence Data , Phylogeny , Salmon/genetics , Salmon/metabolism , Tissue Distribution
9.
Regul Pept ; 109(1-3): 27-37, 2002 Nov 15.
Article in English | MEDLINE | ID: mdl-12409211

ABSTRACT

To better understand the evolution of pituitary adenylate cyclase-activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH), we isolated the cDNAs encoding these peptides from the brains of five species of fish: sturgeon, whitefish, grayling, flounder and halibut. Both hormones are encoded in tandem in full-length cDNAs. We compared the phylogenetic relationship among these and other known sequences encoding PACAP. In closely related species, transcripts encoding PACAP and GHRH are strongly conserved in the hormone coding regions, moderately conserved in the signal peptide, cryptic peptide and 3'-untranslated regions, but are most varied in the 5'-untranslated regions.Next, we compared the deduced amino acid sequences for the peptides to known sequences. Sturgeon and whitefish have a PACAP(38) peptide sequence that is 92% conserved compared to human PACAP(38), the highest for a fish reported to date. GHRH is the lesser conserved of the two peptides with only 39% to 45% conservation between fish and human.Each of the five fish species had a second cDNA encoding a short precursor lacking GHRH(1-32), the bioactive portion of GHRH. This suggests that exon skipping in GHRH-PACAP transcripts may be an important mechanism for regulating the ratio of PACAP to GHRH peptides.


Subject(s)
Alternative Splicing/genetics , DNA, Complementary/genetics , Evolution, Molecular , Exons/genetics , Fishes/genetics , Growth Hormone-Releasing Hormone/genetics , Neuropeptides/genetics , Amino Acid Sequence , Animals , Base Sequence , Flounder/genetics , Humans , Molecular Sequence Data , Phylogeny , Pituitary Adenylate Cyclase-Activating Polypeptide , Salmonidae/genetics , Sequence Homology, Amino Acid , Species Specificity
10.
Methods ; 26(3): 270-80, 2002 Mar.
Article in English | MEDLINE | ID: mdl-12054883

ABSTRACT

Transcription factors determine cell lineages, control cell fate, and regulate cellular responses to stimuli. Many methods are currently used to study the function of transcription factors in a cellular context and several of these involve overexpressing a constitutively active form of the protein and studying its effects. Here we outline an alternative approach involving the inducible expression of dominant-negative transcription factors in human cell lines. Dominant-negative transcription factors can be used to investigate the effect of signaling pathways on complex cellular processes that are regulated by a particular transcription factor. Potent dominant-negative transcription factors can be created by using fusions to the engrailed repressor domain. These fusion proteins can be coupled to inducible expression systems such as the ecdysone-inducible system. The ability to control protein expression has several benefits including the ability to create stable cell lines that express potentially cytotoxic proteins. Therefore when used in tandem, these two methods constitute a new and improved approach for dissecting the cellular role and transcriptional targets of many transcription factors. Here we illustrate this integrated approach by using a conditional dominant-negative Elk-1 protein to identify candidate Elk-1-regulated target genes.


Subject(s)
DNA-Binding Proteins , Eukaryotic Cells/metabolism , Gene Expression Regulation , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Molecular Biology/methods , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Animals , Apoptosis , Cell Cycle , Cell Differentiation , Cell Line , Cell Lineage , Drosophila Proteins/chemistry , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster , Ecdysone/pharmacology , Gene Expression Regulation/drug effects , Genes, Dominant/genetics , Genes, Reporter , Homeodomain Proteins/chemistry , Humans , Oligonucleotide Array Sequence Analysis , Protein Structure, Tertiary , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Transcription Factors/chemistry , Up-Regulation/drug effects , ets-Domain Protein Elk-1
11.
Biol Reprod ; 67(1): 232-9, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12080022

ABSTRACT

Multiple forms of GnRH within individual brains may have different functions. However, some vertebrates such as salmonids continue to reproduce even though they have lost or do not express 1 of the 3 forms of GnRH found in most other teleosts. We examined a basal salmonid, lake whitefish, to determine the mechanism by which a reduction in the number of GnRH forms occurs. We identified for the first time 3 distinct GnRHs in a salmonid. One form is novel and is designated whitefish GnRH. The primary structure is pGlu-His-Trp-Ser-Tyr-Gly-Met-Asn-Pro-Gly-NH(2). HPLC and RIA were used for purification followed by Edman degradation for sequence determination. Mass spectroscopy was used to confirm the sequence and amidation of the peptide. The other 2 forms, salmon GnRH and chicken GnRH-II, are identical to the 2 forms found in salmon, which evolved later than whitefish. Synthetic whitefish GnRH is biologically active, as it increased mRNA expression of growth hormone and the alpha-subunit for LH and thyroid-stimulating hormone in dispersed fish pituitary cells. Our data support the hypothesis that the ancestral salmonid had a third GnRH form when the genome doubled (tetraploidization), but the third form was lost later in some salmonids due to chromosomal rearrangements. We suggest that the salmon GnRH form compensated for the loss of the third form.


Subject(s)
Gonadotropin-Releasing Hormone/metabolism , Salmonidae/physiology , Animals , Blotting, Northern , Brain Chemistry/physiology , Cells, Cultured , Chromatography, High Pressure Liquid , Female , Gonadotropin-Releasing Hormone/chemical synthesis , Gonadotropin-Releasing Hormone/chemistry , Male , Mass Spectrometry , Oncorhynchus mykiss , Peptides/chemistry , Peptides/isolation & purification , Pituitary Gland/drug effects , RNA, Messenger/biosynthesis , Radioimmunoassay
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