Effects of storage on thermomechanical properties of poly(epsilon-caprolactone) blends containing poly(vinyl pyrrolidone/iodine)

This study reports the effects of: the molecular weight ratio of poly(epsilon -caprolactone) (PCL) in blends containing polymer of high (50 000 g mol(-1)) and low (4000 g mol(-1)) molecular weight; the concentration (0, 1, and 5 wt-%) of poly(vinyl pyrrolidone/iodine) (PVP/I); and storage at 30 degreesC and 75% relative humidity; on the thermomechanical properties of films prepared by solvent evaporation from solutions containing both PCL and PVP/I. The tensile properties were found to be statistically dependent on the molecular weight ratio of PCL but not on the concentration of PVP/I. The reductions in tensile strength and elongation at break associated with increasing amounts of low molecular weight PCL were attributed to a reduction in the concentration of chain entanglements. No changes were observed in viscoelastic properties or the glass transition temperature. Following storage there were no changes in the tensile strength, glass transition temperature, or viscoelastic properties of the films; however, significant reductions in elongation at break were observed. It is suggested that this is due to hydrolytic chain scission of amorphous PCL. Inclusion of 5 wt-% PVP/I increased this process in films containing 100:0 and 80:20 high/low molecular weight PCL (but not 60.40), but the extent of this was small. This study highlighted significant aging properties of PCL in a moist atmosphere. Consequently, it is recommended that suitable packaging materials should be employed to control the exposure of PCL films to water during storage.

Effect of preventive primary care outreach on health related quality of life among older adults at risk of functional decline: Randomised controlled trial

Objective: To evaluate the impact of a provider initiated primary care outreach intervention compared with usual care among older adults at risk of functional decline. Design: Randomised controlled trial. Setting: Patients enrolled with 35 family physicians in five primary care networks in Hamilton, Ontario, Canada. Participants Patients: were eligible if they were 75 years of age or older and were not receiving home care services. Of 3166 potentially eligible patients, 2662 (84%) completed the validated postal questionnaire used to determine risk of functional decline. Of 1724 patients who met the risk criteria, 769 (45%) agreed to participate and 719 were randomised. Intervention: The 12 month intervention, provided by experienced home care nurses in 2004-6, consisted of a comprehensive initial assessment using the resident assessment instrument for home care; collaborative care planning with patients, their families, and family physicians; health promotion; and referral to community health and social support services. Main outcome measures: Quality adjusted life years (QALYs), use and costs of health and social services, functional status, self rated health, and mortality. Results: The mean difference in QALYs between intervention and control patients during the study period was not statistically significant (0.017, 95% confidence interval -0.022 to 0.056; P=0.388). The mean difference in overall cost of prescription drugs and services between the intervention and control groups was not statistically significant, (-$C165 (£107; €118; $162), 95% confidence interval -$C16 545 to $C16 214; P=0.984). Changes over 12 months in functional status and self rated health were not significantly different between the intervention and control groups. Ten patients died in each group. Conclusions: The results of this study do not support adoption of this preventive primary care intervention for this target population of high risk older adults. Trial registration: Clinical trials NCT00134836.

The Musical Body: Devising a choreo-musical interpretation for the work Tierkreis (1974-75) by Karlheinz Stockhausen

In this chapter the authors explore a practice-led approach to understanding the role of the body in music performance.

Many writers have discussed the body in music performance, in improvised music, as well as in electronic music. In this chapter the authors offer new modalities of reflection on the musical body in the interpretation of existing contemporary repertoire. Specifically, the authors discuss a re-interpretation of German composer Karlheinz Stockhausen's musical work 'Tierkreis'. Through the development of a specifically physical approach to the performance, the authors investigate the intrinsic relationship between the body and the music and point to an under-explored modality, which is not a musical choreography, but a choreography that is shaped through the musical body itself. It is a modality in which music itself propels forward choreographic ideas, the body becoming the driving force behind musical interpretation. The authors' thinking is influenced by Susan Kozel’s understanding of performance as an ecosystem (Kozel 2007) and framed within a subjective account of musical embodiment.

