The improved giant magnetostrictive actuator oscillations via positive position feedback damper

This article contemplates the demeanor of the giant magnetostrictive actuator (GMA) when a positive position feedback (PPF) damper is used to enable tight control over its vibration. The methodology followed here mathematically searches for the approximate solution for the motion equations of the GMA with the PPF damper, which has been accomplished by using one of the most famous perturbation methods. The multiple scale perturbation technique (MSPT) of the second-order approximation is our strategy to obtain the analytical results. The stability of the system has also been investigated and observed by implementing frequency response equations to close the concurrent primary and internal resonance cases. By utilizing Matlab and Maple programs, all numerical discussions have been accomplished and explained. The resulting influence on the amplitude due to changes in the parameters' values has been studied by the frequency response curves. Finally, a comparison between both the analytical and numerical solutions using time history and response curves is made. In addition to the comparison between our PPF damper's effect on the GMA, previous works are presented. To get our target in this article, we have mentioned some important applications utilized in the GMA system just to imagine the importance of controlling the GMA vibration

Superficial myofibroblastoma of the genital tract: a case report of the imaging findings

Superficial angiomyofibroblastomas are mesenchymal tumours that occur in the genital tract and are well described pathologically. This case report reviews the imaging appearances and highlights the MRI findings, which have not been previously described. We describe the occurrence of this lesion in a vaginal cyst, which to the authors’ knowledge, has also not been previously described. The histological findings are also presented here. Introduction Mesenchymal tumours of the female genital tract are well described pathologically but the imaging findings are less well documented. We present a case of an unusual mesenchymal tumour of the female genital tract, highlight the key sonographic and MRI findings and summarise the current diagnostic and management approach. Clinical history A 50-year-old female presented with a history of prolonged menstrual bleeding and right iliac fossa discomfort. Her past medical history of note included endometriosis, a partially septate uterus and two previous lower segment cesarean sections. She had no allergies and denied any relevant drug history such as tamoxifen or hormonal therapy use. Imaging findings Initial pelvic ultrasound demonstrated normal uterus and ovaries, but detected a 13 mm vascular soft tissue nodule in a 28 × 20 × 25 mm cystic lesion in the left posterior vaginal fornix (Figure 1). The differential diagnosis at this time included a cervical or high vaginal polyp or an endometrioma, although the solid vascular component was unusual for the latter

Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many cancer cells without causing toxicity in vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit in clinical trials. This can, most likely, be attributed to the fact that 50% of all cancer cell lines and most primary human cancers are TRAIL resistant. Consequently, future TRAIL-based therapies will require the addition of sensitizing agents that remove crucial blocks in the TRAIL apoptosis pathway. Here, we identify PIK-75, a small molecule inhibitor of the p110α isoform of phosphoinositide-3 kinase (PI3K), as an exceptionally potent TRAIL apoptosis sensitizer. Surprisingly, PI3K inhibition was not responsible for this activity. A kinome-wide in vitro screen revealed that PIK-75 strongly inhibits a panel of 27 kinases in addition to p110α. Within this panel, we identified cyclin-dependent kinase 9 (CDK9) as responsible for TRAIL resistance of cancer cells. Combination of CDK9 inhibition with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. Mechanistically, CDK9 inhibition resulted in downregulation of cellular FLICE-like inhibitory protein (cFlip) and Mcl-1 at both the mRNA and protein levels. Concomitant cFlip and Mcl-1 downregulation was required and sufficient for TRAIL sensitization by CDK9 inhibition. When evaluating cancer selectivity of TRAIL combined with SNS-032, the most selective and clinically used inhibitor of CDK9, we found that a panel of mostly TRAIL-resistant non-small cell lung cancer cell lines was readily killed, even at low concentrations of TRAIL. Primary human hepatocytes did not succumb to the same treatment regime, defining a therapeutic window. Importantly, TRAIL in combination with SNS-032 eradicated established, orthotopic lung cancer xenografts in vivo. Based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies.Cell Death and Differentiation advance online publication, 20 December 2013; doi:10.1038/cdd.2013.179

Nitric oxide levels in chronic liver disease patients with and without oesophageal varices

