41 research outputs found
Abstract 4136: Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth
No full textAbstract
Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. Tissue renin angiotensin systems (RAS) are known to stimulate angiogenesis, cell proliferation and migration. All of these actions potentiate cancer growth and spread. We have previously demonstrated that endometrioid endometrial cancers express both prorenin and prorenin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signalling pathways. Therefore we hypothesized that endometrial cancer growth can be inhibited by drugs that block Ang II/AT1R interactions and prorenin/(P)RR mediated signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA) at 24h, 48h, 72h & 96h. The effect of RAS blockers on cell viability was also assessed by Resazurin assay at 48h in the three endometrial cancer cell lines.
All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin mRNA, however levels of (P)RR were much higher in Ishikawa cells. Transfection of the three cell lines with a (P)RR siRNA resulted in 90% knockdown of (P)RR mRNA expression and reduced the cell viability of both Ishikawa and AN3CA but not HEC-1A cells, as measured by a resazurin assay after 48h incubation. Aliskiren (a renin inhibitor) inhibited Ishikawa cell growth by 20%. There was no effect of Aliskiren on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and Losartan (an angiotensin II type 1 receptor (AT1R) inhibitor) had no effect on cell viability in any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce cell viability in all cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%).
Removal of the prorenin receptor inhibits the growth and development of some endometrial cancer cell lines. Only telmisartan, which has properties additional to Ang II antagonism, was effective in inhibiting endometrial cancer cell growth. (P)RR knockdown and telmisartan are therefore potential therapeutic drugs for the treatment of endometrial cancer.
Citation Format: Riazuddin Mohammed, Sarah J. Delforce, Yu Wang, Nicole M. Verrills, Eugenie R. Lumbers, Kirsty G. Pringle. Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4136. doi:10.1158/1538-7445.AM2017-4136</jats:p
Investigation on the Failure of a Snap Ring in the Power Shift Transmission (PST) of a Tractor
No full textReactivity of umbilical vessels and ductus arteriosus:Lessons from the chicken embryo model
No full textAnalytical considerations and biology of milk conjugated linoleic acid synthesis in the bovine
Get PDFBiosynthesis of milk conjugated linoleic acid (CLA), a component of milk fat with demonstrated health benefits, requires a dietary source of PUFA. Even with PUFA supplementation, milk CLA is highly variable. Therefore, this study was aimed at identifying factors responsible for the variations in rumen CLA precursors and milk CLA.
Study 1 evaluated the efficiency of CLA production by grazing cows compared to those fed grass silage or fresh grass. Grazing cows were more efficient than those fed grass silage or fresh grass in milk CLA production. About
75% of the variability in milk CLA was related to the differences in PUFA (l8:2n-6 + 18:3n-3) intake and the remainder was related to factors regulating the extent of
PUFA biohydrogenation in the rumen. This study demonstrated that PUFA intake is important but it is not the only factor responsible for the observed variation in
milk CLA production.
Study 2 evaluated the effect of diets differing in rate of starch degradation on rumen PUFA biohydrogenation and milk CLA. Concentrations of ruminal t11-18:1 and milk CLA were greater for barley-based diets than corn-based diets and
were not different between rolling and grinding, indicating that factors inherent in the source of starch were responsible for the observed differences and these
factors could not be modified by rolling or grinding the grain.
Study 3 examined the effect of stage of lactation on persistency of milk t10-18:1, t11-18:1 and CLA for control and test (supplemented with PUFA and monensin) diets from calving to 270 days in milk. Milk concentrations of t11-18:1 and RA remained similar across the lactation length and were greater for the test diet compared to the control. Changes in milk t10-18:1 concentration during
lactation appeared to reflect an effect of the degree of rumen fermentation on PUFA biohydrogenating bacteria.
Although PUFA intake is important for milk CLA production, only those diets that give rise to increased ruminal t11-18:1 result in greater milk CLA. Concentrations of rumen t11-18:1 is influenced by the amount of PUFA consumed, degree of shift to t10-18:1 and the extent of PUFA biohydrogenation in the rumen
Closed retrograde retrieval of the distal broken segment of femoral cannulated intramedullary nail using a ball-tipped guide wire
No full textSevere Metallosis Owing to Intraprosthetic Dislocation in a Failed Dual-Mobility Cup Primary Total Hip Arthroplasty
No full textThe renin-angiotensin system in endometrial cancer
No full textEndometrial cancer is one of the fourth most common cancer in the developed world and its incidence is increasing rapidly. Several studies have shown that there is an upregulation of the pro-angiogenic arm of the renin angiotensin system in endometrial cancer. Endometrial cancers express both prorenin and (pro)renin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA). All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin (REN) mRNA, however levels of (P)RR and AGTR1 were much higher in Ishikawa cells. Transfection with a (P)RR siRNA resulted in knockdown of (P)RR at both gene and protein level in three cell lines. Furthermore, there was a significant reduction in endometrial cancer cell growth (proliferation and cell viability) in Ishikawa and AN3CA cells. Several studies show that (P)RR is released in a soluble form (s(P)RR) into blood and urine. We therefore hypothesized that s(P)RR could be released from endometrial cancer cells and that levels of s(P)RR in blood and uterine fluid would be elevated in women with endometrial cancer. The levels of s(P)RR were measured with a specific s(P)RR ELISA it was found that all three cell lines secrete s(P)RR into the cell culture supernatant. Also, we found that there was significant amount of s(P)RR levels in plasma samples. Therefore, we postulated that endometrial cancer growth can be inhibited by drugs that block Angiotensin (Ang) II/Ang II type 1 receptor interactions and prorenin/(P)RR mediated signaling pathways. Further we