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Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.
Breast cancer is the most commonly diagnosed cancer in the UK, with 44,659 new cases diagnosed in 2004 [1]. Survival among women diagnosed with the disease is relatively good; however, 12,509 breast cancer related deaths in 2005 [1] demonstrate the potential for improving both diagnostic and therapeutic procedures.
After menarche, the cyclical release of the steroid hormones oestrogen and progesterone stimulates the primitive ducts of the immature breast to differentiate into terminal end buds, which branch into alveolar buds. During pregnancy, high circulating steroid hormone levels stimulate increased lobular differentiation to the mature secretory gland. Upon withdrawal of sex steroid hormones at menopause, involution to an undifferentiated morphology occurs [2].
Normal mammary ducts consist of a layer of luminal epithelial cells, surrounded by a layer of myoepithelial cells, encased in delimiting fibroblasts set in a fatty, collagenous stroma [3]. Most breast carcinomas are of epithelial origin and are either localised to the duct/lobule of origin or capable of invading surrounding stroma [4]. Whilst age is the biggest contributory risk factor for developing breast cancer, use of hormone replacement therapy (HRT) and oral contraceptives have also been implicated, implicating hormone signalling in breast cancer development [1,4]. A further increased risk with combined oestrogen-progesterone HRT compared to oestrogen alone also bears out the significant role of progesterone signalling through progesterone receptor (PR) in breast cancer development [5-7].
PR, along with oestrogen receptor (ER), status is routinely measured in breast cancer specimens. PR+ patients are more likely to respond to hormonal therapies and survive disease [8]. Approximately 40% of breast tumours are ER+/PR+ and these patients are considered to have the best prognosis and are most likely to respond to hormonal therapies [4,9]. These cancers are associated with a lower rate of cell proliferation and well differentiated tumours, leading to a better prospect of overall survival [9]. Since PR is an oestrogen responsive gene, PR positivity indicates not only ER being present but also functional [8]. However, a small proportion of tumours are ER-/PR+ and still respond more favourably to hormonal therapies than ER-/PR- tumours [9,10], demonstrating the independent importance of PR in breast cancer development and treatment, not just as an indicator of ER function.
Potential mechanisms for PR loss or down-regulation in response to growth factor signalling have been described. In some tumours PR-status appears to correlate with upregulation of epidermal growth factor receptor; it has been proposed that cross-talk between ER and epidermal growth factor receptor pathways may account for the resistance to selective oestrogen receptor modulators (SERMS; for example, Tamoxifen) of PR-tumours, which can still respond to removal of oestrogen signal by aromatase inhibitors [10,11]. Another study has shown that insulin-like growth factor-1 inhibits transcription of PR in breast cancer cells, via the PI3K/Akt/mTOR signalling pathway, which appears to be independent of ER levels or activity [12]. Loss of PR also occurs by a phosphorylation-dependent process in which ligand binding activates PR phosphorylation by mitogen-activated protein kinases, which in turn targets the receptors to the ubiquitinproteosome for degradation [13]; these researchers demonstrate that growth factors can paradoxically activate transcription of PR yet rapidly down-regulate PR protein. It is plausible, therefore, that PR variants may be difficult to detect at the protein level because they have relatively short half-lives and rapid turnover.
In addition to down-regulation of PR by growth factor-oestrogen receptor cross-talk, other potential mechanisms for the development of PR- tumours include: low circulating oestrogen levels in post menopausal women being insufficient to generate detectable levels of PR, consistent with the higher incidence of ER+/PR- tumours in older women; loss of heterozygosity at the PR gene; or hypermethylation of the PR promoters, common in many cancer cell types, including breast cancer, causing transcriptional silencing [11,14,15]. One further possibility is that alternative splicing of PR pre-mRNA might generate cancer specific PR variants that are not detectable by current pathological screening methods, thus leading to potential misdiagnosis of a tumour as PR-.
This review will describe the structure and function of PR, and outline the mechanisms of alternative splicing, their implications in cancer and evidence for the existence of alternatively spliced PR isoforms. The potential gain or loss of function associated with each PR variant and their significance in breast cancer will be discussed.
Progesterone receptor structure and function
The human PR gene consists of eight coding exons separated by seven non-coding introns [16]. The two main nuclear isoforms, PR-A and PR-B [17-20], are independently regulated from defined promoter regions within the PR gene [18,21]. PR-A is a truncated form of PR-B, lacking the amino-terminal 164 amino acids that form the third transactivation domain (AF-3) [18,20]. Other than this, the two forms are structurally identical (Figure 1).
Figure 1. Progesterone receptor (PR) gene and main isoforms. (a) Exon organisation map of the PR gene, showing PR-A and PR-B promoters (indicated by arrows). (b) PR-B and PR-A protein structures. The A/B region is encoded by exon 1 and part of exon 2, and contains the PR-B specific transactivation domain AF-3, AF-1, common to PR-B and PR-A, and the PR-A specific inhibitory domain (ID). The C region forms the DNA binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3, and forms the hinge region responsible for the nuclear location signal (NLS). The E region contains AF-2, common to PR-B and PR-A, and the hormone (ligand) binding domain (LBD), encoded by exons 4 to 8. (c) PR-C, an amino-terminally deleted PR protein predicted to result from alternative translation initiation at a methionine at position 595. PR-C lacks a complete DBD and the first two transactivation domains (AF-3 and AF-1).
PR is a member of the steroid/thyroid hormone-retinoid receptor superfamily of ligand activated nuclear transcription factors [18,22]. The mechanisms by which PR regulates hormone-response genes are complex. Progesterone binds PR, inducing a conformational change in PR causing its nuclear translocation, dimerisation and interaction with specific DNA progesterone response elements (PREs) present in the promoter regions of target genes. However, the presence of a PRE does not necessarily predict progestin responsiveness. PR can also mediate its effect independently of PREs, through the protein-protein interactions of PR with other sequence-specific transcription factors [23]. Protein products from PR target genes are involved in a diverse range of cellular activities, including transcription, steroid and lipid metabolism, cell growth and apoptosis, protein and nucleic acid processing and membrane associated signalling, indicating a broad range of potential progesterone effects [24]. Some of these proteins are associated with mammary gland and breast cancer development, including the transcription factors STAT5A and C/EBPβ.
In breast cancer cells expressing either PR-B or PR-A, most PR regulated genes are reported to be controlled by PR-B [24], less by PR-A and only a minority by both isoforms. PR-A has been shown to act as a trans-dominant repressor of PR-B controlled transcription in a cell and promoter specific manner [24,25]. The balance of PR isoform expression is also important in breast cancer management. Overexpression of PR-A protein compared to PR-B is common in breast cancer [17,26], changing progestin responsiveness of cells [26]. Predominant PR-A protein expression signifies a poorer outcome of hormonal therapies [27], and predominance of PR-B poorer outcome of chemotherapy. Predominance of one isoform is also seen in women at high risk of breast cancer, for example, women with a BRCA1 or BRCA2 mutation commonly exhibit a lack of PR-B [26]. Therefore, not only could PR variants lead to incorrect assessment of hormone receptor status, but could also alter the progestin responsiveness of tissue, providing potential new indicators of efficacy and targets for therapeutics.
In addition to the nuclear hormone receptors PR-A and PR-B, a truncated and predominantly cytoplasmic PR protein has also been described. PR-C is a 60 kDa protein, first detected in the T47-D breast cancer cell line, resulting from initiation at a methionine at position 595 [28] and is capable of forming heterodimers and modulating the activity of PR-A and PR-B in vitro [28,29]. The PR-C protein lacks a full DNA binding domain (DBD) [30] as well as the first two transactivation domains (AF-3 and AF-1), so although potentially able to bind hormone, it would not directly bind PRE (Figure 1c). However, PR-C may still influence transcription events since it has the capacity to dimerise and also interact with common nuclear co-factors. A potential physiological role for PR-C in human pregnancy has been proposed [31]; this study shows that PR-C mRNA and protein levels significantly increase within the fundus of uterus of women in labour. The authors suggest that the observed increase in the ratio of PR-C to PR-B may influence functional progesterone withdrawal by blocking the activity of PR-B to maintain uterine quiescence in pregnancy [31].
Alternative splicing
Alternative pre-mRNA splicing is a vital mechanism for generating protein diversity from a relatively small number of genes. In excess of 60% of all human genes undergo alternative splicing. Splicing occurs at sites determined by the presence of a 5' donor splice sequence (usually ending -GU), a branch point adenosine and a 3' acceptor splice sequence (usually ending -AG) within pre-mRNA sequences [32,33]. The proximity of cis-regulatory sequences, either enhancers or silencers of exon or intron splicing, influences the binding of different trans-splicing factors to the splice sites (Figure 2a) and aids assembly of the spliceosome multi-protein complex, resulting in cleavage and ligation of introns and exons, respectively [32,33]. At least five basic types of alternative splicing have been described [32-34] (Figure 2b).