By merging theory with praxis the authors offer a deeper understanding of the role of the body in music performance and consider how such contributions might lead to new and exciting interpretive frameworks for existing musical repertoires.

A 75-81 GHz, 14.3 dBm Peak Output Power, 21 dB Peak Gain, SiGe Power-Combining Amplifier Operating from a Single 3.3 V Supply

A compact differential 4-way power combiner with 2.3 dB loss and high common-mode rejection characteristic for use in mm-wave PAs is presented. A complete circuit comprised of a power splitter, two-stage cascode PA array, and a power combiner was implemented in SiGe technology. Measured small-signal gain of at least 17 dB was obtained from 74.5 GHz to 80.5 GHz with a peak 21 dB at 79 GHz. The prototype delivered 13.2 dBm P1dB and 14.3 dBm Psat when operated from a single 3.3 V supply at 75 GHz.

Introduction:Antiquity's first 75 years

15 papers derived from Society of American Archaeology conference, Denver. Colorado

Effect of heating vermiculites on extractability of phosphorus and some essential plant micronutrients

The study assessed the effect of heating vermiculites on extractability of phosphorus, iron, zinc and manganese with respect to their potential agricultural use. Of these elements, phosphorus was from apatite and monazite that occur as accessory minerals in vermiculites. Vermiculites were heated at 15-800 degrees C and digested by acetic acid for extracting phosphorus and diethylene triamine pentaacetic acid (DTPA) for extracting zinc, iron and manganese. Phosphorus in the extract was analysed by a flow injection method while zinc, iron and manganese were measured by atomic absorption spectrometry. The results showed that heating vermiculites to 400 C enhanced extractability of phosphorus from apatite and monazite to a level of 335 mg kg(-1). Further heating to 800 degrees C reduced extractable phosphorus to less than 75 mg kg(-1). Maximum extractable zinc, iron and manganese found were 2.7, 19.1 and 22.9 mg kg(-1), respectively, values that are beneficial and tolerable by most plants. Thus, it was concluded that heating vermiculites to

Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in β-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence.

miR-433 overexpression attenuates the spindle assembly checkpoint response to paclitaxel

Paclitaxel is a microtubule inhibitory chemotherapeutic drug that is increasingly used for the treatment of solid tumours. In vitro studies have demonstrated that attenuating the spindle assemble checkpoint (SAC) alters the post-mitotic responses to paclitaxel. Furthermore, the aberrant expression of a number of the SAC proteins, MAD2, BUBR1, and Aurora A kinase, are associated with poor patient prognosis. We have identified a microRNA, miR-433, that regulates the expression of MAD2. Overexpression of miR-433 in Hela cells induced downregulation of MAD2 mRNA and protein expression. We have also shown that Hela cells overexpressing miR-433 and treated with paclitaxel are no longer capable of cyclin B stabilisation, and thus have lost the ability to activate the SAC in response to paclitaxel. In addition, cell viability assays showed that Hela cells overexpressing miR-433 and treated with paclitaxel have an attenuated response to paclitaxel compared with microRNA scrambled controls. We have characterised the levels of miR-433, MAD2 gene expression and MAD2 protein levels in a cohort of ovarian cancer cell lines. Cell viability assays on this cohort revealed that responsiveness to paclitaxel is associated with high MAD2 protein expression and lower miR-433 expression. We hypothesise that the expression of miR-433 when deregulated in cancer leads to altered MAD2 expression and a compromised SAC, a key feature underlying drug resistance to paclitaxel. In a pilot study of paired human breast tumour and normal breast tissue samples we have shown that expression levels of miR-433 are elevated in cancer tissue. Targeting this microRNA in cancer may improve the efficacy of paclitaxel in treating breast cancer and ovarian cancer.

MiR-433 induces cellular senescence rendering ovarian cancer cells less likely to undergo chemotherapy-induced apoptosis

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynaecological malignancy. Such mortality is predominantly associated with the development of an intrinsic and acquired resistance to chemotherapy, the lack of targeted therapies and the lack of biomarkers predicting therapeutic response.

