Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m−2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m−2. The maximum tolerated dose was 70 mg m−2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile

Gluino-Squark Production at the LHC: The Threshold

An analysis of the cross section for hadronic production of gluino-squark pairs close to threshold is presented. Within the framework of non-relativistic QCD a significant enhancement compared to fixed order perturbation theory is observed which originates from the characteristic remnants of the gluino-squark resonances below the nominal pair threshold. The analysis includes all colour configurations of S-wave gluino-squark pairs, i.e. triplet, sextet and 15 representation. Matching coefficients at leading order are separately evaluated for all colour configurations. The dominant QCD corrections, arising from initial- and final-state radiation are included. The non-relativistic dynamics of the gluino pair is solved by calculating the Green's function in Next-to-Leading Order (NLO). The results are applied to benchmark scenarios, based on Snowmass Points and Slopes (SPS). As a consequence of the large decay rate of at least one of the constituents squark or gluino annihilation decays of the bound state (\tilde{g}\tilde{q})\rightarrow gq, q\gamma, qZ or q'W^{\pm} are irrelevant. Thus the signatures of gluino-quark production below and above the nominal threshold are identical. Numerical results for the cross section at the Large Hadron Collider (LHC) at \sqrt{s}=7 TeV and 14 TeV are presented. The enhancement of the total cross section through final state interaction amounts to roughly 3%.Comment: 25 pages, 9 figures, Eq. 10 modified. Reference [30] added. Discussion of the expected quality of the approximation added before eq. 23. Some changes in notation. Typos correcte

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m²; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m²on days 1 and 15).</p> <p>Results</p> <p>Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed.</p> <p>Conclusions</p> <p>This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.</p

The effect of an intracerebroventricular injection of metformin or AICAR on the plasma concentrations of melatonin in the ewe: potential involvement of AMPK?

<p>Abstract</p> <p>Background</p> <p>It is now widely accepted that AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis. Recently, it has been shown to regulate circadian clocks. In seasonal breeding species such as sheep, the circadian clock controls the secretion of an endogenous rhythm of melatonin and, as a consequence, is probably involved in the generation of seasonal rhythms of reproduction. Considering this, we identified the presence of the subunits of AMPK in different hypothalamic nuclei involved in the pre- and post-pineal pathways that control seasonality of reproduction in the ewe and we investigated if the intracerebroventricular (i.c.v.) injection of two activators of AMPK, metformin and AICAR, affected the circadian rhythm of melatonin in ewes that were housed in constant darkness. In parallel the secretion of insulin was monitored as a peripheral metabolic marker. We also investigated the effects of i.c.v. AICAR on the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in brain structures along the photoneuroendocrine pathway to the pineal gland.</p> <p>Results</p> <p>All the subunits of AMPK that we studied were identified in all brain areas that were dissected but with some differences in their level of expression among structures. Metformin and AICAR both reduced (p < 0.001 and p < 0.01 respectively) the amplitude of the circadian rhythm of melatonin secretion independently of insulin secretion. The i.c.v. injection of AICAR only tended (p = 0.1) to increase the levels of phosphorylated AMPK in the paraventricular nucleus but significantly increased the levels of phosphorylated ACC in the paraventricular nucleus (p < 0.001) and in the pineal gland (p < 0.05).</p> <p>Conclusions</p> <p>Taken together, these results suggest a potential role for AMPK on the secretion of melatonin probably acting trough the paraventricular nucleus and/or directly in the pineal gland. We conclude that AMPK may act as a metabolic cue to modulate the rhythm of melatonin secretion.</p