Figure 2. Regulation and different patterns of alternative splicing. (a) Alternative pre-mRNA splicing involves a complex interplay of trans-acting splicing factors with numerous cis-acting regulatory elements within the precursor mRNA sequences of eukaryotic genes. Trans-acting factors recognise and interact with different cis-acting RNA motifs present within the pre-mRNA sequence of genes; these include 5' donor and 3' acceptor sites at exon-intron boundaries; exon and intron enhancer elements (ESE, ISE), which can promote the use of specific splice sites; and exon and intron silencer elements (ESS, ISS), which when bound by proteins can repress the use of specific splice sites (adapted from [59]). (b) Different patterns of alternative splicing include: (i) normal pattern of splicing – removing introns 1, 2 and 3; (ii) whole exon exclusion – introns 1, 2 and 3, and entire exon 2 are removed; (iii) mutually exclusive exons – either exon 2 or exon 3 is removed and both exons are never retained together; (iv) intron retention – intron 2 is retained in the mRNA; and (v) cryptic splice sites – exon 2 contains a 3' cryptic splice site and exon 3 contains a 5' cryptic splice site. These compete with the native splice site to generate mRNA lacking part of an exon.
A wide range of alternatively spliced genes have been described in cancers [33,35], affecting disease initiation, resistance to apoptosis, invasion and angiogenesis [36]. Alternative splicing appears to be increased in cancer, possibly due to mutations in trans-splicing or cis-regulatory elements allowing increased competition from cryptic splice sites and misdirected spliceosome formation [34]. Alternatively spliced genes involved in breast cancer have been observed; BRCA1 variants [35,37] as well as variants of other members of the steroid receptor superfamily such as an androgen receptor variant lacking exon 3 and several ER variants with differing expression in normal and tumourigenic breast tissues [38-40].
Alternatively spliced progesterone receptor isoforms
As well as PR-A, PR-B and PR-C, several other smaller isoforms encoded by the PR gene have also been described [28,41-44] (Figure 3). Screening of a testicular cDNA library revealed a PR mRNA isoform containing a novel sequence before exon 4 termed exon S [41]; mRNA for this isoform was found to be present in ejaculated spermatozoon and the uterine endometrium. A protein encoded from this mRNA would lack the entire DBD but would most likely possess nearly the entire sequence for the progesterone-binding domain and be capable of dimerisation. This isoform, PR-S, and another isoform, PR-T, resulting from retention of another intronic sequence before exon 4 (exon T) [42], could give rise to identical proteins. Neither exon S nor exon T encode a translation initiation site, so translation is likely to start at the first methionine in exons 4 to 8 [42]. Exons S and T are located between exons 3 and 4 in the PR gene [45]. Since both PR-S and PR-T proteins lack the ability to bind DNA, they may be important in mediating non-genomic PR mediated responses or recruiting co-factors to PR heterodimers.
Figure 3. Truncated progesterone receptor (PR) isoforms. The upper part of each diagram shows the PR gene; darker shading indicates regions removed by splicing, lighter regions those retained in mRNA. The lower part of each diagram shows the predicted protein structure. PR-S: retention of intronic sequence termed exon S and initiation of transcription within exons 4 to 8. PR-T: retention of intronic sequence termed exon T and initiation of transcription within exons 4 to 8. PR-S and PR-T mRNA are likely to give rise to identical proteins that are amino-terminally truncated, lacking AF-1, AF-2 and the DNA binding domain. PR-i45: retention of two intronic sequences termed exons i45a and i45b leads to a change in reading frame and truncation of the protein E region so the PR-i45 protein lacks a functional ligand-binding domain and dimerisation domain. PR-M: inclusion of an intronic 5' untranslated region sequence causes amino-terminal truncation and leads to encoding of a protein with a 5' signal sequence and complete ligand-binding domain and dimerisation domain, consistent with a function as a membrane bound receptor.
A study of endometrial carcinomas revealed a variant PR mRNA that contained a 252 base-pair insertion between exons 4 and 5 [44]. This was termed PR-i45 and the insertion is the result of transcription of two intronic sequences termed exons i45a and i45b. The protein translated from PR-i45 mRNA would have the normal amino-terminal domain of genomic PR, the DBD and nuclear location signal (NLS). A change in reading frame due to the insertion would cause truncation of the ligand binding domain (LBD) [44].
PR-M mRNA was discovered in the T47D breast cancer cell line that contained a 5'-untranslated region consistent with use of a promoter within intron 3 [43]. This encoded a short 5' signal sequence of hydrophobic amino acids, suggesting that the protein may be processed for either expression on the cell membrane or secretion. PR-M contains the full LBD and dimerisation domain (DD) so is likely to be physiologically active despite lacking the DBD [43], consistent with a role on the plasma membrane or as a secreted protein. PR-M was later detected in the PR- T47D-Y cell line by immunofluorescent antibody staining. Cells that overexpressed PR-M demonstrated a decreased rate of calcium influx consistent with PR-M functioning as a membrane bound protein associated with non-genomic responses to progesterone [46].
Other progesterone receptor spliced variants
The initial observation of a 78 kDa protein detected by anti-PR antibodies [17,47] prompted the analysis of alternatively spliced variant (ASV) PR mRNAs by reverse transcription PCR. Due to the predicted size of proteins encoded by PR variant mRNAs, a deletion of exon 3 or part of exon 4 was suggested [47]. If this was a PR protein lacking either of these exons, it could still be transcriptionally active as it was capable of binding progesterone [47] and, therefore, may be able to elicit a response or modulate the activity of other PR isoforms.
Many alternatively spliced, whole exon deleted, PR variant mRNAs have since been described. Exon 2 deleted PRΔ2 was found in breast tumour tissue and in two PR+ breast cancer cell lines MCF-7 and T47DCO [47,48]. A protein encoded from this mRNA would lack the first zinc finger of the DBD, making DNA binding doubtful, and a change in reading frame would lead to the insertion of a stop codon in exon 3 so it would also lack a LBD [48]. It is probable, therefore, that were this protein translated it would be unable to bind DNA or hormone so not be functional as a PR. Exon 3 deleted PRΔ3 mRNA was seen at low levels in most breast tumour samples examined and in T47D cells [47,49]. A protein from this ASV would lack the second zinc finger of the DBD but might still be active if it were able to bind progesterone and dimerise with other PR forms. Exon 4 deleted PRΔ4 mRNA was detected in both normal and tumour tissue from the breast and in T47-D cells [47,48,50]. This variant was also found in normal endometrial, normal ovarian and ovarian endometriotic tissues [51] as well as in vascular smooth muscle [52]. The putative protein from this mRNA would lack the hinge region, so be segregated from the nucleus and would lack the proximal end of the LBD, though the rest of the LBD would be intact. It has been demonstrated that PRΔ4 is unable to bind PRE and is not responsive to the progestin R5020 [48]. It is unlikely, therefore, to function as a PR, but may compete for dimerisation with other PR rendering them inactive, or compete for cofactor binding.
Exon 6 deleted PRΔ6 mRNA has been detected in normal and tumour samples from the breast [50] and has since been detected more frequently in tumour than normal breast tissue, and at a higher rate in PR- tumours than PR+ [53]. PRΔ6 mRNA has also been detected in tissue samples from vascular smooth muscle [52], normal ovaries, ovarian endometriosis and normal endometrium [51]. The protein encoded from PRΔ6 mRNA lacks a functional LBD but possesses the NLS, ability to dimerise and bind DNA and has been shown to be a dominant negative inhibitor of wild-type PR-A and PR-B function [48]. Therefore, PRΔ6 protein expression, which may be elevated in breast cancer, could be an important regulator of PR function in the disease. It has further been demonstrated that PRΔ6 is able to bind PRE independent of progestin activation and suggested that this constitutive binding of transcriptionally inactive PRΔ6 to PRE may block wild-type PR binding [48]. The protein encoded by PR-i45 mRNA is likely to be similar in structure to a PRΔ6 protein, so may have a similar ability to inhibit PR-A and PR-B [45]. Interestingly, the expression of PRΔ6 and PRΔ4, relative to wild-type PR, in vascular smooth muscle appears to be decreased in post-menopausal women [52]. If this pattern was also true in breast tissue, then perhaps the associated change in progesterone responsiveness could relate to the increased risk of developing breast cancer after menopause. However, in this very small study, three of the four post-menopausal subjects were receiving oestrogen only HRT [52]. Since PR is, in part, an oestrogen responsive gene, the use of exogenous oestrogens could alter PR expression. Perhaps the increased risk of breast cancer associated with HRT could reflect a change in PR variant expression.