looked at the individual effects and combined effects of RAS blockers with ATP6AP2 siRNA on cell viability and cell proliferation in three endometrial cancer cell lines. There was no effect of aliskiren (a renin inhibitor) on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and losartan (an AT1R receptor antagonist) had no effect on the cell viability of any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce the viability of the three cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%). The combination of telmisartan + troglitazone had a similar effect to that of telmisartan on its own. Aliskiren + perindoprilat reduced the viability of HEC-1A cells, there was no effect in Ishikawa and AN3CA cells. Conversely, the combination of (P)RR siRNA + telmisartan significantly reduced cell viability and cell proliferation in Ishikawa cells. We also looked at the effect of ovarian steroids (estrogen and progesterone) on RAS expression in two other cancer cell lines (an endometrial cancer cell line (RL-952) and a breast cancer cell line (MCF-7). Treatment with estrogen had no effect on RAS expression in RL-952 or MCF-7 cells. This study is the first to characterize the functional role of prorenin and (P)RR in endometrial cancer, and to demonstrate that drugs that inhibit the (P)RR and/the RAS pathway could reduce endometrial cancer growth. Finally, measurement of s(P)RR could be used as a biomarker for endometrial cancer detection
Persistency of milk <i>trans</i>-18:1 isomers and rumenic acid in Holstein cows over a full lactation
No full text Mohammed, R., Khorasani, R. G., Goonewardene, L. A., Kramer, J. K. G. and Kennelly, J. J. 2011. Persistency of milk trans-18:1 isomers and rumenic acid in Holstein cows over a full lactation. Can. J. Anim. Sci. 91: 147–167. A long-term lactation study was undertaken to determine whether the previously reported short-term persistency in vaccenic acid [VA; trans(t)11-18:1] and rumenic acid (RA) could be maintained. To test this hypothesis, 24 Holstein cows were allotted to two experimental diets (control and test) from 2 wk before calving until they were 270 d in milk (DIM). The test diet was similar to the control diet, but supplemented with sunflower seed (11.2% diet DM), fish oil (0.5%) and monensin (22 mg/kg DM) by replacing an equivalent amount of barley grain. The forage: concentrate ratio was 50:50 (DM basis) with 35% barley silage and 15% alfalfa hay. Milk was sampled every fortnight from the start of lactation until cows were 270 DIM. Data obtained were averaged into three equal periods of 90 d each, representing three stages of lactation (SOL): early-lactation (EL), mid-lactation (ML) and late-lactation (LL). Dry matter intakes were not different between treatments with greater intakes observed during ML than during EL or LL. Milk yield was not different between treatments and decreased with increasing DIM. Milk fat content and yield showed interaction between treatment and SOL with lower values observed for the test diet than control diet during EL and ML. De novo synthesized fatty acids (4:0–15:0), 16:0–16:1 and preformed fatty acids (17:0 and above) showed interaction between treatment and SOL with the former two being greater for control diet than test diet and the latter greater for the test diet than control diet within each SOL. Milk t10-18:1 (% fatty acid methyl esters, FAME) was greater for the test diet compared with control diet (4.38 vs. 1.32) and was greater during ML (3.79) than during EL (2.38) or LL (2.38). Milk VA and RA showed interactions between treatment and SOL with greater values observed for the test diet than the control diet within each SOL. When analyzed by treatment, milk VA was not different across SOL for both diets. Milk RA was not different across SOL for the test diet, but was different for the control diet; it was lower during EL than during ML. Step-wise regression analysis revealed that the variability in milk RA for the control diet (P<0.01; R2=0.97) was determined by VA (70%) and RA/VA (27%); and for the test diet (P<0.01; R2=0.987) by VA (88.7%), RA/VA (5%) and t10-18:1 (3.8%). Desaturase index based on RA/VA showed an interaction between treatment and SOL; it was greater for the control diet than the test diet within each SOL. Overall findings revealed that the differences in milk t10- and VA across SOL reflected possible differences in starch and PUFA intakes, respectively. Differences in milk RA across SOL for the control diet could be attributed to possible differences in mammary desaturase activity based on differences in RA/VA. </jats:p
Percutaneous elastic intramedullary nailing of metacarpal fractures: Surgical technique and clinical results study
Get PDFAbstract Background We reviewed our results and complications of using a pre-bent 1.6 mm Kirschner wire (K-wire) for extra-articular metacarpal fractures. The surgical procedure was indicated for angulation at the fracture site in a true lateral radiograph of at least 30 degrees and/or in the presence of a rotatory deformity. Methods A single K-wire is pre-bent in a lazy-S fashion with a sharp bend at approximately 5 millimeters and a longer smooth curve bent in the opposite direction. An initial entry point is made at the base of the metacarpal using a 2.5 mm drill by hand. The K-wire is inserted blunt end first in an antegrade manner and the fracture reduced as the wire is passed across the fracture site. With the wire acting as three-point fixation, early mobilisation is commenced at the metacarpo-phalangeal joint in a Futuro hand splint. The wire is usually removed with pliers post-operatively at four weeks in the fracture clinic. Results We studied internal fixation of 18 little finger and 2 ring finger metacarpal fractures from November 2007 to August 2009. The average age of the cohort was 25 years with 3 women and 17 men. The predominant mechanism was a punch injury with 5 diaphyseal and 15 metacarpal neck fractures. The time to surgical intervention was a mean 13 days (range 4 to 28 days). All fractures proceeded to bony union. The wire was extracted at an average of 4.4 weeks (range three to six weeks). At an average follow up of 8 weeks, one fracture had to be revised for failed fixation and three superficial wound infections needed antibiotic treatment. Conclusions With this simple and minimally invasive technique performed as day-case surgery, all patients were able to start mobilisation immediately. The general outcome was good hand function with few complications.</p
