Cancer-selective, single agent chemoradiosensitising gold nanoparticles

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics

Continuity and change in human resources policies for health: lessons from Brazil

publishersversionpublishe

Carotid stenting: is there an operator effect? A pooled analysis from the carotid stenting trialists' collaboration.

BACKGROUND AND PURPOSE: Randomized clinical trials show higher 30-day risk of stroke or death after carotid artery stenting compared with surgery. We examined whether operator experience is associated with 30-day risk of stroke or death in the Carotid Stenting Trialists' Collaboration database. METHODS: The Carotid Stenting Trialists' Collaboration is a pooled individual patient database including all patients recruited in 3 randomized trials of stenting versus endarterectomy for symptomatic carotid stenosis (Endarterectomy Versus Angioplasty in patients with Symptomatic Severe Carotid Stenosis trial, Stent-Protected Angioplasty versus Carotid Endarterectomy trial, and International Carotid Stenting Study). Lifetime carotid artery stenting experience, lifetime experience in stenting procedures excluding the carotid, and annual number of procedures performed within the trial (in-trial volume), divided into tertiles, were used to measure operator experience. The outcome event was the occurrence of any stroke or death within 30 days of the procedure. The analysis was done per protocol. RESULTS: Among 1546 patients who underwent carotid artery stenting, 120 (7.8%) had a stroke or death within 30 days of the procedure. The 30-day risk of stroke or death did not differ according to operator lifetime carotid artery stenting experience (P=0.8) or operator lifetime stenting experience excluding the carotid (P=0.7). In contrast, the 30-day risk of stroke or death was significantly higher in patients treated by operators with low (mean ≤3.2 procedures/y; risk 10.1%; adjusted risk ratio=2.30 [1.36-3.87]) and intermediate annual in-trial volumes (3.2-5.6 procedures/y; 8.4%; adjusted risk ratio=1.93 [1.14-3.27]) compared with patients treated by high annual in-trial volume operators (>5.6 procedures/y; 5.1%). CONCLUSIONS: Carotid stenting should only be performed by operators with annual procedure volume ≥6 cases per year

Development of a short form of Mini-Mental State Examination for the screening of dementia in older adults with a memory complaint: a case control study

<p>Abstract</p> <p>Background</p> <p>Primary care physicians need a brief and accurate screening test of dementia. The objective of this study was to determine whether a short form of Mini-Mental State Examination (SMMSE) was as accurate as the Mini-Mental State Examination (MMSE) in screening dementia.</p> <p>Methods</p> <p>Based on case control design study, SMMSE and MMSE were assessed in 184 community-dwelling older adults (mean age 81.3 ± 6.5 years, 71.7% women) with memory complaint sent by their primary care physician to a memory clinic. Included participants were separated into two groups: cognitively healthy individuals and demented individuals.</p> <p>Results</p> <p>The trade-off between sensitivity and specificity of the SMMSE for clinically diagnosed dementia was 4. Based on the cut-off value ≤ 4 for SMMSE and a cut-off value ≤ 24 for MMSE, the sensitivity of both tests was similar (89.5% for SMMSE versus 90.0% for MMSE), whereas the specificity, the positive predictive values (PPV) and the negative predictive values (NPV) were higher for SMMSE compared to MMSE (85.4 versus 75.5% for specificity; 95.5% versus 92.8% for PPV; 70.0 versus 68.9 for NPV). The positive and negative Likehood Ratio (LR) of SMMSE were higher than those of MMSE (respectively, 6.1 versus 3.7; 8.1 versus 7.7). In addition, odds ratio (OR) for dementia was higher for the SMMSE compared to the MMSE (OR = 49.8 with 95% confident interval (CI) [18.0; 137.8] versus OR = 28.6 with 95% CI [11.6; 70.3]).</p> <p>Conclusions</p> <p>SMMSE seems to be an efficient short screening test for dementia among community-dwelling older adults with a memory complaint. Further research is needed to confirm its predictive values among unselected primary care older patients.</p

Cells activated for wound repair have the potential to direct collective invasion of an epithelium.

Mechanisms regulating how groups of cells are signaled to move collectively from their original site and invade surrounding matrix are poorly understood. Here we develop a clinically relevant ex vivo injury invasion model to determine whether cells involved in directing wound healing have invasive function and whether they can act as leader cells to direct movement of a wounded epithelium through a three-dimensional (3D) extracellular matrix (ECM) environment. Similar to cancer invasion, we found that the injured cells invade into the ECM as cords, involving heterotypical cell-cell interactions. Mesenchymal cells with properties of activated repair cells that typically locate to a wound edge are present in leader positions at the front of ZO-1-rich invading cords of cells, where they extend vimentin intermediate filament-enriched protrusions into the 3D ECM. Injury-induced invasion depends on both vimentin cytoskeletal function and MMP-2/9 matrix remodeling, because inhibiting either of these suppressed invasion. Potential push and pull forces at the tips of the invading cords were revealed by time-lapse imaging, which showed cells actively extending and retracting protrusions into the ECM. This 3D injury invasion model can be used to investigate mechanisms of leader cell-directed invasion and understand how mechanisms of wound healing are hijacked to cause disease