As well as these single exon deleted mRNAs, many variants exist in which multiple exons have been deleted; PRΔ2+3 [47,49], PRΔ3+4 [54], PRΔ3+6 [50], PRΔ4+6 [51], PRΔ5+6 [50], PRΔ4+5+6 [51], PRΔ3+4+5+6 [54]. Some of these would be unlikely to encode functional PR since they would lack too many of the protein domains; for example, PRΔ4+6 would lack the nuclear location signal and LBD but has been shown to be present more frequently in malignant than 'normal' breast tissue [55], and is perhaps indicative of a breakdown in normal splicing control mechanisms. Furthermore, any transcriptionally inactive PR variants expressed may be able to compete with wild-type receptors for co-factor binding ('squelching'), thereby interfering with normal progestin responsiveness. In this context, PR mutants deleted of their LBD have been shown to be constitutively active and capable of binding PRE [56]. In addition, ASV such as PRΔ5+6, would encode a protein with a complete DBD and NLS as well as being able to dimerise and possessing both AF-1 and AF-2. This protein has been demonstrated to be a dominant repressor of wild-type PR function, but is not itself progestin responsive or able to bind PRE [48], and its distribution in a wide range of normal and pathological tissue types [48,50,51] suggests an important physiological role. Another ASV with the potential to encode a functional protein is PRΔ2+3. This putative variant protein would lack the entire DBD but could still modulate PR activity by binding progesterone, dimerising and migrating to the nucleus. Some of the variants, although unlikely to encode functional PR, seem to be tissue specific. PRΔ3+6 has to date only been seen in breast tumour tissue, and PRΔ4+5+6 only in endometrial tissue, suggesting that any protein encoded from these mRNA could have an important role in a specific progesterone target tissue. Alternatively, the presence of the mRNA could be indicative of a breakdown in splicing control mechanisms in cancer.
Other ASV mRNAs are seen that lack a specific part of an exon rather than being whole exon deleted. PRΔ4/2 mRNA, in which the first 126 base-pairs of exon 4 have been deleted, was detected frequently but at a low level in breast tumour tissue [47,49]. This deletion could be due to a donor splice sequence in intron 3 and an acceptor splice sequence within exon 4 forming a cryptic splice site and acting in competition to the normal exon 4 splice site in some transcripts [49]. PRΔ4/2 has since been observed in normal endometrial tissue [57] and would encode a protein lacking the NLS but probably able to dimerise and bind progesterone so could well be able to modulate PR function. A second partial exon deleted PR variant mRNA is PRΔ6/2 [58] in which a 52 base-pair section of exon 6 has been deleted. This mRNA has been detected at a far greater frequency in tumour compared to normal breast tissue, suggesting that the protein could be functional in cancer and may be a result of a cancer associated breakdown in splicing control. The protein would lack a fully functional LBD but would retain all of the other functional domains required to act as a transcription factor. Two further variants lacking part of exon 6, along with either exon 3 (PRΔ3+6/2) or exon 4 (PRΔ4+6/2) [58], have been observed infrequently, but appear specific to breast cancer tissue. Neither of these variants is likely to encode functional hormone-responsive receptors but again their presence in breast cancer tissue suggests mis-splicing leading to a change in PR expression.
Discrepancies between ER/PR status and response to hormone therapies could be due to the presence of these variant PRs (or variant ERs) that are either not detected (amino-terminally truncated variants) or not distinguishable from full-length receptor (functional domain deleted variants) by current screening methods that use antibodies directed against the PR-A/B common amino-terminal region. It has already been demonstrated that differences in the ratio of PR-A:PR-B can affect the outcome of breast cancer treatment [27]. The discovery of truncated PR isoforms adds another level of complexity to the study of PR in breast cancer. This is further complicated by reports of many exon deleted ASV PR mRNA species in a variety of cell lines, as well as normal and malignant human tissues. If translated, the proteins encoded by theses ASV mRNAs may have transcriptional activities that differ from the full length PR-A or PR-B to which they are related, or could interact with the full-length PR to modulate its activity, as is seen with PR-A repression of PR-B [25]. Moreover, PR spliced variants may also modulate PR-A and PR-B activity indirectly, by competitively binding to common nuclear co-regulatory proteins.
The expression of any isoform or variant proteins could modify progesterone responsiveness of a target tissue, for example, providing a mechanism for the differing responses to the same dose of progesterone in the uterus (proliferative) and breast (anti-proliferative) [48]. Variant PR expression breast cancer could, therefore, provide a mechanism for abnormal epithelial proliferation. Alternatively, the presence of variant mRNAs that are not translated to protein could be indicative of a loss of normal PR expression and thus normal response to progesterone.
Although the expression of many of these variants is yet to be reported in breast tissue at the protein level, the possibility that shorter forms of PR may be functional and perhaps not detected by conventional screening methods could lead to discrepancies between the reported PR status of a tumour and the progression of the disease or response to endocrine therapies. Therefore, detailed and accurate characterisation of PR variant expression in breast cancer could generate novel and more efficient biomarkers of disease prognosis or targets for therapeutics.
AF = transactivation domain; ASV = alternatively spliced variant; DBD = DNA binding domain; DD = dimerisation domain; ER = oestrogen receptor; HRT = hormone replacement therapy; LBD = ligand binding domain; NLS = nuclear location signal; PR = progesterone receptor; PRE = progesterone response element.
Competing interests
The authors declare that they have no competing interests.
DMW Cork is funded by the Royal Victoria Infirmary Breast Cancer Appeal, Newcastle-upon-Tyne, UK.
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Zhang QX, Hilsenbeck SG, Fuqua SA, Borg A: Multiple splicing variants of the estrogen receptor are present in individual human breast tumors.
J Steroid Biochem Mol Biol 1996, 59:251-260. PubMed Abstract | Publisher Full Text
Hirata S, Shoda T, Kato J, Hoshi K: The novel isoform of the progesterone receptor cDNA in the human testis and detection of its mRNA in the human uterine endometrium.
Oncology 2000, 59(Suppl 1):39-44. PubMed Abstract | Publisher Full Text
Hirata S, Shoda T, Kato J, Hoshi K: The novel exon, exon T, of the human progesterone receptor gene and the genomic organization of the gene.
J Steroid Biochem Mol Biol 2002, 80:365-367. PubMed Abstract | Publisher Full Text
Saner KJ, Welter BH, Zhang F, Hansen E, Dupont B, Wei Y, Price TM: Cloning and expression of a novel, truncated, progesterone receptor.
Mol Cell Endocrinol 2003, 200:155-163. PubMed Abstract | Publisher Full Text
Yamanaka T, Hirata S, Shoda T, Hoshi K: Progesterone receptor mRNA variant containing novel exon insertions between exon 4 and exon 5 in human uterine endometrium.
Endocr J 2002, 49:473-482. PubMed Abstract | Publisher Full Text
Hirata S, Shoda T, Kato J, Hoshi K: Novel isoforms of the mRNA for human female sex steroid hormone receptors.
J Steroid Biochem Mol Biol 2002, 83:25-30. PubMed Abstract | Publisher Full Text
Lee KL, Hansen EL, Price TM: Characterisation of a novel non-genomic truncated progesterone receptor.
Fertility Sterility 2004, 82(Suppl 2):S4. Publisher Full Text
Yeates C, Hunt SM, Balleine RL, Clarke CL: Characterization of a truncated progesterone receptor protein in breast tumors.
J Clin Endocrinol Metab 1998, 83:460-467. PubMed Abstract | Publisher Full Text
Richer JK, Lange CA, Wierman AM, Brooks KM, Tung L, Takimoto GS, Horwitz KB: Progesterone receptor variants found in breast cells repress transcription by wild-type receptors.
Breast Cancer Res Treat 1998, 48:231-241. PubMed Abstract | Publisher Full Text
Balleine RL, Hunt SM, Clarke CL: Coexpression of alternatively spliced estrogen and progesterone receptor transcripts in human breast cancer.
J Clin Endocrinol Metab 1999, 84:1370-1377. PubMed Abstract | Publisher Full Text
Leygue E, Dotzlaw H, Watson PH, Murphy LC: Identification of novel exon-deleted progesterone receptor variant mRNAs in human breast tissue.
Biochem Biophys Res Commun 1996, 228:63-68. PubMed Abstract | Publisher Full Text
Misao R, Sun WS, Iwagaki S, Fujimoto J, Tamaya T: Identification of various exon-deleted progesterone receptor mRNAs in human endometrium and ovarian endometriosis.
Biochem Biophys Res Commun 1998, 252:302-306. PubMed Abstract | Publisher Full Text
Hodges YK, Richer JK, Horwitz KB, Horwitz LD: Variant estrogen and progesterone receptor messages in human vascular smooth muscle.
Circulation 1999, 99:2688-2693. PubMed Abstract | Publisher Full Text
Leygue E, Dotzlaw H, Watson PH, Murphy LC: Altered expression of exon 6 deleted progesterone receptor variant mRNA between normal human breast and breast tumour tissues.
Brit J Cancer 1999, 80:379-382. PubMed Abstract | Publisher Full Text
Misao R, Nakanishi Y, Sun W, Iwagaki S, Fujimoto J, Tamaya T: Identification of exon-deleted progesterone receptor mRNAs in human uterine endometrial cancers.