Our clinical data demonstrates that increased miR-433 expression in primary high grade serous OC (HGSOCs) is significantly associated with poor PFS (n=46, p=0.024). Interestingly, the IHC analysis of two miR-433 targets: MAD2 [Furlong et al., 2012 PMID:22069160] and HDAC6 shows that low IHC levels of both proteins is also significantly associated with worse outcome (p=0.002 and 0.002 respectively; n=43). Additionally, the analysis of miR 433 in the publicly available TCGA dataset corroborates that high miR-433 is significantly correlated with worse OS for patients presenting with OC (n=558 and p=0.027). In vitro, in a panel of OC cell lines, higher miR-433 and lower MAD2 and HDAC6 levels were associated with resistance to paclitaxel.

To further investigate the role of miR-433 in the cellular response to chemotherapy, we generated an OC cell line stably expressing miR-433, or miR-control. MTT viability assays and Western Blot analyses established that miR-433 cells were more resistant to paclitaxel treatment (50nM) compared to miR-controls. Importantly, we have shown for the first time that miR 433 induced senescence, exemplified by a flattened morphology and down-regulation of phosphorylated Retinoblastoma (p-Rb), a molecular marker of senescence. Surprisingly, miR 433 induced senescence was independent from two well recognised senescent drivers: namely p53/p21 and p16. To explore this further we performed an in silico analysis of seven microRNA platforms which indicated that miR 433 potentially targets Cyclin-dependent kinase CDK6, which promotes sustained phosphorylation of Rb and thus cell cycle progression. In vitro, the overexpression of pre-miR-433 resulted in diminished CDK6 expression demonstrating a novel interaction between miR-433 and CDK6.

In conclusion, this study demonstrates that high miR-433 expression predicts poor outcome in OC patients by putatively rendering OC cells resistant to paclitaxel treatment through the induction of cellular senescence identifying this microRNA as a potential marker of chemoresponse.

Stabilisation of MAD2 expression through inhibition of miR-433; A novel mechanism for restoring chemo-responsiveness in ovarian tumours

Epithelial ovarian carcinoma (EOC) is characterised by late diagnosis and recurrences, both of which contribute to the high morbidity and mortality of this cancer. Unfortunately, EOC has an innate susceptibility to become chemo-resistant. Specifically, up to 30% of patients may not respond to current standard chemotherapy (paclitaxel and platinum in combination) and of those who have an initial response, some patients relapse within a few months. Therefore, in order to improve patient outcome it is crucial to establish what factors influence a patients' individualised response to chemotherapy. We analysed MAD2 protein expression in a patient cohort of 35 ovarian tumours and a panel of 5 ovarian cancer cell lines. We have demonstrated that low nuclear MAD2 expression intensity was significantly associated with chemo-resistant ovarian tumours (p=0.0136). Moreover, in vitro studies of the 5 ovarian cancer cell lines revealed that reduced MAD2 expression was associated with paclitaxel resistance. In silico analysis identified a putative miR-433 binding domain in the MAD2 3′UTR and expression profiling of miR-433 in the ovarian cancer cell lines showed that low MAD2 protein expression was associated with high miR-433 levels. In vitro over-expression of miR-433 attenuated MAD2 protein expression with a concomitant increase in cellular resistance to paclitaxel. Over-expression of a morpholino oligonucleotide that blocks miR-433 binding to MAD2 3′UTR stabilised MAD2 protein expression and protects from miR-433 induced degradation. Furthermore, miR-433 expression analysis in 35 ovarian tumour samples revealed that high miR-433 expression was associated with advanced stage presentations (p=0.0236). In conclusion, ovarian tumours that display low nuclear MAD2 intensity are chemo-resistant and stabilising MAD2 expression by antagonising miR-433 activity is a potential mechanism for restoring chemo-responsiveness in these tumours.

MIR-433 Predicts poor response to chemotherapy in ovarian cancer patients by the induction of cellular senescence

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynaecological malignancy. Such mortality is predominantly associated with the development of an intrinsic and acquired resistance to chemotherapy, the lack of targeted therapies and the lack of biomarkers predicting response to standard treatment.