A prognostic tool to identify adolescents at high risk of becoming daily smokers

<p>Abstract</p> <p>Background</p> <p>The American Academy of Pediatrics advocates that pediatricians should be involved in tobacco counseling and has developed guidelines for counseling. We present a prognostic tool for use by health care practitioners in both clinical and non-clinical settings, to identify adolescents at risk of becoming daily smokers.</p> <p>Methods</p> <p>Data were drawn from the Nicotine Dependence in Teens (NDIT) Study, a prospective investigation of 1293 adolescents, initially aged 12-13 years, recruited in 10 secondary schools in Montreal, Canada in 1999. Questionnaires were administered every three months for five years. The prognostic tool was developed using estimated coefficients from multivariable logistic models. Model overfitting was corrected using bootstrap cross-validation. Goodness-of-fit and predictive ability of the models were assessed by R², the c-statistic, and the Hosmer-Lemeshow test.</p> <p>Results</p> <p>The 1-year and 2-year probability of initiating daily smoking was a joint function of seven individual characteristics: age; ever smoked; ever felt like you needed a cigarette; parent(s) smoke; sibling(s) smoke; friend(s) smoke; and ever drank alcohol. The models were characterized by reasonably good fit and predictive ability. They were transformed into user-friendly tables such that the risk of daily smoking can be easily computed by summing points for responses to each item. The prognostic tool is also available on-line at <url>http://episerve.chumontreal.qc.ca/calculation_risk/daily-risk/daily_smokingadd.php</url>.</p> <p>Conclusions</p> <p>The prognostic tool to identify youth at high risk of daily smoking may eventually be an important component of a comprehensive tobacco control system.</p

Role of the PAS sensor domains in the Bacillus subtilis sporulation kinase KinA

Histidine kinases are sophisticated molecular sensors that are used by bacteria to detect and respond to a multitude of environmental signals. KinA is the major histidine kinase required for initiation of sporulation upon nutrient deprivation in Bacillus subtilis. KinA has a large N-terminal region (residues 1 to 382) that is uniquely composed of three tandem Per-ARNT-Sim (PAS) domains that have been proposed to constitute a sensor module. To further enhance our understanding of this "sensor" region, we defined the boundaries that give rise to the minimal autonomously folded PAS domains and analyzed their homo- and heteroassociation properties using analytical ultracentrifugation, nuclear magnetic resonance (NMR) spectroscopy, and multiangle laser light scattering. We show that PAS(A) self-associates very weakly, while PAS(C) is primarily a monomer. In contrast, PAS(B) forms a stable dimer (K-d [dissociation constant] o

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test “loop grafting,” a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α1A-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α1A-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles

Characterization and Expression of Glutamate Dehydrogenase in Response to Acute Salinity Stress in the Chinese Mitten Crab, Eriocheir sinensis

Glutamate dehydrogenase (GDH) is a key enzyme for the synthesis and catabolism of glutamic acid, proline and alanine, which are important osmolytes in aquatic animals. However, the response of GDH gene expression to salinity alterations has not yet been determined in macro-crustacean species.GDH cDNA was isolated from Eriocheir sinensis. Then, GDH gene expression was analyzed in different tissues from normal crabs and the muscle of crabs following transfer from freshwater (control) directly to water with salinities of 16‰ and 30‰, respectively. Full-length GDH cDNA is 2,349 bp, consisting of a 76 bp 5'- untranslated region, a 1,695 bp open reading frame encoding 564 amino acids and a 578 bp 3'- untranslated region. E. sinensis GDH showed 64-90% identity with protein sequences of mammalian and crustacean species. Muscle was the dominant expression source among all tissues tested. Compared with the control, GDH expression significantly increased at 6 h in crabs transferred to 16‰ and 30‰ salinity, and GDH expression peaked at 48 h and 12 h, respectively, with levels approximately 7.9 and 8.5 fold higher than the control. The free amino acid (FAA) changes in muscle, under acute salinity stress (16‰ and 30‰ salinities), correlated with GDH expression levels. Total FAA content in the muscle, which was based on specific changes in arginine, proline, glycine, alanine, taurine, serine and glutamic acid, tended to increase in crabs following transfer to salt water. Among these, arginine, proline and alanine increased significantly during salinity acclimation and accounted for the highest proportion of total FAA.E. sinensis GDH is a conserved protein that serves important functions in controlling osmoregulation. We observed that higher GDH expression after ambient salinity increase led to higher FAA metabolism, especially the synthesis of glutamic acid, which increased the synthesis of proline and alanine to meet the demand of osmoregulation at hyperosmotic conditions