Oncology 2000, 58:60-65. PubMed Abstract | Publisher Full Text
Nagao K, Kohno N, Wakita K, Hikiji K, Yamamoto S, Hirata H, Hisatomi H: Expression of a novel splicing variant deleting exons 4 and 6 of the progesterone receptor gene is a rare event in breast cancer.
Oncol Rep 2003, 10:305-308. PubMed Abstract
Bain DL, Franden MA, McManaman JL, Takimoto GS, Horwitz KB: The N-terminal region of human progesterone B-receptors: biophysical and biochemical comparison to A-receptors.
J Biol Chem 2001, 276:23825-23831. PubMed Abstract | Publisher Full Text
Marshburn PB, Zhang J, Bahrani-Mostafavi Z, Matthews ML, White J, Hurst BS: Variant progesterone receptor mRNAs are co-expressed with the wild-type progesterone receptor mRNA in human endometrium during all phases of the menstrual cycle.
Mol Hum Reprod 2005, 11:809-815. PubMed Abstract | Publisher Full Text
Hisatomi H, Kohno N, Wakita K, Nagao K, Hirata H, Hikiji K, Harada S: Novel alternatively spliced variant with a deletion of 52 BP in exon 6 of the progesterone receptor gene is observed frequently in breast cancer tissues.
Int J Cancer 2003, 105:182-185. PubMed Abstract | Publisher Full Text
Tyson-Capper AJ: Alternative splicing: an important mechanism for myometrial gene regulation that can be manipulated to target specific genes associated with preterm labour.
BMC Pregnancy Childbirth 2007, 7(Suppl 1):S13. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text


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subset: commoncrawl


text:
These are surveillance video images from three bank robberies in Western North Carolina this year in which the suspect is believed to be a woman. The picture on the left is from a robbery on Jan. 4 at Champion Credit Union in Waynesville. The photo in the middle is of the suspect in the robbery Thursday at SunTrust Bank in Black Mountain. The image on the right is of the suspect in the robbery Wednesday at First Citizens Bank in Leicester.
- Filed Under
Local law enforcement agencies are working together trying to find the person or persons responsible for a pair of bank robberies in Buncombe County within a day of each other.
The latest robbery happened around 11:45 a.m. Thursday at SunTrust Bank, located at 200 N.C. 9 in Black Mountain. About 21 hours earlier, First Citizens Bank, 601 New Leicester Highway, was robbed in a similar fashion by a person wearing similar clothing.
Both robberies, according to witnesses, involved a white woman dressed in dark clothing and outerwear with her face covered. In each case, according to ...


text:
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text:
Vodafone Germany will eliminate 500 jobs by 2015 and re-asisgn the position to India and Romania, where it can hire cheaper labor. German-language newspapers RP Online and Frankfurter Allgemeine both reported the plans to cut jobs Tuesday, after obtaining copies of an internal letter written by Vodafone Germany CEO Jens Schulte-Bockum.
In the letter, Schulte-Bockum said the company could not afford high salaries in such a tough operating environment.
"We are currently paying starting salaries that are significantly above the market rate," Schulte-Bockum said in his letter. He added the affected jobs will be in the network technology, IT and customer service business units.
A Vodafone spokesperson confirmed to Reuters Monday the outsourcing would be completed by 2015.
However, Bloomberg reported Tuesday the number of jobs was not disclosed in the letter. "Commercial pressure is increasing", and regulation of the industry "has been hostile to investment for years", it quoted Schulte-Bockum's letter.
The German office's decision to move jobs to India and Romania is the opposite of its Australian counterparts. In March, Vodafone Australia CEO Bill Morrow said it plans to hire 750 people in its Tasmanian call center and shift away from using its Indian one, and this is the first step in rebuilding the company's brand.
The company will continue to maintain the Indian operation, but it will be "more of back office-type activity", Morrow added.


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Back for a return visit this week is Jay Payleitner. You might recall he wrote in this column last week about the need for men to be willing to apologize to their wives when they mess up. He listed three reasons why men should be saying "I'm sorry" more than their wives. If you missed that column and would like to read it send me an email at the address listed below and I'll be happy to send it to you.
This week, in the interest of fairness and balance, I asked Jay to address an issue that women need to consider as they seek to have a healthy marriage and a better relationship with their man.
Most women can imagine the scene. Maybe you've been a part of the scene. Between three and 10 charming, intelligent women sitting in a living room, restaurant or community center trash talking their husbands or ex-husbands. It may be a work outing. It may be a new mom support group. It may be a booster club planning some fundraising event and all the volunteers happen to be women. It may even be a women's Bible study.
One woman innocently makes a joke. Another makes a slightly meaner joke. And pretty soon the entire conversation drags down everyone in the room, their husbands and their marriages. The community too, for that matter.
Years ago, my wife, Rita, was part of a bi-weekly gathering of homemakers who brought their sewing, needlepoint and knitting projects. Please excuse the expression, but they literally called it "Stitch and Bitch." Funny? Perhaps. Uplifting? Not at all.
As you're reading this, there are probably two or three women who come to mind who are always ready to start the negative chatter. I'm not sure why they are so miserable. But I'm assuming they have also left a trail of husbands (or ex-husbands) who are also miserable.
If you find yourself in an ongoing vortex of bitterness, how should you respond? If you feel compelled to join in, please don't. And excuse yourself from other such meetings with that group. But if you feel empowered by your relationship with your husband and confident that your voice will be heard, could you do all of us guys a favor? Find the right words to deflect the bashing, or at least give the group something to think about.
"There's such a negative vibe going on here -- especially against husbands -- is that really necessary?"
"Let's change the direction of this conversation, what do you think?'
"I'm not sure where this is all coming from, but men are not the enemy."
"I have to say, you're starting to make me really appreciate my husband."
You goal is not to paint yourself as a saint or suggest your husband is perfect. And it's quite possible all that husband bashing is really just a cry for help. The best answer might not be to confront the culprit in the large group setting, but rather talk to her one on one after your meeting. A simple, "Are you OK?" might be exactly what she needs to hear and may even open the door to some counseling or an invitation to your church or a study group with a better attitude.
Any intervention you attempt may not change the heart of the worst offenders. But you might prevent collateral damage among the other quieter women in the group. There may be some younger participants who have not built up any immunity to the rampant spread of man-hating poison. If you can prevent one or two from becoming infected, you may save a marriage or discourage one young bride from picking a fight with her unsuspecting husband later that evening.
I've never attended an all women's meeting, but my sources tell me that husband bashing is quite contagious. Immunize yourself with good thoughts and a new appreciation for your own man. Protect others with a pro-marriage comment or quip. And see if you can't stop the infection at its source.
Of course, this article might have put you on the defense. You might even find yourself justifying your actions, "Sure, I joke about my husband, but it's all in good fun. Besides, he's guilty of all the things I accuse him of." If that's the case, I encourage you to think back. Once upon a time, did he make a few tiny flubs which you then blew way out of proportion and joked about maliciously? And did he react by beginning to erect a wall or holding himself at a distance? Can you blame him? Your husband knows he's not perfect and he certainly doesn't need you to remind him.
Husband bashing is a classic example of a self-fulfilling prophecy. Trash talk your man and you'll begin to treat him like garbage. His only choice will be to start smelling and going bad. That's lose-lose. A better strategy for clever wives is to acknowledge your husband's shortcomings with a smile and say, "My dear, you are still the man of my dreams. Nothing silly you say or goofy you do will ever cause me to love you any less." Don't worry, you're not giving him an excuse to screw up again. You're giving him a reason to love you even more. That's a win-win.
OK, so maybe Jay just did some major party pooping and took all the fun out of some gatherings, but ladies he is absolutely correct. If you doubt that at all please picture yourself as the target of an all men's wife bashing gala. That, by-the-way, does occur at times and is absolutely just as wrong as it is for women.
So I hope you'll follow Jay's suggestions for how to put an end to such conversations and seek to be more supportive of your marriage and your mate. For more wise counsel from Jay, please visit his website at jaypayleitner.com. You can also hear more from Jay and his book "52 Things Husbands Need From Their Wives" tomorrow at 6 p.m. on 107.1FM. He will be my guest on TWOgether as ONE.


text:
Have you visited Dr. George Feltin? Rate you experience below.
Internal Medicine Physicians in Medford, MA
Dr. George Feltin specializes in internal medicine in Medford, Massachusetts.
Dr. George Feltin has been compared 110 times. Details of Dr. Feltin's 36 years experience as an MD, his hospital affiliation and education at Universite de l'Etat a Liege are available on your free doctor report.
Dr. George Feltin has an average rating of 5 stars (out of 5) with a rating of Excellent based on 2 reviews.
Have you visited Dr. George Feltin? Rate you experience below.
Dr. George Feltin has been identified as specializing in Internal Medicine.
A hospital affiliation covers any doctor who has an affiliation, association or admitting privilege with a hospital. A doctor's particular affiliation to a specific hospital can translate to the overall quality of that provider.
Dr. Feltin is affiliated with 1 hospital:
Dr. Feltin attended medical school at Universite de l'Etat a Liege Faculte de Medecine and graduated in 1979 having 36 years experience.
