Protein Kinase C α Modulates Estrogen-Receptor-Dependent Transcription and Proliferation in Endometrial Cancer Cells.

Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The most prevalent endometrioid tumors are linked to excessive estrogen exposure and hyperplasia. However, molecular mechanisms and signaling pathways underlying their etiology and pathophysiology remain poorly understood. We have shown that protein kinase C α (PKC α ) is aberrantly expressed in endometrioid tumors and is an important mediator of endometrial cancer cell survival, proliferation, and invasion. In this study, we demonstrate that expression of active, myristoylated PKC α conferred ligand-independent activation of estrogen-receptor- (ER-) dependent promoters and enhanced responses to estrogen. Conversely, knockdown of PKC α reduced ER-dependent gene expression and inhibited estrogen-induced proliferation of endometrial cancer cells. The ability of PKC α to potentiate estrogen activation of ER-dependent transcription was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K) and Akt. Evidence suggests that PKC α and estrogen signal transduction pathways functionally interact, to modulate ER-dependent growth and transcription. Thus, PKC α signaling, via PI3K/Akt, may be a critical element of the hyperestrogenic environment and activation of ER that is thought to underlie the development of estrogen-dependent endometrial hyperplasia and malignancy. PKC α -dependent pathways may provide much needed prognostic markers of aggressive disease and novel therapeutic targets in ER positive tumors.

Silencing of germline-expressed genes by DNA elimination in somatic cells.

Chromatin diminution is the programmed elimination of specific DNA sequences during development. It occurs in diverse species, but the function(s) of diminution and the specificity of sequence loss remain largely unknown. Diminution in the nematode Ascaris suum occurs during early embryonic cleavages and leads to the loss of germline genome sequences and the formation of a distinct genome in somatic cells. We found that ∼43 Mb (∼13%) of genome sequence is eliminated in A. suum somatic cells, including ∼12.7 Mb of unique sequence. The eliminated sequences and location of the DNA breaks are the same in all somatic lineages from a single individual and between different individuals. At least 685 genes are eliminated. These genes are preferentially expressed in the germline and during early embryogenesis. We propose that diminution is a mechanism of germline gene regulation that specifically removes a large number of genes involved in gametogenesis and early embryogenesis.

Effect of green tea catechins with or without caffeine on anthropometric measures: a systematic review and meta-analysis.

BACKGROUND: Green tea catechins (GTCs) with or without caffeine have been studied in randomized controlled trials (RCTs) for their effect on anthropometric measures and have yielded conflicting results. OBJECTIVE: The objective was to perform a systematic review and meta-analysis of RCTs of GTCs on anthropometric variables, including body mass index (BMI), body weight, waist circumference (WC), and waist-to-hip ratio (WHR). DESIGN: A systematic literature search of MEDLINE, EMBASE, CENTRAL, and the Natural Medicines Comprehensive Database was conducted through April 2009. RCTs that evaluated GTCs with or without caffeine and that reported BMI, body weight, WC, or WHR were included. The weighted mean difference of change from baseline (with 95% CIs) was calculated by using a random-effects model. RESULTS: Fifteen studies (n = 1243 patients) met the inclusion criteria. On meta-analysis, GTCs with caffeine decreased BMI (-0.55; 95% CI: -0.65, -0.40), body weight (-1.38 kg; 95% CI: -1.70, -1.06), and WC (-1.93 cm; 95% CI: -2.82, -1.04) but not WHR compared with caffeine alone. GTC ingestion with caffeine also significantly decreased body weight (-0.44 kg; 95% CI: -0.72, -0.15) when compared with a caffeine-free control. Studies that evaluated GTCs without concomitant caffeine administration did not show benefits on any of the assessed anthropometric endpoints. CONCLUSIONS: The administration of GTCs with caffeine is associated with statistically significant reductions in BMI, body weight, and WC; however, the clinical significance of these reductions is modest at best. Current data do not suggest that GTCs alone positively alter anthropometric measurements.

Implementation of home-based medication order entry at a community hospital.

PURPOSE: The implementation of a home-based order-entry program at a community hospital is described. SUMMARY: Parkview Hospital is a 600-bed, community-based facility located in Fort Wayne, Indiana, that provides 24-hour pharmacy services. The main purpose for establishing a home-based order-entry program was to provide extra pharmacist coverage during the event of a spontaneous order surge in an effort to maintain excellent customer service. A virtual private network (VPN) was created to ensure the security and confidentiality of patients' health care information. The names of volunteer pharmacists who met specific criteria and who were capable of performing home-based order entry were collected. These pharmacists were trained and tested in the home-based order-entry process. When home-based order-entry is needed, the lead pharmacist contacts the pharmacists on the list by telephone. If available, the pharmacists (maximum of three) are notified to log into the Internet, access the VPN, and perform order entry with the same vigilance, confidentiality, and care as they would onsite. Home-based order entry is discontinued when off-trigger points are met. Pharmacists entering orders from home are paid by the time spent conducting order entry. Pharmacists reported that the program was easy to contact home-based order-entry volunteers, there were no problems with logging into the VPNs, and turnaround time was close to our target of 25 minutes. CONCLUSION: A community-based hospital successfully implemented a home-based medication order-entry program. The program alleviated the shortage of pharmacists during spontaneous surges of medication orders.

Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis.

Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCalpha, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCalpha protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCalpha knockdown increased levels of the cyclin-dependent kinase (CDK) inhibitors p21(Cip1/WAF1) (p21) and p27(Kip1) (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCalpha knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3beta (GSK-3beta). PKCalpha knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCalpha regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCalpha expression, with foci of elevated PKCalpha staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCalpha signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKCalpha may provide novel therapeutic options in endometrial tumors.

c-Jun N-terminal kinase regulates apoptosis in endometrial cancer cells.

c-Jun N-terminal kinases (JNKs) are important regulators of cell proliferation and apoptosis that have been implicated in tumorigenesis. We investigated the role of JNKs in apoptotic responses in Ishikawa and HEC-50 cells, models of type I and type II endometrial cancer, respectively. Etoposide treatment or UV irradiation resulted in sustained activation of JNK, correlating with the induction of apoptosis. Inhibition of JNK, or MAP kinase kinase 4 (MKK4), selectively suppressed apoptotic responses in both Ishikawa and HEC-50 cells. Knockdown of protein kinase C delta (PKCdelta) also attenuated apoptosis in endometrial cancer cells and inhibited the sustained, UV-mediated JNK activation in HEC-50, but not Ishikawa cells. Etoposide-induced JNK phosphorylation was unaffected by PKCdelta knockdown, implying that JNK can regulate apoptosis by PKCdelta-dependent and independent pathways, according to stimulus and cell type. Thus, expression and activity of JNK and PKCdelta in endometrial cancer cells modulate apoptosis and sensitivity to chemotherapeutic agents and may function as tumor suppressors in the endometrium.