A covalent fragment-based strategy targeting a novel cysteine to inhibit activity of mutant EGFR kinase.

Several generations of ATP-competitive anti-cancer drugs that inhibit the activity of the intracellular kinase domain of the epidermal growth factor receptor (EGFR) have been developed over the past twenty years. The first-generation of drugs such as gefitinib bind reversibly and were followed by a second-generation such as dacomitinib that harbor an acrylamide moiety that forms a covalent bond with C797 in the ATP binding pocket. Resistance emerges through mutation of the T790 gatekeeper residue to methionine, which introduces steric hindrance to drug binding and increases the for ATP.

Antimicrobial Efficacy of Different Irrigant Solutions Using a Novel Biofilm Model: An In Vitro Confocal Laser Scanning Microscopy Experiment.

Aim: To determine the ability of different irrigation solutions to biomechanically remove Enterococcus faecalis biofilm from a novel artificial root canal model during chemomechanical preparation.

Methods: High resolution micro-computer-tomography scans of a mandibular molar's mesial root were used to produce 50 identical 3D-printed resin root canal models. These were cultured with E.

Targeting DYRK1A/B kinases to modulate p21-cyclin D1-p27 signalling and induce anti-tumour activity in a model of human glioblastoma.

The dual-specificity tyrosine-regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence-proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi-cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER-239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure-guided drug discovery.

Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors.

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity.

UDP-3--acyl--acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation.

An international, cross-sectional survey of the management of Vancouver type B1 periprosthetic femoral fractures around total hip arthroplasties.

Introduction: The incidence of periprosthetic femoral fractures around total hip arthroplasties is increasing. Fractures around a stable implant stem (Vancouver type B1) are among the most common of these fractures. Various fixation strategies for Vancouver type B1 periprosthetic fractures have been reported in the literature; however, little high-level evidence exists.

Anthropogenic nitrogen deposition alters growth responses of European beech (Fagus sylvativa L.) to climate change.

Global change affects the functioning of forest ecosystems and the services they provide, but little is known about the interactive effects of co-occurring global change drivers on important functions such as tree growth and vitality. In the present study we quantified the interactive (i.e.

Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe.

Introduction: Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan-European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills.

Isolated Head and Liner Exchange in Revision Hip Arthroplasty.

As the number of primary total hip arthroplasties increases, so does the burden of revision procedures. The decision to revise well-fixed components in the setting of polyethylene wear and osteolysis is controversial. Modular head and liner exchange offers the advantages of reduced invasiveness, faster recovery, and bone preservation.

Biomechanical analysis of the cephalomedullary nail versus the trochanteric stabilizing plate for unstable intertrochanteric femur fractures.

Unstable intertrochanteric fractures are commonly treated with a cephalomedullary nail due to high failure rates with a sliding hip screw. The Omega3 Trochanteric Stabilizing Plate is a relatively new device that functions like a modified sliding hip screw with a proximal extension; however, its mechanical properties have not been evaluated. This study biomechanically compared a cephalomedullary nail, that is, Gamma3 Nail against the Omega3 plate.

A Global Synthesis of Jatropha Cultivation: Insights into Land Use Change and Management Practices.

Despite setbacks, interest in Jatropha cultivation remains high. This study addressed the question to what extent Jatropha cultivation has replaced specific vegetation and land use types and how the existing areas are managed. Major forms of land use change and management practices were identified based on cluster analysis of data from 106 interviewee's responses to a comprehensive global survey.

Combined Volar Hamate Dislocation and Scapholunate Ligament Rupture: A Case Report.

Case: A twenty-two-year-old male patient presented to our trauma center after a motor-vehicle accident in which he sustained multiple injuries, including a volar dislocation of the hamate and ipsilateral scapholunate dissociation. Following closed reduction of the hamate dislocation, open reduction and stabilization of these carpal injuries was undertaken two days post-injury via a dorsal approach. Percutaneous Kirschner wires were used as well as two mini suture anchors to repair the scapholunate ligament.

Compartment Syndrome following Open Femoral Fracture with an Isolated Femoral Vein Injury Treated with Acute Repair.