While there is no proven correlation between the quality of one's educational institution and the quality of one's professional competence, it is often an indicator. Medical schools have various levels of selectivity (some are harder to get into than others), and both the quality of their clinical training and level of research are measured. Additional medical training in both residency and fellowships and the facilities they are conducted at also provide a history of the doctors' level of training and experience.
Patients may also know Dr. George Feltin MD as:
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+ Reply to Thread
Results 1 to 16 of 16
Thread: What temperature
What temperature
is considered to be high in a 5 year old? My lo has a temp of 39.2C, should I be calling out a dr, or is it not that high?
Vicki, x.
anything above 37.5 is high at any age.
but if it's just a temp and otherwise well give some calpol and check it again in half an hour
Just found this of the Calpol Site
If your child or baby has a high temperature, especially if it reaches 39°C (102.2°F), you should contact your GP for advice.
He had some calpol about 1hr ago, I suppose I should just keep an eye on it.
He hasn't been well for a few days now so think I'll try to get an appt tomorrow morning.
Yes my digital thermometer says if it goes over 39 to seek medical advice.
I found this chick:
Children whose temperatures are lower than 102 degrees Fahrenheit (38.9 degrees Celsius) usually don't require medication, unless they're uncomfortable. There's one important exception to this rule: If you have an infant 3 months or younger with a rectal temperature of 100.4 degrees Fahrenheit (38 degrees Celsius) or higher, call your baby's doctor or go to the emergency department. Even a slight fever can be a sign of a potentially serious infection in very young infants.
For older children, take behavior and activity level into account. By watching how your child behaves, you can get a pretty good idea as to whether he or she has a minor illness or needs to be seen by a doctor.
The illness is probably not serious if your child:
is still interested in playing
is eating and drinking well
is alert and smiling at you
has a normal skin color
looks well when his or her temperature comes down
And don't worry too much about a child with a fever who doesn't want to eat. This is very common with infections that cause fever.
Thanks Jane, you must have posted that as I was posting my previous, maybe I'll give nhs direct a call.
To be honest if he has already had some Calpol and still is reading what you have said, then give the Doctor a ring as the Advice from them says...
You have nothing to lose by phoning the Doctors, as they are the ones that are medically trained..
Better to be safe than your little one be poorly
We must keep posting at the same time
if you gave the calpol 1 hour ago and his temp now is 39.2 then you should give some ibuprofen (calprofen) as well and try other ways of cooling him down - take all clothes off him, just have a sheet covering him and if you can't get his temp to come down then get on to the drs tonight.
My daughter had a temp of just over 39 as well today, I just kept an eye on her and gave lots of fluids and calpol and stripped her down to vest and nappy. Within a couple of hours she was playing again (even tho she looked like a ghost). If it had carried on or got any higher I would of called dr or nhs direct as I think they are at rist of fits if temp gets near 40. SHe has been ill recently with a very bad cold and is currently suffering with her last two top molars which gave a reason for a fever. hth
Like Jane said I would call a doctor you got nothing to loose.
Last thing you want is for your LO to et really bad.
I always give my ds nurofen was he has a temperature cause at a year old he had a convulsionit was horrible something i neverever would like to see again!!!!!!
Keep your lo dosed up if they have a temp.
If youv'e already given him calpol and its still that high i'd phone doctors or nhs direct,strip him off and try and cool him down with cool water,have you got any ice lollys or something like that to give him
keep an eye on him my dd had a fit when she was little and her temp got to over 40,not something i would like anyone to go through
hope hes ok sending you hugs xx
Serena had a temp of 40 on thursday... I dragged her out in the snow to get to docs.. he gave me a perscription for childrens ibpfrofen and told to alternate it with calpol... did the trick and lowered her temp loverly!
Hi everyone,just read not too cold sponge etc in case of lowering body temp too quickly,and causing shivering,which will bring temp up quickly...not sure how accurate this is just thought it might help😃 my lo has a temp of around 39 just giving her Calpol now...emily


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A variety of academic and learning skills assessment tests can be taken through the Advising Center. The results are used to help develop your personalized educational plan. If you have not taken the ACT or SAT in the last 5 years, or have submitted ACT scores of 17 or lower in English or Reading and/or 18 or lower in Math, transfer students may elect to take Accuplacer to better their placement, or be placed into MTH 097 (Developmental Math), ENG 097 (Reading) & ENG 098 (Writing). Students are able to enter college-level English and Math courses by providing appropriately high ACT or SAT scores or transfer credit for college-level English and Math courses. If necessary, transfer students take Accuplacer examinations for appropriate placement into college-level English and Math courses."
Accuplacer at Lourdes
The purpose of the Accuplacer test is to assess the student's basic algebra, grammar and reading skills. The multiple-choice instrument is computerized, but no previous experience with computers is necessary. The student manipulates the computer mouse to select the answer to questions. The assessment is not timed, but generally students need two hours to complete both the English and math portions. The results are given in the form of appropriate placement into classes taught here at Lourdes. Advisors use Accuplacer to help students select classes appropriate to their skill level. For this reason we ask that students schedule the Accuplacer assessment before they meet with their advisors to register for classes. With the results, we can make better suggestions as to classes in which the student can have a reasonable expectation of success.
To the Student:
Some Suggestions for Taking Accuplacer


text:
Treason charge sought against presidentComment on this story
Prague - Opponents of the Czech Republic's president have gained sufficient support to attempt to press high treason charges against him over his controversial amnesty.
To mark the country's 20th anniversary of independence on January 1, Vaclav Klaus used a traditional tool of Czech presidents and ordered the release of more than 6 000 inmates serving short prison terms.
But what really infuriated many Czechs was that the decree also halted court proceedings in several high-profile fraud cases and financial scams on the grounds he wanted to stop "endless criminal proceedings."
The office of the Senate, Parliament's upper house, said Wednesday that 28 lawmakers - one more than needed - have requested the issue to be debated. It said Speaker Milan Stech now has to set a date for an extraordinary session, possibly Monday.
Only the Senate has the power to file treason charges at the Constitutional Court. A majority of the present lawmakers in the 81-seat house, which is controlled by the left-wing opposition, has to approve that to happen.
Klaus doesn't have much to worry about because the major punishment he faces would be loss of the presidential job: his second and final term in office ends March 7.
But the amnesty has touched a raw nerve in a nation that has become increasingly angered by widespread corruption. About 73,000
Czechs have signed a petition, backing the charges while Klaus' portrait has been torn down in anger in schools and offices across the country.
A group of 30 senators has already challenged Klaus' decree at the Constitutional Court.
But the conservative president has previously said he doesn't regret the amnesty and "would do it again in the absolutely same way."
During his visit to Slovakia on Wednesday, Klaus called the move by the opposition lawmakers "political games."
Prime Minister Petr Necas, who is chairman of the Civic Democratic Party that Klaus established, said he was feeling ashamed that the lawmakers want to sue the president.
"Shame on them," Necas said. - Sapa-AP
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1 Paul, called to be an apostle of Christ Jesus through the will of God, and Sosthenes our brother, 2to the church of God sanctified in Christ Jesus that is in Corinth,#Some manuscripts have "to the church of God that is in Corinth, sanctified in Christ Jesus" called to be saints, together with all those who call upon the name of our Lord Jesus Christ in every place, their Lord#*Here "Lord" must be supplied to indicate the referent; otherwise this could be understood as "their place and ours" and ours. 3Grace to you and peace from God our Father and the Lord Jesus Christ.
Thanksgiving for the Corinthian Believers
4I give thanks to my God always concerning you, because of the grace of God which was given to you in Christ Jesus, 5that#*Or "because"; the conjunction either (1) introduces a content clause ("that") giving the content of Paul's thanks, or (2) introduces a causal clause ("because") giving the reason for Paul's thanks in everything you were made rich in him, in all speech and all knowledge, 6just as the testimony about Christ has been confirmed in you, 7so that you do not lack in any spiritual gift as you#*Here "as" is supplied as a component of the participle ("eagerly await") which is understood as temporal eagerly await the revelation of our Lord Jesus Christ, 8who will also confirm you until the end, blameless in the day of our Lord Jesus Christ. 9God is faithful, by whom you were called to fellowship with his Son Jesus Christ our Lord.
Divisions in the Church at Corinth
10Now I exhort you, brothers, by the name of our Lord Jesus Christ, that you all say the same thing and there not be divisions among you, and that you be made complete in the same mind and with the same purpose. 11For it has been made clear to me concerning you, my brothers, by Chloe's people#Literally "those of Chloe", that there are quarrels among you. 12But I say this, that each of you is saying, "I am with Paul," and "I am with Apollos," and "I am with Cephas," and "I am with Christ." 13Has Christ been divided? Paul was not crucified for you, was he?#*The negative construction in Greek anticipates a negative answer here Or were you baptized in the name of Paul? 14I give thanks#Some manuscripts have "I give thanks to God" that I baptized none of you except Crispus and Gaius, 15lest anyone should say that you were baptized in my name. 16(Now I also baptized the household of Stephanas. Beyond that I do not know if I baptized anyone else.) 17For Christ did not send me to baptize, but to proclaim the gospel, not with clever speech#Literally "wisdom of word", lest the cross of Christ be emptied.