Mitochondrial Function Is Required for Secretion of DAF-28/Insulin in C. elegans

While insulin signaling has been extensively studied in Caenorhabditis elegans in the context of ageing and stress response, less is known about the factors underlying the secretion of insulin ligands upstream of the insulin receptor. Activation of the receptor governs the decision whether to progress through the reproductive lifecycle or to arrest growth and enter hibernation. We find that animals with reduced levels of the mitochondrial outer membrane translocase homologue TOMM-40 arrest growth as larvae and have decreased insulin signaling strength. TOMM-40 acts as a mitochondrial translocase in C. elegans and in its absence animals fail to import a mitochondrial protein reporter across the mitochondrial membrane(s). Inactivation of TOMM-40 evokes the mitochondrial unfolded protein response and causes a collapse of the proton gradient across the inner mitochondrial membrane. Consequently these broadly dysfunctional mitochondria render an inability to couple food abundance to secretion of DAF-28/insulin. The secretion defect is not general in nature since two other neuropeptides, ANF::GFP and INS-22::VENUS, are secreted normally. RNAi against two other putative members of the TOMM complex give similar phenotypes, implying that DAF-28 secretion is sensitive to mitochondrial dysfunction in general. We conclude that mitochondrial function is required for C. elegans to secrete DAF-28/insulin when food is abundant. This modulation of secretion likely represents an additional level of control over DAF-28/insulin function

Multidisciplinary outpatient care program for patients with chronic low back pain: design of a randomized controlled trial and cost-effectiveness study [ISRCTN28478651]

<p>Abstract</p> <p>Background</p> <p>Chronic low back pain (LBP) is a major public and occupational health problem, which is associated with very high costs. Although medical costs for chronic LBP are high, most costs are related to productivity losses due to sick leave. In general, the prognosis for return to work (RTW) is good but a minority of patients will be absent long-term from work. Research shows that work related problems are associated with an increase in seeking medical care and sick leave. Usual medical care of patients is however, not specifically aimed at RTW.</p> <p>The objective is to present the design of a randomized controlled trial, i.e. the BRIDGE-study, evaluating the effectiveness in improving RTW and cost-effectiveness of a multidisciplinary outpatient care program situated in both primary and outpatient care setting compared with usual clinical medical care for patients with chronic LBP.</p> <p>Methods/Design</p> <p>The design is a randomized controlled trial with an economic evaluation alongside. The study population consists of patients with chronic LBP who are completely or partially sick listed and visit an outpatient clinic of one of the participating hospitals in Amsterdam (the Netherlands). Two interventions will be compared. 1. a multidisciplinary outpatient care program consisting of a workplace intervention based on participatory ergonomics, and a graded activity program using cognitive behavioural principles. 2. usual care provided by the medical specialist, the occupational physician, the patient's general practitioner and allied health professionals. The primary outcome measure is sick leave duration until full RTW. Sick leave duration is measured monthly by self-report during one year. Data on sick leave during one-year follow-up are also requested form the employers. Secondary outcome measures are pain intensity, functional status, pain coping, patient satisfaction and quality of life. Outcome measures are assessed before randomization and 3, 6, and 12 months later. All statistical analysis will be performed according to the intension-to-treat principle.</p> <p>Discussion</p> <p>Usual care of primary and outpatient health services isn't directly aimed at RTW, therefor it is desirable to look for care which is aimed at RTW. Research shows that several occupational interventions in primary care are aimed at RTW. They have shown a significant reduction of sick leave for employee with LBP. If a comparable reduction of sick leave duration of patients with chronic LBP of who attend an outpatient clinic can be achieved, such reductions will be obviously substantial for the Netherlands and will have a considerable impact.</p> <p>Trial registration</p> <p>ISRCTN28478651</p

Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

International audienceBACKGROUND: The von Hippel-Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC. METHODS: A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC. CONCLUSION: Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy

Neuronal Conduction of Excitation without Action Potentials Based on Ceramide Production

International audienceBACKGROUND: Action potentials are the classic mechanism by which neurons convey a state of excitation throughout their length, leading, after synaptic transmission, to the activation of other neurons and consequently to network functioning. Using an in vitro integrated model, we found previously that peripheral networks in the autonomic nervous system can organise an unconventional regulatory reflex of the digestive tract motility without action potentials. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we used combined neuropharmacological and biochemical approaches to elucidate some steps of the mechanism that conveys excitation along the nerves fibres without action potentials. This mechanism requires the production of ceramide in membrane lipid rafts, which triggers in the cytoplasm an increase in intracellular calcium concentration, followed by activation of a neuronal nitric oxide synthase leading to local production of nitric oxide, and then to guanosine cyclic monophosphate. This sequence of second messengers is activated in cascade from rafts to rafts to ensure conduction of the excitation along the nerve fibres. CONCLUSIONS/SIGNIFICANCE: Our results indicate that second messengers are involved in neuronal conduction of excitation without action potentials. This mechanism represents the first evidence-to our knowledge-that excitation is carried along nerves independently of electrical signals. This unexpected ceramide-based conduction of excitation without action potentials along the autonomic nerve fibres opens up new prospects in our understanding of neuronal functioning

