Clinical trials and treatment of the elderly diagnosed with ovarian cancer.

Elderly patients are more commonly diagnosed with advanced ovarian cancer and represent a growing proportion of all ovarian cancer cases. Despite this, the elderly have historically been underrepresented in clinical trials. Because clinical trials form the basis for most treatment guidelines and the elderly have been, to date, largely excluded from this process, little is known about the appropriate assessment and treatment of elderly ovarian cancer patients.

Exploring palliative treatment outcomes in women with advanced or recurrent ovarian clear cell carcinoma.

Objective: Clear cell carcinoma (CCC) of the ovary is increasingly recognized as responding poorly to chemotherapy (CT). This review examines the outcomes achieved with a variety of CT regimens, looking for evidence of activity that might guide the development of more effective treatments.

Methods: A retrospective chart review of all cases of CCC referred to the BC Cancer Agency (BCCA) between 2000 and 2008 was conducted.

The design, synthesis and pharmacological characterization of novel β₂-adrenoceptor antagonists.

Background And Purpose: Selective and potent antagonists for the β(2) -adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology.

Experimental Approach: A range of pharmacological assays was used to assess potency, affinity, selectivity (β(2) -adrenoceptor vs. β(1) -adrenoceptor) and efficacy.

In situ maleimide bridging of disulfides and a new approach to protein PEGylation.

The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development and manipulation of peptide and protein therapeutics. The reduction of native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points for such chemical modification. The optimum bioconjugation strategy utilizing these cysteine residues should include the reconstruction of a bridge to mimic the role of the disulfide bond, maintaining structure and stability of the protein.

In vitro and in vivo cardiomyogenic differentiation of amniotic fluid stem cells.

Cell therapy has developed as a complementary treatment for myocardial regeneration. While both autologous and allogeneic uses have been advocated, the ideal candidate has not been identified yet. Amniotic fluid-derived stem (AFS) cells are potentially a promising resource for cell therapy and tissue engineering of myocardial injuries.

Characterization of a binding site for anionic phospholipids on KCNQ1.

The KCNQ family of potassium channels underlie a repolarizing K(+) current in the heart and the M-current in neurones. The assembly of KCNQ1 with KCNE1 generates the delayed rectifier current I(Ks) in the heart. Characteristically these channels are regulated via G(q/11)-coupled receptors and the inhibition seen after phospholipase C activation is now thought to occur from membrane phosphatidylinositol (4,5)-bisphosphate (PIP(2)) depletion.

Sarcolemmal cardiac K(ATP) channels as a target for the cardioprotective effects of the fluorine-containing pinacidil analogue, flocalin.

Background And Purpose: A class of drugs known as K(ATP) -channel openers induce cardioprotection. This study examined the effects of the novel K(ATP) -channel opener, the fluorine-containing pinacidil derivative, flocalin, on cardiac-specific K(ATP) -channels, excitability of native cardiac myocytes and on the ischaemic heart.

Experimental Approach: The action of flocalin was investigated on: (i) membrane currents through cardiac-specific K(ATP) -channels (I(KATP) ) formed by K(IR) 6.

Do caveolae have a role in the fidelity and dynamics of receptor activation of G-protein-gated inwardly rectifying potassium channels?

In atrial and nodal cardiac myocytes, M2 muscarinic receptors activate inhibitory G-proteins (G(i/o)), which in turn stimulate G-protein-gated inwardly rectifying K(+) channels through direct binding of the Gbetagamma subunit. Despite also releasing Gbetagamma, G(s)-coupled receptors such as the beta-adrenergic receptor are not able to prominently activate this current. An appealing hypothesis would be if components were sequestered in membrane domains such as caveolae/rafts.

Absence of the inhibitory G-protein Galphai2 predisposes to ventricular cardiac arrhythmia.

Background: We explored the role that inhibitory heterotrimeric G-proteins play in ventricular arrhythmia.

Methods And Results: Mice with global genetic deletion of Galpha(i2) [Galpha(i2) (-/-)] were studied and found, based on telemetry, to have a prolonged QT interval on surface ECG when awake. In vivo electrophysiology studies revealed that the Galpha(i2) (-/-) mice have a reduced ventricular effective refractory period and a predisposition to ventricular tachycardia when challenged with programmed electrical stimulation.

K+ channels in the heart: new insights and therapeutic implications.

K+ channels in the heart shape the cardiac action potential, and many existing drugs can inhibit or activate these currents. In particular, their potential therapeutic benefit has been explored in the treatment and prevention of abnormal heart rhythm. Their use in the management of malignant ventricular arrhythmias has been disappointing and is frequently complicated by proarrhythmia.

An efficient asymmetric synthesis of the potent beta-blocker ICI-118,551 allows the determination of enantiomer dependency on biological activity.