Christ Crucified, the Power and Wisdom of God
18For the message about the cross is foolishness to those who are perishing, but to us who are being saved it is the power of God. 19For it is written,
"I will destroy the wisdom of the wise,
and the intelligence of the intelligent I will confound."#A quotation from Isa 29:14
20Where is the wise person? Where is the scribe? Where is the debater of this age? Has not God made foolish the wisdom of the world? 21For since, in the wisdom of God, the world through its wisdom did not know God, God was pleased through the foolishness of preaching to save those who believe. 22For indeed, Jews ask for sign miracles and Greeks seek wisdom, 23but we preach Christ crucified, to the Jews a cause for stumbling, but to the Gentiles foolishness, 24but to those who are called, both Jews and Greeks, Christ is the power of God and the wisdom of God. 25For the foolishness of God is wiser than human wisdom,#Literally "man" and the weakness of God is stronger than human strength.#Literally "man"
Boast in the Lord
26For consider your calling, brothers, that not many were wise according to human standards,#Literally "according to flesh" not many were powerful, not many were well born. 27But the foolish things of the world God chose in order that he might put to shame the wise, and the weak things of the world God chose in order that he might put to shame the strong, 28and the insignificant of the world, and the despised, God chose, the things that are not, in order that he might abolish the things that are, 29so that all flesh may not boast before God. 30But from him you are in Christ Jesus, who became wisdom to us from God, and righteousness and sanctification and redemption, 31so that, just as it is written, "The one who boasts, let him boast in the Lord."#A quotation from Jer 9:24
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text:
Bloomberg (02/08/12) Schoenberg, Tom; Frier, Sarah
The Center for Reproductive Rights recently asked a federal judge to reopen their 2005 lawsuit on access to the emergency contraceptive Plan B, in an effort to overturn the FDA's age restrictions for those who can access the drug. The center had supported the application made by Teva Pharmaceuticals to have Plan B One-Step made available in all stores, but the application failed as Secretary of Health and Human Services Kathleen Sebelius ordered the FDA to reject it. In 2009, Brooklyn District Judge Edward Korman ordered the FDA to reconsider approving Plan B to be sold on drugstore shelves without age restrictions, along with his order that they make the pill available to those as young as 17 without a prescription. The center has asked to add Sebelius as a defendant in their reopened case.


text:
Just months after brain surgery, the schoolgirl who was shot in the head by the Taliban goes back to school.
18:08, UK, Tuesday 19 March 2013
A Pakistani schoolgirl who was shot in the head by the Taliban has returned to lessons for the first time since the attack last October.
Malala Yousafzai was flown to the UK to be treated after she was shot for campaigning for the rights of girls to receive an education.
After months of surgery and rehabilitation at Birmingham's Queen Elizabeth Hospital, the 15-year-old has joined pupils at Edgbaston High School for Girls.
Malala said: "I am excited that today I have achieved my dream of going back to school.
"I want all girls in the world to have this basic opportunity.
"I miss my classmates from Pakistan very much but I am looking forward to meeting my teachers and making new friends here in Birmingham."
She is in Year 9 and will soon be selecting which GCSEs to take.
During the teenager's time in hospital, she had a titanium plate placed in her skull and a cochlear implant fitted.
Islamist gunmen said they shot Malala because she had promoted girls' education and "Western thinking".
She was attacked on a school bus in northwestern Pakistan, with the bullet entering just above her left eye and running along her jaw, "grazing" her brain.
Surgeons in Pakistan removed the bullet before she was flown to the UK.
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By susiecue
from Liberty, SC
About Me Casual Cook
Comments about My Favorite™ Spatula:
This product will be used to lift casseroles and desserts from their dishes. I wish it were a little wider but I'm sure I will find many other uses for it.
Bottom LineYes, I would recommend this to a friend
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My Favorite spatula
By Laurie
from Hilo, Hawaii
Good for turning small omelets
cake spatula
By molly brown
from henderson, nv
removes all of pies in plste
Really a Favorite with Me.
By Nancy
from Centre Hall, PA
Sturdy enough to handle my peach pie.
My Favorite Soatula
By Cooking in Texas
from TX
We had one, but my husband liked it so well that we ordered two more. It is the only spatula that he will use.
Long lost friend
By Whatever
from Upstate New York
About Me Avid Cook
I use this item for removing brownies, etc. from the pan. I had one for years and during a move it disappeared.I really missed it and was very glad to find another one.
Best spatula for brownies, etc!!
By Prissy
from Bedford, TX
Great utensil for serving brownies or any bar shaped goodies, like blueberry or chocolate chip rectangle cakes! It always goes with me when I take my baked goodies to a pot luck. It's been through the dishwasher several times and still looks new. I may get some of these as stocking stuffers for Christmas!! Great price, too!
Truly the most used spatula!
By Stitchtins
from Santa Ana, CA
I truly use this spatula more than any other larger spatulas I own. I see why everyone loves this slim spatula that is convenient for everyday use.
I love it!it works well getting brownies and cookies off she
By Retired armt
from Sebring,Florida
I,m still finding more uses everyday, works great for cookie sheets
looks sturdy
By NCbear
from North Carolina
haven't used it yet; spatula edge is just short of 2" wide to abt. 1-1/2" wide @ handle; flat part is about 4-1/2" long to bend @ handle; looks like about the right size to get the 1st brownie out of the pan; handle is hollow, but appears sturdy enough; overall, looks like a good addition to an every-day kitchen


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|Rape: Why men DO IT, and do they have REMORSE?
by Dedra Muhammad
|Husband rapes wife
|Are you the victim/perpetrator of abuse?
|Characteristics of a Rapist
Is it true that all rapists are visibly identifiable? I don't think so, but they all have certain visible tendencies. How does a lady know that the man she brings home for a date would not harm her daughter? And when is it the daughter's "fault", and not the new boyfriend's "fault?" Unfortunately, many women are so vulnerable, loving and trusting (also so lonely) that we miss the clues and characteristics of rapists and molesters. Also, our sometime over-inflated egos tend to blind us to certain social ques that could suggest the need to be especially watchful. For instance, it is hard to imagine that the sweet talking slickster would have his eye on our pocketbook, daughter, or just a plain "good time" when we are searching for a long and enduring relationship.
Below is the tip of the day to keep the rapist at bay:
Friday's Tip:
* Be weary of any man who tries to send you on errands while he stays in your house with your child---even if the errand will only take 5 minutes.
Saturday's Tip
* Many perpetrators do not pre-meditate on their indecent acts...they actually believe that the girl will enjoy it and won't say no. And THEN, anger, embarrassment, resentment, and selfishness takes over (not necessarily in that order) and thus the perpetrator arrives at "the point of no return." Keep in mind that on this site our main focus is the acquaintance or family rape, as opposed to the viscious stranger rape. Anyway, because of the above, it is essential to take into account PREVENTIVE MEASURES.
Sunday's Tip:
When molestation occurs inside of families, it is the least reported. Many boyfriends, fathers, uncles, friends of the fmily are able to get away with raping their victims for years with no familial intervention. And usually, someone knows or suspects it, but for family political reasons chooses to keep silent. Again, to avoid this, practice preventive measures. Children should not be left unsupervised or in the care of men and boys who are older and more "street wise" than they. Mothers should consider not working during afternoon and night hours at the expense of their child's chastity.
Monday's Tip: When a man rapes a woman, he gets an immediate sense of satisfaction that he does not get from a normal intercourse. It's almost like a crack-cocaine high. Seriously! And then it wears off until he meets his next victim or until he rapes her again. In the meantime, he survives off of the lust of his memories. Repeat sex offenders have a low sense of self-accusing spirit, and are unable to feel remorse for his act, and the high of it rules him. For prevention, pay close attention to the man who comes around and small ignoble acts he does has no moral effect on him. In the book Making Mary, the rapist in Chapter 15 has no remorse and his first rape unquestionably is just that...his FIRST.
Read below for more TIPS.....................
|"He raped me!"
|Take a ride to the North Star and see how easy it is for sexual abuse to creep into a relationship where the man and woman supposedly love one another.
|Women Issues:
What are the characteristics of a rapist? Is it true that many people fantasize about raping or being raped? What would cause a woman to fantasize about being raped? Why do so many feel that women secretly enjoy the prospect of being raped, and that in many instances, they "like" it, especially if she doesn't get beat too badly. And why do many women decide not to report it, and to even turn a blind eye when it happens in their own families? What is the difference in the characteristics of rapists between stranger rape, date rape, and family rape? And how does the perpetrator "feel" after he commits the act? Why does he do it over and over?
| No one wants to talk about rape, especially in terms of prevention. Rape can be considered one of the highest forms of emotional abuse, although it has a catergory all to herself (or his self). So many of us stick our heads under the sand with our bottoms exposed--refusing to accept that "it could happen to me" ...and once a sexual predator overtakes his victim, there is no turning back and it cannot be un-done. If the perpetrator is convicted, the irreversible damage still has been done. And at trials, prosecuters light into the victims as though they are the guilty ones. In fact, many rapes don't even get to trial because the victim refuses to re-live the horrors of his or her tradegy while being made to feel cheap and dirty. Thus, we'd rather say or hear, "I was raped," years later when it is safe to admit that we were violated and then leave it at that. But, what happens emotionally, spiritually, and psychologically to a person who undergoes such an assault, and what about the perpetrators?