Effect of a web-based chronic disease management system on asthma control and health-related quality of life: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Asthma is a prevalent and costly disease resulting in reduced quality of life for a large proportion of individuals. Effective patient self-management is critical for improving health outcomes. However, key aspects of self-management such as self-monitoring of behaviours and symptoms, coupled with regular feedback from the health care team, are rarely addressed or integrated into ongoing care. Health information technology (HIT) provides unique opportunities to facilitate this by providing a means for two way communication and exchange of information between the patient and care team, and access to their health information, presented in personalized ways that can alert them when there is a need for action. The objective of this study is to evaluate the acceptability and efficacy of using a web-based self-management system, My Asthma Portal (MAP), linked to a case-management system on asthma control, and asthma health-related quality of life.</p> <p>Methods</p> <p>The trial is a parallel multi-centered 2-arm pilot randomized controlled trial. Participants are randomly assigned to one of two conditions: a) MAP and usual care; or b) usual care alone. Individuals will be included if they are between 18 and 70, have a confirmed asthma diagnosis, and their asthma is classified as not well controlled by their physician. Asthma control will be evaluated by calculating the amount of fast acting beta agonists recorded as dispensed in the provincial drug database, and asthma quality of life using the Mini Asthma Related Quality of Life Questionnaire. Power calculations indicated a needed total sample size of 80 subjects. Data are collected at baseline, 3, 6, and 9 months post randomization. Recruitment started in March 2010 and the inclusion of patients in the trial in June 2010.</p> <p>Discussion</p> <p>Self-management support from the care team is critical for improving chronic disease outcomes. Given the high volume of patients and time constraints during clinical visits, primary care physicians have limited time to teach and reinforce use of proven self-management strategies. HIT has the potential to provide clinicians and a large number of patients with tools to support health behaviour change.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN34326236">ISRCTN34326236</a>.</p

Time-resolved single-crystal X-ray crystallography

In this chapter the development of time-resolved crystallography is traced from its beginnings more than 30 years ago. The importance of being able to “watch” chemical processes as they occur rather than just being limited to three-dimensional pictures of the reactant and final product is emphasised, and time-resolved crystallography provides the opportunity to bring the dimension of time into the crystallographic experiment. The technique has evolved in time with developments in technology: synchrotron radiation, cryoscopic techniques, tuneable lasers, increased computing power and vastly improved X-ray detectors. The shorter the lifetime of the species being studied, the more complex is the experiment. The chapter focusses on the results of solid-state reactions that are activated by light, since this process does not require the addition of a reagent to the crystalline material and the single-crystalline nature of the solid may be preserved. Because of this photoactivation, time-resolved crystallography is often described as “photocrystallography”. The initial photocrystallographic studies were carried out on molecular complexes that either underwent irreversible photoactivated processes where the conversion took hours or days. Structural snapshots were taken during the process. Materials that achieved a metastable state under photoactivation and the excited (metastable) state had a long enough lifetime for the data from the crystal to be collected and the structure solved. For systems with shorter lifetimes, the first time-resolved results were obtained for macromolecular structures, where pulsed lasers were used to pump up the short lifetime excited state species and their structures were probed by using synchronised X-ray pulses from a high-intensity source. Developments in molecular crystallography soon followed, initially with monochromatic X-ray radiation, and pump-probe techniques were used to establish the structures of photoactivated molecules with lifetimes in the micro- to millisecond range. For molecules with even shorter lifetimes in the sub-microsecond range, Laue diffraction methods (rather than using monochromatic radiation) were employed to speed up the data collections and reduce crystal damage. Future developments in time-resolved crystallography are likely to involve the use of XFELs to complete “single-shot” time-resolved diffraction studies that are already proving successful in the macromolecular crystallographic field.</p