Our clinical data demonstrates that increased miR-433 expression in primary high grade serous OC (HGSOCs) is significantly associated with poor PFS (n=46, p=0.024). Interestingly, the IHC analysis of two miR-433 targets: MAD2 [1] and HDAC6 shows that low IHC levels of both proteins is also significantly associated with worse outcome (p=0.002 and 0.002 respectively; n=43). Additionally, the analysis of miR 433 in the publicly available TCGA dataset corroborates that high miR-433 is significantly correlated with worse OS for patients presenting with OC (n=558 and p=0.027). In vito, in a panel of OC cell lines, higher miR-433 and lower MAD2 and HDAC6 levels were associated with resistance to paclitaxel.

To further investigate the role of miR-433 in the cellular response to chemotherapy, we generated an OC cell line stably expressing miR-433 or miR-control. MTT viability assays and Western Blot analyses established that miR-433 cells were more resistant to paclitaxel treatment (50nM) compared to miR-controls. Importantly, we have shown for the first time that miR 433 induced senescence resulting in a chracteristic flattened morphology and down-regulation of phosphorylated Retinoblastoma (p Rb), a molecular marker of senescence. Surprisingly, miR 433 induced senescence was independent from two well recognised senescent drivers: namely p53/p21 and p16. To explore this further we performed an in silico analysis of seven microRNA platforms which indicated that miR 433 potentially targets Cyclin-dependent kinase CDK6, which promotes sustained phosphorylation of Rb and thus cell cycle progression. In vitro, the overexpression of pre-miR-433 resulted in diminished CDK6 expression demonstrating a novel interaction between miR-433 and CDK6.

In conclusion, this study demonstrates that high miR-433 expression predicts poor outcome in OC patients by putatively rendering OC cells resistant to paclitaxel treatment through the induction of cellular senescence identifying this microRNA as a potential marker of chemoresponse.

Resistance to chemotherapy in ovarian cancer is miRrored by the microRNA miR-433-dependent dysregulation of the cell cycle.

An understanding of the mechanisms underlying the development of resistance to chemotherapy treatment is a gateway to the introduction of novel therapies and improved outcomes for women presenting with ovarian cancer (OC). The desired apoptotic death post-chemotherapy depends on an intact and fully functioning cell cycle machinery.

In this study we demonstrate that stable expression of miR-433 renders OC cells more resistant to paclitaxel treatment. Interestingly, only cells with the highest miR-433 survived paclitaxel suggesting the possible role of miR-433 in cancer recurrence. Importantly, for the first time we demonstrate that miR 433 induces cellular senescence, exemplified by a flattened morphology, the downregulation of phosphorylated Retinoblastoma (p Rb) and increased β galactosidase activity. Surprisingly, miR 433 induced senescence was independent of two well recognised senescent drivers: p21 and p16. Further in silico analysis followed by in vitro experiments identified CKD6 as a novel miR-433 target gene possibly explaining the observed p21 and p16-independent induction of cellular senescence. Another in silico identified miR-433 target gene was CDC27, a protein involved in the regulation of the cell cycle during mitosis. We demonstrate that the overexpression of pre-miR-433 leads to the downregulation of CDC27 in vitro revealing a novel interaction between miR-433 and CDC27, an integral cell cycle regulating protein.

Interestingly, miR-433 expressing cells also demonstrated an ability to impact their tumour microenvironment. We show that miR-433 is present in exosomes released from miR-433 overexpressing and high miR-433 naïve cells. Moreover, growth condition media (GCM) harvested from cells with high miR-433 have higher levels of IL-6 and IL-8, two key cytokines involved in the senescence associated secretory phenotype (SASP). Importantly, GCM from miR-433-enriched cells repressed the growth of co-cultured cells with initial studies showing a GCM-dependent induction of chemoresistance.

In conclusion, data in this study highlights how the aberrant expression miR-433 contributes to chemoresistance in OC cells. We postulate that standard chemotherapy, particularly paclitaxel, used to treat women with OC may have an attenuated ability to kill cells harbouring increased levels of miR-433, allowing for a subsequent chemoresistant phenotype post-therapy.