There are many kinds of victims as well as perpetrators. For the purposes of this paper, the author is speaking mainly to those who are victims and perpetrators of family type crimes or date rape incidences as opposed to strangers who may also be stranglers and murderers--notwithstanding rape is a kind of murder. In dealing with prevention, though, it becomes more tricky to guard against one's father or uncle, or even a man one is dating.
Sure, we can generalize it and describe the characteristics of a rapist, but those generalizations and characteristics don't always fit, nor do they reduce the chances of one getting raped or of one committing the act simply because certain characteristics are known. Even if boys are taught at a young age that they should respect women, we live in a morally bankrupt society and most of the perpetrators DO know right from wrong, yet knowing does not stop them. No...it's deeper than that. Rape is such a gruesome crime because healing can never be complete once one is raped---one can only take steps in the direction of closure. Picture a perfectly baked caked, and then a rat tears into it from the middle and guts it out. the cake was already baked, and one cannot go back and add eggs or other things of sustenance that were ripped away--one can only place patches over the holes. So rape has to be done away with and understood because the usual victims are women--women who give birth and nurture children who could have grown to become world leaders.
It may appear that society (and even the author) is hard on women, but when you read Making Mary, you'll see that is not the case AT ALL. Here, I am merely trying to point women and girls in the right direction as a measure of prevention.
Rape (against men or women) is gruesome, and the perpetrators should not be excused because he or she was "led on" as I often hear. The Honorable Elijah Muhammad said that 75% of the work is with the female. Let's look at this in terms of how a woman can protect herself and her children from such crimes:
Women have to face that their very own boyfriends have in mind to rape their daughters, and it is ignorant to get angry at the daughter when the boyfriend seduces or rapes her. We must not place our daughters in vulnerable situations, especially when they are taught and ruled by the television, where girls are half-naked and where foreplay is shown in different aspects on most channels right at prime time, and even on the Disney channel.
Women have to face the fact that no, they should not get into a limo with a celebrity at 2:00 a.m. and then enter his hotel room. Women should not "neck" with a man and then expect him to stop when her bra is half-way off, and her pants are done to her knees. sure he should stop when asked, but what if he is out-of control? How does one really know what another will do when that person is led by the flesh?
It doesn't matter what church home the boy belongs to, or whether or not he's from a decent family---what matters is the position in which we place ourselves and others. If someone is hungry but is not supposed to eat until dinner time, why would you put a thick piece of Salmon cooked until tender with lemon slices soak through up under the hungry man's nose, and then charge him with disorderly conduct because he snatches a bite? Girls, keep the Salmon out of his nose and you would have done your part.
Nonetheless, because we all have needs, women act as temptresses--and we take from men all that we want sometimes, and then we decide when it is over. Mothers have to steer their daughters away from such indecent behavior. Of course if the girl is so unwise, this does not give any man the excuse to rape, and rape in some Islamic communities is punishable by death. Still, women need work because we consistently place ourselves in such vulnerable postions. A woman should not disrobe in front of a man and walk down America's streets half-clad and teach her daughters to do the same thing becasue a man will then see her as a piece of flesh that he so desires to devour. And once the rape is committed, there is no going back--it stays with the woman forever.
The book Making Mary is just as important for men as women. Making Mary shows the thought processes one may have before committing the crime.
And thought processing is extremely important because we know that in most instances, rape indeed is a crime of anger and passion versus strict lust. The author ventures to take the Rational/Behavioral Emotive Therapy base a step further: The thought processes that the perpetrators undergo does not start when they meet the victim--the processing is a way of life and can be identified in other aspects of the perpetrator's life. Notwithstanding, many victims seem to have a paralleling set of identifiers which make them fall prey to not simply oe incident of abuse, but a pattern of accepting abuse over a length of time. Haven't you ever heard the expression "Water seeks its own level?" Oftentimes, something has happened in the victim's life that plays a major role in the deterioration of high self-esteem. And whether the tragic episode(s) are identified or not makes little difference in the case of preventing abuse. For example, it is not enough to "know you were molested" as a small boy or girl. It is not enough to be able to intellectualize the circumstances and even to become a doctor in a helping profession.
In Making Mary, the person who was raped was placed in a vulnerable position by someone she loved and trusted. However, she didn't have the knowledge to recognize what was about to take place because in her situation, the rape could have been avoided, despite the fact that she was placed in such a seemingly trapworthy situation.
Making Mary is suggested for all rape victims, and to the perpetrators of rape. Do you want to understand a little more about why this happens? Counselor Dedra Muhammad reveals the a-b-c's of rape in the chapter entitled "Making Mary" and in other places throughout the book. There are so many things that lead up to the "rape" chapter, which, it should be no surprise about what happens in Chapter 15, yet, the readers I talked to for whatever reason "didn't see it coming" except that when they think back on all the signs, it became clear after the fact.
Do you know someone who needs to talk about it? Send an email to email@example.com
|Tuesday's Tip:
We all have pleasure and pain centers in our brains--and this is why people can get addicted to drugs, even prescription drugs that hit the pleasure centers in a special way. We also have natural stimulators that, when not suppressed can allow us to achieve a high sense of satisfaction. Yet, when we are not eating properly, not in tune with our spirituality, overwhelmed with external stimuli, we lose the immediate power to access whatever we need from within to "deal with" life's pressures. Rape is one way men compensate from this loss of inner strength and ability. For prevention, you must be like a psychologist...who are those people hanging around your family who have poor coping skills? Who are those people who use aggression and the "easy way out" to handle what should be simple tasks?
Wednesday's Tip:
Many women who have been abused or who have witnessed some fort of abuse when they were young fantasize about being in an abusive relationship because they rationalize that the abusive male shows great love intensity. They further fantasize about getting raped by someone they know or a stranger who just "has to have them." They fantasize of dramatically resisting, but the "knight" overpowers them and has "his way." When it is over, these women imagine that the rapist is very caring and concerned over whether or not they hurt their prey. This being the case, many women make themselves more susceptible of entering into a rape crisis situation as they subconsciously invite the rapist into their lives. They inadvertantly seek the man with characteristics of a rapist.
Thursday's Tip:
The main way to spot a potential abuser is the level of control he or she assumes and right at the beginning of the relationship. Even in "stranger rape," the positioning of control is immediate. Rapist feel powerless and weak, yet they of course do not wish to feel this way so they must compensate at every turn. Be weary of the overly "macho" man because what he has to prove may cost you your life.


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Hasan Davis
Hasan Davis worked in the Kentucky Department of Juvenile Justice from 2008 to 2014, serving as deputy commissioner for facilities and operations and then as commissioner. Davis is the founder of Empowerment Solutions, which offers training on issues relating to youth, race, culture and art. He also served as director of cultural arts outreach for Bluegrass Community and Technical College. A 1992 graduate of Berea College, he earned his law degree from the University of Kentucky.
This guest appears in ...
Lonnie Clinkscale and Hasan Davis (#204)
Renee interviews Lonnie Clinkscale about the Touch Someone's Life Ministries and Hasan Davis, founder of Empowerment Solutions.
Hasan Davis (#704)
Hasan Davis, deputy commissioner of operations at the Kentucky Department of Juvenile Justice, talks about his own journey from troubled youth to respected attorney and youth advocate, as well as the juvenile justice system in the state.
Hasan Davis (#931)
Renee speaks with Hasan Davis, former Kentucky Commissioner of the Department of Juvenile Justice, about recent juvenile justice reform. Davis was featured in the recent PBS Frontline program "Prison State," about Kentucky's corrections system, and interviewed for KET's follow-up program, Prison State: A Kentucky Community Conversation.


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- Study at Deakin
- Life at Deakin
- Research
- Alumni
- Industry and community
- About Deakin
What makes an archaeological artefact significant?
How do we decide?
How many artefacts can we afford to keep?
This project will produce a model for assessing the scientific significance of artefacts from historic sites. The result of this study will be a doctoral thesis, and the development of a guide for conducting assessments of the scientific significance of archaeological collections, which will be available to relevant heritage and educational institutions.
Australia is facing a crisis in the management of archaeological collections. As a consequence of 1970s federal and state legislation protecting archaeological sites many hundreds of sites have been excavated and this has resulted in a rapidly increasing number of collections to be stored and conserved. It is no longer possible to preserve every object in perpetuity and informed decisions have to be made about what to curate.
