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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 K m for ATP. A third generation of drugs, such as osimertinib were developed which were effective against T790M EGFR in which an acrylamide moiety forms a covalent bond with C797, although resistance has emerged by mutation to S797. A fragment-based screen to identify new starting points for an EGFR inhibitor serendipitously identified a fragment that reacted with C775, a previously unexploited residue in the ATP binding pocket for a covalent inhibitor to target. A number of acrylamide containing fragments were identified that selectively reacted with C775. One of these acrylamides was optimized to a highly selective inhibitor with sub-1 μM activity, that is active against T790M, C797S mutant EGFR independent of ATP concentration, providing a potential new strategy for pan-EGFR mutant inhibition., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

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. Inhibition of DYRK1A/B by VER-239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re-expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth-promoting factors. DYRK inhibition-induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition-induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER-239353 as a treatment for glioblastoma is therefore warranted., (© 2021 Vernalis R&D LTD and Servier Research Institute. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

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. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.

UDP-3- O -acyl- N -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. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1 S -hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa , which is little affected by the presence of albumin.

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. This study was designed to determine the current management strategies and opinions among orthopaedic surgeons treating Vancouver type B1 periprosthetic femoral fractures, and to evaluate the need for a large prospective randomized controlled trial for the management of these injuries., Methods: Orthopaedic surgeon members of the Orthopaedic Trauma Association (OTA), the Canadian Orthopaedic Association (COA), and the Hip Society were invited to participate in a 51-item web-based survey surrounding the management of periprosthetic femoral fractures around total hip replacements, as well as the perceived need for future research in this area. Responses were summarized using proportions, and further stratified by practice type, case volume, surgeon age, and fellowship training., Results: For Vancouver type B1 fractures, open reduction and internal fixation (ORIF) with locked plating was favoured slightly over ORIF with cable plating ± cortical strut allograft (51.1% versus 45.5%). When compared to cable plating with cortical strut allograft, respondents believed that isolated locked plating resulted in lower nonunion and reoperation rates, but similar infection and malunion rates. Subgroup analyses revealed that practice type, surgeon age, case volume, and fellowship training influenced surgeons' management of periprosthetic femoral fractures and beliefs regarding complications. There is high demand for a large prospective randomized controlled trial for Vancouver type B1 fracture fixation., Conclusions: Consensus surrounding the management of Vancouver type B1 periprosthetic femoral fractures is lacking, and there is a perceived need among orthopaedic surgeons for a large prospective randomized controlled trial in order to define the optimal management of these injuries., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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. synergistic or antagonistic) effects of atmospheric nitrogen (N) deposition and climatic variables (temperature, precipitation) on tree growth (in terms of tree-ring width, TRW), taking forest ecosystems with European beech (Fagus sylvatica L.) as an example. We hypothesised that (i) N deposition and climatic variables can evoke non-additive responses of the radial increment of beech trees, and (ii) N loads have the potential to strengthen the trees' sensitivity to climate change. In young stands, we found a synergistic positive effect of N deposition and annual mean temperature on TRW, possibly linked to the alleviation of an N shortage in young stands. In mature stands, however, high N deposition significantly increased the trees' sensitivity to increasing annual mean temperatures (antagonistic effect on TRW), possibly due to increased fine root dieback, decreasing mycorrhizal colonization or shifts in biomass allocation patterns (aboveground vs. belowground). Accordingly, N deposition and climatic variables caused both synergistic and antagonistic effects on the radial increment of beech trees, depending on tree age and stand characteristics. Hence, the nature of interactions could mediate the long-term effects of global change drivers (including N deposition) on forest carbon sequestration. In conclusion, our findings illustrate that interaction processes between climatic variables and N deposition are complex and have the potential to impair growth and performance of European beech. This in turn emphasises the importance of multiple-factor studies to foster an integrated understanding and models aiming at improved projections of tree growth responses to co-occurring drivers of global change., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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. These advantages come at the expense of higher rates of revision surgery for instability. Using the native locking mechanism for securing the new liner is preferred; however, cementing a liner into a well-fixed acetabular component is a practical alternative. The use of bone allograft or bone graft substitute for areas of osteolysis is controversial. In the setting of osteolysis, outcomes associated with the use of highly cross-linked polyethylene liners have been better than those associated with the use of conventional polyethylene; therefore, thinner liners and larger femoral heads can be used and reduce the risk of instability.