Introduction Patients with chronic liver disease ultimately progress to develop cirrhosis and portal hypertension. Recently it seems well established that nitric oxide disturbances play a key role in the pathogenesis of chronic liver disease and portal hypertension. The aim of this work was to clarify the correlation between chronic liver disease stages, liver function status, esophageal varices presence and nitric oxide disturbances. Subjects and methods All subjects (n = 120) in the present study were classified into; group I which included 15 age and sex matched healthy volunteers (taken as control), group II which included 20 patients with chronic active hepatitis, and group III which included 85 patients with hepatic cirrhosis. All subjects included were subjected to full clinical assessment, routine laboratory investigations, serum nitrate level determination using colorimetric method, abdominal ultrasonography and upper endoscopy. Results Increased serum nitrate level could not be detected in patients with chronic active hepatitis as well as those with early cirrhosis (Child’s class A). Progressive and significant increase of serum nitrate levels were detected in more advanced stages of cirrhosis (Child’s class B & C). The best non-invasive predictor for the presence of oesophageal varices was a combination of platelet count <150.000/mm3, splenomegaly >18 cm, Child’s class B or C and serum nitrate ≥38 μmol/l, with 93.3% sensitivity and 100% specificity. Conclusion Serum nitrate level can be used as a non-invasive predictor for progression of chronic liver disease as well as for the presence of oesophageal varices

The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome

The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (pT, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy

Tumor suppressor role of phospholipase C epsilon in Ras-triggered cancers

Phospholipase Cε (PLCε) has been characterized as a direct effector of Ras in vitro and in cellular systems; however, the role of PLCε in tumorigenesis and its link to Ras in this context remain unclear. To assess the role of PLCε in Ras-driven cancers, we generated two new mouse strains: one carrying a targeted deletion of Plce (Plce(-/-)) and the other carrying mutant alleles of Plce unable to bind to Ras (Plce(RAm/RAm)). The Plce(-/-) and, to a lesser degree, Plce(RAm/RAm) transgenic mice exhibited increased susceptibility to tumor formation in the two-stage skin carcinogenesis protocol, revealing a tumor suppressor function for this PLC. This result also suggests that in this context Ras binding in part regulates functions of PLCε. Although significant differences were not seen in the LSL-Kras(G12D) nonsmall cell lung carcinoma model, down-regulation of PLCε was found in animal tumors and in cellular systems following expression of the oncogenic Ras. An inhibitory impact of PLCε on cell growth requires intact lipase activity and is likely mediated by protein kinase C enzymes. Further cellular studies suggest involvement of histone deacetylase in the mechanism of PLCε down-regulation. Taken together, our results show a previously unidentified tumor suppressor role for this PLC in animal models and, together with observations of marked down-regulation in colorectal, lung, and skin tumors, suggest its use as a biological marker in cancer

Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study

Background Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. Methods Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. Results Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Conclusions NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive

CpG-island methylation study of liver fluke-related cholangiocarcinoma

Background: Genetic changes have been widely reported in association with cholangiocarcinoma (CCA), while epigenetic changes are poorly characterised. We aimed to further evaluate CpG-island hypermethylation in CCA at candidate loci, which may have potential as diagnostic or prognostic biomarkers. Methods: We analysed methylation of 26 CpG-islands in 102 liver fluke related-CCA and 29 adjacent normal samples using methylation-specific PCR (MSP). Methylation of interest loci was confirmed using pyrosequencing and/or combined bisulfite restriction analysis, and protein expression by immunohistochemistry. Results: A number of CpG-islands (OPCML, SFRP1, HIC1, PTEN and DcR1) showed frequency of hypermethylation in >28% of CCA, but not adjacent normal tissues. The results showed that 91% of CCA were methylated in at least one CpG-island. The OPCML was the most frequently methylated locus (72.5%) and was more frequently methylated in less differentiated CCA. Patients with methylated DcR1 had significantly longer overall survival (Median; 41.7 vs 21.7 weeks, P=0.027). Low-protein expression was found in >70% of CCA with methylation of OPCML or DcR1. Conclusion: Aberrant hypermethylation of certain loci is a common event in liver fluke-related CCA and may potentially contribute to cholangiocarcinogenesis. The OPCML and DcR1 might serve as methylation biomarkers in CCA that can be readily examined by MSP

Prognostic Significance of Wnt-1, β-catenin and E-cadherin Expression in Advanced Colorectal Carcinoma

Wnt/β-catenin pathway plays an important role in initiation and progression of colorectal oncogenesis. The aim of this study was to determine expression and localization of E-cadherin, β-catenin and Wnt-1 proteins in colorectal tumors. Expression of β-catenin, E-cadherin and Wnt-1 was determined by immunohistochemistry on advanced colorectal cancers. Abnormal expression of E-cadherin, β-catenin, Wnt-1 was observed. Additionally, we revealed correlations between levels of studied proteins and histoclinical data. In multivariate analysis nuclear β-catenin, higher carcinoembryonic antigen serum level before treatment, female sex and tumor localized in colon or rectum were independent unfavorable prognostic factors. These findings support the hypothesis that Wnt/β-catenin pathway plays an important role in advanced colorectal carcinoma