Under the Victorian Government Heritage Act (1995), Heritage Victoria, the industry partner in this project, is the statutory authority overseeing the excavation of historic archaeological sites in Victoria. By default excavated collections have become the responsibility of Heritage Victoria as the government agency administering the legislation. A similar situation is seen in all states. It is important that a set of criteria are established which will permit systematic assessment of the scientific significance of the collections and provide the basis upon which museums and other repositories of historic artefacts can establish a Collections Policy to guide the composition and growth of collections.
Significance assessment is now an integral part of Australian heritage policy and practice. Nevertheless, there has to date been no formal treatment of the significance assessment of archaeological artefacts, how to design criteria for their assessment, nor practical examples of the application of such a methodology. Very few guidelines exist which deal with assessing the scientific significance of objects. The only example in Australia is a guide recently published by the Heritage Collections Council of Australia (2001) that provides a framework for the assessment of individual objects, and identifies as primary criteria historical, aesthetic and social or spiritual significance. However, with the exception of a brief note, the guide does not address the specific characteristics of archaeological collections that govern any assessment of their research potential assessment. Nor does the guide address issues of assessing collections as a whole rather than as individual objects.
This research project will be the first to attempt to provide a national framework for assessing the research potential of archaeological collections from historic sites. The success of the research will depend on integrating the issues of academic or research archaeology with the needs of collection managers and conservators. The proposed research aims to bridge this professional distinction between archaeologists and curators, consulting with members of both disciplines to determine the best strategy for developing a model for assessing the research potential of archaeological collections.
Stage 1
Literature review:
• Background to the problem and discussion of issues in the literature
• Identify core issues for archaeological and historical research
• With archaeologists, academics
• With heritage managers and museum professionals
Model development:
• Review of current models for assessing heritage significance
• Development of model criteria for assessing archaeological significance
Stage 2
Model testing:
• Sample of Heritage Victoria's collections used to test model protocol on a variety of artefacts and materials (recovered from a range of contexts and conditions)
• Refining of model developed in Stage 1.
• Testing of model on additional collections interstate
• Writing of statements of significance for collections examined
Stage 3
• Evaluation of testing results
• Writing up of research findings as a doctoral dissertation
• Criteria published as a guide to assessing archaeological collections
If you have any questions or comments, suggestions or ideas, please contact:
Ilka Schacht
Cultural Heritage Centre for Asia and the Pacific,
Faculty of Arts, Deakin University
221 Burwood Highway,
Burwood, Victoria 3125
Telephone (03) 9251 7206
Fax: (03) 9251 7158
Email: email@example.com
Ilka Schacht as an Australian Postgraduate Award (APAI) funded researcher and PhD candidate, working on the ARC research project Making Room for the Past: Determining significance in archaeological collections from historic sites. Ilka holds a Masters of Archaeological Science in Archaeological Computing from Southampton University in the U.K and a Bachelor of Arts (Hons) from the University of Queensland, where she majored in Classics and Ancient History.
After graduating from her Masters of Science degree, Ilka participated in excavations in the U.K and then returned to Australia, working with a colleague at the University of Queensland to research and build a CD-ROM of the antiquities collection held in the university's antiquities museum.
Shortly thereafter, Ilka turned her attention to the archaeology of the Middle East, working for 2 years at the British Institute in Amman for Art and Archaeology (in Jordan) and then moving to Egypt. For the past 4 years Ilka has worked with the Theban Mapping Project, an Egyptological project at the American University in Cairo, renowned for its discovery and excavation of the tomb of the sons of Ramses II in the Valley of the Kings and the survey of the monuments of the west bank of Thebes, Luxor. Ilka was the coordinator for the production of the project's multi award-winning website (www.thebanmappingproject.com) which documents in extreme detail, using a variety of media, the tombs of the Valley of the Kings and related sites and information. She was also responsible for developing and maintaining the project's in-house archaeological and image databases, to which access is given on the project's website.
Whilst in Egypt, Ilka took part in the excavation of Berenike, an important Roman harbour on the Red Sea Coast and, as a member of the North Kharga Oasis Project, carried out an hydrological survey of the previously unknown underground aqueducts of the Kharga Oasis in Egypt's western desert.


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Gifts that Diabetics Will Appreciate
Gifts that Focus on Healthy Living and Healthy Eating
Of course, buying a gift for someone with diabetes isn't any different from buying a gift for someone without diabetes: in both scenarios, you should take into consideration what the person likes, what they already have, and what they don't have (but would certainly appreciate). The list below does just that—gives you some ideas for what a person with diabetes might need or appreciate.
Many of the ideas focus on healthy living: healthy eating with diabetes or exercising with diabetes, for example. We hope this list will help you give a much-appreciated gift to someone with either type 1 diabetes or type 2 diabetes.
- Fresh food of the month clubs are wonderful. You can order vegetables or fruit and extend the holiday giving over a year.
- If your friend lives in a cold climate, think of warm gloves, thermal socks, cashmere scarves, or warm hats. These will keep the cold winter winds out and the stress on organs lower.
- Exercise machines are welcome. Make sure you select an appropriate one in terms of space needed and skills.
- Hire a personal trainer for a number of sessions. There is no better way of saying "I love you and want you to live a long life" than to share good health.
- A membership at a health club.
- A series of massages, facials, or other pampering sort of things.
- If the person with diabetes needs to be in contact with others because of health issues, think of a cell phone. This will help allay anxiety when they are alone.
- If you have youngsters on your list, how about lessons in Karate, dancing, fencing, basketball, or whatever?
- A good book on health written by a major teaching hospital to use as a reference is always helpful.
- An indoor grill or a grooved pan to use on the stove for cooking—the lines on the meat are worth it as the fat drains away.
- If the diabetic works, buy them a slow cooker. They can leave for work in the morning and come home to dinner at night.
- Give the gift of travel to an important person in your life. Plane tickets and hotel reservations in a special city or resort will be welcomed. How about a weekend or week at a spa someplace you've always wanted to visit?
- One of those new small cameras that take both regular and wide angle shots might be just the thing. What could be easier than a camera that fits in your pocket and that takes panorama shots of scenic views or the whole family at a reunion?
- A small color TV for the kitchen makes cooking more tolerable to those who can't miss a favorite show.
- A garage door opener for the person who has difficulty raising and lowering theirs will always be welcome. Nowadays this is more a necessity than a luxury, so if mom doesn't have one, now is the time to get her one.
- A new bicycle or other sports equipment for anyone on your list is another thought. All of us have old athletic stuff in the garage, but the technology has made them obsolete. Find out what sport turns him or her on, and buy the newest gadget or equipment you can find.
- A gift of music is a joy. Send tickets to the symphony, the opera, a rock concert, or to a jazz festival.
- Donate money to your friend's favorite charity in their name and enclose that notice with a small gift or holiday card.
- Give hand, feet, and body creams to your friend with diabetes. This will help with dry skin and allow for easier blood glucose monitoring, but more than that, it will make your friend feel good. (Plus, taking good care of your feet is essential for people with diabetes; we all want to avoid diabetic neuropathy, as you can learn about on our sister site, EndocrineWeb.)
First published on: March 11, 2011
Updated on: October 2, 2012


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Rihanna tours Coco Chanel's French home
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Rihanna lived out a fashion fan's dream on June 4, 2013, after she was treated to a tour of legendary designer Coco Chanel's Paris home.
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The R&B beauty documented the outing by sharing photos with fans on Twitter, including a shot of her on the Chanel founder's couch with the label's accessories designer Laetitia Crahay -- and another pic of the singer posing solo on the icon's mirrored staircase.
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In a tweet on June 5, she writes, "Got the keys to CoCoChanels apartment!!! Yesterday=Most Legendary day in Paris!!!!"
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Chanel bosses marked the end of the tour by presenting the "Umbrella" hit maker with a small yellow handbag as a special gift.
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Anyway what he had us do was
- take a 30-60cc syringe (with needle attached!) and fill it full of salt water. And just spray it at the wound a granulated tissue several times. The salt and water being pressured into the tissue will make it fall right off.
- The get DMSO and Cut heal or Wound Care. And mix it to a 75% 25% ratio. It should be 75% Cut heal/Wound care and 25% DMSO and just spray this one the wound. Mixing the dmso and cut heal will help it get deep down in there and cleanse it out. The dmso will mix with the cut heal and take the cut heal all the way down there to the tissue and help it heal quickly with little to no scaring.
- once you have this sprayed on. Put gauze on the wound and wrap it semi tightly to keep the proud flesh from growing.


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Teen Wolf: Season 2, Episode 3
Ice Pick (11 Jun. 2012)
Ratings: 8.6/10 from 468 users
Reviews: write review | 4 critic
Scott and Stiles take Allison and Lydia on an ice skating date. Derek converts Erica. Mrs. Argent begins to suspect that Allison is still seeing Scott despite her promise not to.
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