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. Unstable intertrochanteric fractures were created in 24 artificial femurs. Experimental groups were as follows: Nail (i.e. Gamma3 Nail) (n = 8), Plate A (i.e. Omega3 plate with four distal non-locking screws and no proximal locking screws) (n = 8), Plate B (i.e. Plate A plus five proximal locking screws) (n = 8), Plate C (i.e. Omega3 plate with three distal locking screws and no proximal locking screws) (n = 8), and Plate D (i.e. Plate C plus five proximal locking screws) (n = 8). All specimens were stiffness tested, while the Nail and Plate D groups were also strength tested. For lateral bending, Plate B was less stiff than the Nail (p = 0.001) and Plate A (p = 0.009). For torsion, Plate A was less stiff than Plate D (p = 0.020). For axial compression, the Nail was less stiff than Plate A (p = 0.036) and Plate B (p = 0.008). Axial strength for the Nail (5014 ± 308 N) was 66% higher than the Plate D construct (2940 ± 411 N) (p < 0.001). All Nails failed by partial or complete cutout through the femoral head and neck, but Plate D failed by varus collapse and deformation of the lag screw. When the cephalomedullary nail is clinically contra-indicated, this study supports the use of the Omega3 plate, since it had similar stiffness in three test modes to the Gamma3 Nail, but had lower strength. Stability of Omega3 plate constructs was not improved with locked fixation proximally or distally., (© IMechE 2016.)

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. Of the 1.04 × 10(6) ha cultivated with Jatropha in 2011 40% were established on land that was cleared of vegetation as a result of logging activities unrelated to Jatropha cultivation, 34% was defined as unused, and the remainder was attributable to areas previously used for crops or animal husbandry. With the exception of croplands, these areas were dominated (90-98%) by a few internationally active companies whose cultivation models were almost exclusively based on outgrower schemes. Management practices were largely extensive in nature (low mechanical input and infrequent use of fertilizers, pesticides and herbicides), and also dominated by large projects. Broad surveys, such as this, are useful in identifying general trends in this emerging global industry, but detailed case studies, particularly of large projects, are needed in order to draw more informed conclusions about the site-specific impacts of Jatropha cultivation.

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. The patient was immobilized for six weeks and Kirschner wires were removed at twelve weeks postoperatively., Conclusion: To our knowledge, hamate dislocation with scapholunate dissociation and its surgical treatment have not previously been described. Successful surgical treatment for this injury pattern may be performed dorsally via direct reduction and repair of the scapholunate ligament with percutaneous pinning of the affected carpal bones.

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. She was subsequently found to have a DVT in her femoral vein at the level of the repair and was started on therapeutic anticoagulation. This case highlights the importance of recognition of isolated venous injuries in a trauma setting as a risk factor for developing compartment syndrome.

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. It can be distinguished from similar conditions by the absence of fever, as well as unremarkable bloodwork (WBC, CRP, ESR), radiographs, and hip aspiration. Conservative treatment and observation are the mainstay of management. Resolution of symptoms generally occurs by 1 week and may be accelerated by NSAIDs. Although numerous papers have emerged over the years with an effort to advance our understanding, many questions remain about its pathomechanics, etiology, and how to exclude other more serious conditions that present similarly.

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., Methods: The records of all total hip and knee arthroplasties (THA; TKA) performed for primary osteoarthritis in one calendar year at one large university hospital were retrospectively reviewed. Demographic data, surgery start time and duration, intraoperative complications, radiographic component alignment and functional outcome scores (SF-12 and Western Ontario and McMaster Universities Osteoarthritis Index) were collected and analyzed using linear and nonparametric rank correlation statistics. Data were corrected for sex, body mass index, surgeon and postcall operating days., Results: In the THA cohort (n=341), a later surgery start time was significantly related to duration of surgery (p= 0.004, mean difference -7.1 min). There was a trend toward significance between a later surgery start time and intraoperative femur fracture (p= 0.05). Postoperative complications, component alignment and functional outcome scores were not significantly affected by surgery start time. There were no significant findings for any of the intraoperative or postoperative outcomes in the TKA cohort (n=292)., Conclusion: Duration of surgery and incidence of intraoperative complications for THA may increase with later surgery start time; however, the relatively small statistical differences observed imply that they likely are not clinically significant.

Crigler-Najjar (CN) syndrome is a rare genetic disease characterized by hyperbilirubinemia due to a deficiency in the hepatic enzyme UDP-glucuronosyl-transferase. We describe the first case of total knee arthroplasty in a patient with CN syndrome (type II). This procedure was complicated by kernicterus 1 week after hospital discharge. He also developed Klebsiella bacteremia and sepsis, requiring a brief ICU stay. He was discharged in good condition 2 months later. It is evident that physicians involved in the care of patients with CN syndrome in the peri-operative period need to have a high index of suspicion for the development of severe hyperbilirubinemia and kernicterus in order to appropriately manage and, possibly, prevent this complication. A literature review and intra-operative observations provide insight into the possible relationship between hyperbilirubinemia and osteoarthritis as well as the peri-operative considerations to be made for this group of patients.