Acute compartment syndrome is a surgical emergency and its diagnosis is more difficult in obtunded or insensate patients. We present the case of a 34-year-old woman who sustained a Gustilo-Anderson grade III open midshaft femur fracture with an isolated femoral vein injury treated with direct repair. She developed lower leg compartment syndrome at 48 hours postoperatively, necessitating fasciotomies.

Implant-supported mandibular denture: planning to delivery--a case report.

Unlabelled: Restoring the edentulous mandible with a removable prosthesis can be a challenging prospect for both the dentist and patient during and after treatment. Poor retention and support are the major problems reported with a mandibular complete denture and these can be significantly improved with the use of implants and retentive attachments. Utilizing implants requires careful planning from both the surgical and restorative aspects to ensure that the intended treatment aim and outcome is achieved.

Long and short term management of implant-supported mandibular overdentures.

Unlabelled: Common problems with the long term clinical use of implant-supported mandibular overdentures (ISMDs) include fractures of dentures, bars and clips, and reactivation of clips. Many general dental practitioners (GDPs) are reticent to be involved in the maintenance of ISMDs, especially if they have not had any further training or are unfamiliar with implant components and systems. This article highlights the need for the training of GDPs in maintenance and management of ISMDs as an increasing number of edentulous patients are being provided with ISMDs, resulting in an increasing need for the maintenance of the prosthesis in the primary care setting at a possible cost to the patient.

Transient synovitis of the hip: a comprehensive review.

Transient synovitis is a benign, self-limiting condition that is diagnosed after the exclusion of more serious causes of acute hip pain in children. Although its etiology remains unclear, it is largely believed to be viral in nature. Transient synovitis typically presents as an acute onset of thigh pain with a limp or an unwillingness to bear weight.

Recommendations for the development of e-modules for the continuing professional development of European dentists.

Aims: To provide evidence-based and peer-reviewed recommendations for the development of dental continuing professional development (CPD) learning e-modules.

Methods: The present recommendations are consensus recommendations of the DentCPD project team and were informed by a literature research, consultations from e-learning and IT expert, discussions amongst the participants attending a special interest group during the 2012 ADEE meeting, and feedback from the evaluation procedures of the exemplar e-module (as described in a companion paper within this Supplement). The main focus of these recommendations is on the courses and modules organised and offered by dental schools.

The development of an exemplar e-module for the continuing professional development of European dentists.

Aim: To present the development of an exemplar e-module for dental continuing professional development (CPD) provided by dental schools and other dental educational providers.

Materials And Methods: The exemplar e-module covered the topic of 'Sterilisation and cross-infection control in the dental practice' as this is one of the most recommended topics for dental CPD in Europe. It was developed by a group of topic experts, adult learning and distance learning experts and a technical developer.

Guidelines for the organisation of continuing professional development activities for the European dentist.

Aim: Free movement of dental professionals across the European Union calls for more uniform continuing education in dentistry to ensure up-to-date, high-quality patient care and patient safety. This article provides guidelines for the management and delivery of high-quality continuing professional development (CPD) by European dental schools and other CPD providers.

Method: The guidelines are based on an extensive literature inventory, a survey of existing practices (both available as separate publications), discussions during meetings of the Association for Dental Education in Europe in 2011 and 2012 and debate amongst the members of the DentCPD project team representing six dental schools.

International peer review in undergraduate dentistry: enhancing reflective practice in an online community of practice.

To stimulate and enhance student learning in the areas of global citizenship, critical reflection and e-learning, an online international peer review using a purpose-built web platform, has been developed between international dental schools. Since its inception in 2007, n = 6 dental schools from six different countries have participated with n = 384 dental students engaged in online peer review. Project development was conceptually analysed utilising Lave and Wenger's notion of a community of practice (CoP).

Effect of surgeon fatigue on hip and knee arthroplasty.

Background: There is growing support in the literature that patient outcomes are adversely affected by physician fatigue in operator-dependent cognitive and technical tasks. Recent increases in total joint arthroplasty caseloads have resulted in longer operative days and increased surgeon fatigue. We sought to determine if time of day predicts perioperative complications and outcomes in total joint arthroplasty.