A highly efficient, practical and flexible two-step asymmetric synthesis of the beta(2)-selective beta-blocker ICI 118,551 is reported, allowing an unambiguous determination of the dependency of biological activity with optical activity, revealing the S,S-enantiomer to be the most potent.

The intracellular localization and function of the ATP-sensitive K+ channel subunit Kir6.1.

Our aim was to determine the subcellular localization and functional roles of the K(ATP) channel subunit Kir6.1 in intracellular membranes. Specifically, we focused on the potential role of Kir6.

Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel.

The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.

HL-1 cells express an inwardly rectifying K+ current activated via muscarinic receptors comparable to that in mouse atrial myocytes.

An inwardly rectifying K(+) current is present in atrial cardiac myocytes that is activated by acetylcholine (I(KACh)). Physiologically, activation of the current in the SA node is important in slowing the heart rate with increased parasympathetic tone. It is a paradigm for the direct regulation of signaling effectors by the Gbetagamma G-protein subunit.

Malignant transformation within ovarian dermoid cysts: an audit of treatment received and patient outcomes. an Australia New Zealand gynaecological oncology group (ANZGOG) and gynaecologic cancer intergroup (GCIG) study.

Introduction: Malignant transformation in an ovarian dermoid cyst occurs in 1% to 2% of cases. Our knowledge about this tumor type is limited and largely based on case reports. We aimed to collate and analyze the cumulative experience of how these patients have been managed in an effort to identify the most appropriate treatment strategies.

Direct observation of individual KCNQ1 potassium channels reveals their distinctive diffusive behavior.

We have directly observed the trafficking and fusion of ion channel containing vesicles and monitored the release of individual ion channels at the plasma membrane of live mammalian cells using total internal reflection fluorescence microscopy. Proteins were fused in-frame with green or red fluorescent proteins and expressed at low level in HL-1 and HEK293 cells. Dual color imaging revealed that vesicle trafficking involved motorized movement along microtubules followed by stalling, fusion, and subsequent release of individual ion channels at the plasma membrane.

Mechanisms of disease pathogenesis in long QT syndrome type 5.

KCNE1 associates with the pore-forming alpha-subunit KCNQ1 to generate the slow (I(Ks)) current in cardiac myocytes. Mutations in either KCNQ1 or KCNE1 can alter the biophysical properties of I(Ks) and mutations in KCNE1 underlie cases of long QT syndrome type 5 (LQT5). We previously investigated a mutation in KCNE1, T58P/L59P, which causes severe attenuation of I(Ks).

Advancing newborn health: The Saving Newborn Lives initiative.

Until recently, newborn health was virtually absent from the global health agenda. Now, assistance agencies, national governments and non-governmental organisations are increasingly addressing this previously neglected issue of close to four million newborns dying every year. The experience of the Saving Newborn Lives initiative documents some of the progress that has been made and the challenges and opportunities that lie ahead.

A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184.

Objective: Vascular endothethial growth factor (VEGF) and stem cell factor (c-KIT) signaling may play a role in the development and progression of cervical carcinoma. Sunitinib malate is an oral, multi-targeted tyrosine kinase inhibitor that inhibits receptors for VEGF, c-Kit and platelet-derived growth factor. This multi-centre phase II study was performed to evaluate the activity of sunitinib in women with locally advanced or metastatic cervical carcinoma who had received up to one prior line of chemotherapy for advanced disease.

Ca2+/calcineurin regulation of cloned vascular K ATP channels: crosstalk with the protein kinase A pathway.

Background And Purpose: Vascular ATP-sensitive potassium (K(ATP)) channels are activated by cyclic AMP elevating vasodilators through protein kinase A (PKA). Direct channel phosphorylation is a critical mechanism, though the phosphatase opposing these effects is unknown. Previously, we reported that calcineurin, a Ca(2+)-dependent phosphatase, inhibits K(ATP) channels, though neither the site nor the calcineurin isoform involved is established.

Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice.

Elevated levels of the cardiac transcription factor Hand1 have been reported in several adult cardiac diseases but it is unclear whether this change is itself maladaptive with respect to heart function. To test this possibility, we have developed a novel, inducible transgenic system, and used it to overexpress Hand1 in adult mouse hearts. Overexpression of Hand1 in the adult mouse heart leads to mild cardiac hypertrophy and a reduction in life expectancy.

Mistreatment of older people in the United Kingdom: findings from the first National Prevalence Study.

There have been few national studies of the prevalence of elder mistreatment (abuse and neglect) in private households. This article provides an overview of the UK National Prevalence Study of Elder Mistreatment that took place in 2006. It addressed 2,111 respondents in four countries who answered a face-to-face survey questionnaire.

Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas.

Purpose: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.

Experimental Design: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays.