Intraoperative application of three-dimensional printed guides in total hip arthroplasty: A systematic review.

BACKGROUND: Acetabular component positioning in total hip arthroplasty (THA) is of key importance to ensure satisfactory post-operative outcomes and to minimize the risk of complications. The majority of acetabular components are aligned freehand, without the use of navigation methods. Patient specific instruments (PSI) and three-dimensional (3D) printing of THA placement guides are increasingly used in primary THA to ensure optimal positioning. AIM: To summarize the literature on 3D printing in THA and how they improve acetabular component alignment. METHODS: PubMed was used to identify and access scientific studies reporting on different 3D printing methods used in THA. Eight studies with 236 hips in 228 patients were included. The studies could be divided into two main categories; 3D printed models and 3D printed guides. RESULTS: 3D printing in THA helped improve preoperative cup size planning and post-operative Harris hip scores between intervention and control groups (P = 0.019, P = 0.009). Otherwise, outcome measures were heterogeneous and thus difficult to compare. The overarching consensus between the studies is that the use of 3D guidance tools can assist in improving THA cup positioning and reduce the need for revision THA and the associated costs. CONCLUSION: The implementation of 3D printing and PSI for primary THA can significantly improve the positioning accuracy of the acetabular cup component and reduce the number of complications caused by malpositioning.

Risk for re-revision and type of antibiotic-loaded bone cement in hip or knee arthroplasty revisions: report of the Dutch Arthroplasty Register.

BACKGROUND AND PURPOSE: High-dose dual antibiotic-loaded bone cement (ALBC) may reduce the risk of revision after total hip and knee replacements. The aim of our study therefore was to determine the risk of re-revision following first time aseptic hip or knee revision using single versus dual ALBC. PATIENTS AND METHODS: Patients from the Dutch Arthroplasty Register treated from 2007 to 2018 with first time cemented aseptic hip (n = 2,529) or knee revisions (n = 7,124) were incorporated into 2 datasets. The primary endpoint of this observational cohort study was subsequent all-cause re-revision. Multivariable Cox proportional hazard and competing risk was analyzed for both groups. RESULTS: There was no difference in re-revision rate (any reason) with single versus dual ALBC (hazard ratio 1.06, 95% confidence interval [CI] 0.83-1.35 for hip and 0.93, CI 0.80-1.07 for knee revisions). The 10-year crude cumulative re-revision rate also showed no differences for single versus dual ALBC use. The crude cumulative 7-year THA re-revision and 9-year TKA re-revision rates did not show any difference in implant survival for common cement types used. CONCLUSION: We could not confirm the potential benefit of using dual ALBC compared with single ALBC for aseptic hip and knee revisions.

Wound drainage after arthroplasty and prediction of acute prosthetic joint infection: prospective data from a multicentre cohort study using a telemonitoring app.

Background: Differentiation between uncomplicated and complicated postoperative wound drainage after arthroplasty is crucial to prevent unnecessary reoperation. Prospective data about the duration and amount of postoperative wound drainage in patients with and without prosthetic joint infection (PJI) are currently absent. Methods: A multicentre cohort study was conducted to assess the duration and amount of wound drainage in patients after arthroplasty. During 30 postoperative days after arthroplasty, patients recorded their wound status in a previously developed wound care app and graded the amount of wound drainage on a 5-point scale. Data about PJI in the follow-up period were extracted from the patient files. Results: Of the 1019 included patients, 16 patients (1.6 %) developed a PJI. Minor wound drainage decreased from the first to the fourth postoperative week from 50 % to 3 %. Both moderate to severe wound drainage in the third week and newly developed wound drainage in the second week after a week without drainage were strongly associated with PJI (odds ratio (OR) 103.23, 95 % confidence interval (CI) 26.08 to 408.57, OR 80.71, 95 % CI 9.12 to 714.52, respectively). The positive predictive value (PPV) for PJI was 83 % for moderate to heavy wound drainage in the third week. Conclusion: Moderate to heavy wound drainage and persistent wound drainage were strongly associated with PJI. The PPV of wound drainage for PJI was high for moderate to heavy drainage in the third week but was low for drainage in the first week. Therefore, additional parameters are needed to guide the decision to reoperate on patients for suspected acute PJI.

AutoDesigner, a De Novo Design Algorithm for Rapidly Exploring Large Chemical Space for Lead Optimization: Application to the Design and Synthesis of d-Amino Acid Oxidase Inhibitors.

The lead optimization stage of a drug discovery program generally involves the design, synthesis, and assaying of hundreds to thousands of compounds. The design phase is usually carried out via traditional medicinal chemistry approaches and/or structure-based drug design (SBDD) when suitable structural information is available. Two of the major limitations of this approach are (1) difficulty in rapidly designing potent molecules that adhere to myriad project criteria, or the multiparameter optimization (MPO) problem, and (2) the relatively small number of molecules explored compared to the vast size of chemical space. To address these limitations, we have developed AutoDesigner, a de novo design algorithm. AutoDesigner employs a cloud-native, multistage search algorithm to carry out successive rounds of chemical space exploration and filtering. Millions to billions of virtual molecules are explored and optimized while adhering to a customizable set of project criteria such as physicochemical properties and potency. Additionally, the algorithm only requires a single ligand with measurable affinity and a putative binding model as a starting point, making it amenable to the early stages of an SBDD project where limited data are available. To assess the effectiveness of AutoDesigner, we applied it to the design of novel inhibitors of d-amino acid oxidase (DAO), a target for the treatment of schizophrenia. AutoDesigner was able to generate and efficiently explore over 1 billion molecules to successfully address a variety of project goals. The compounds generated by AutoDesigner that were synthesized and assayed (1) simultaneously met not only physicochemical criteria, clearance, and central nervous system (CNS) penetration (Kp,uu) cutoffs but also potency thresholds and (2) fully utilize structural data to discover and explore novel interactions and a previously unexplored subpocket in the DAO active site. The reported data demonstrate that AutoDesigner can play a key role in accelerating the discovery of novel, potent chemical matter within the constraints of a given drug discovery lead optimization campaign.

Association between Baseline Osteoarthritic Features on MR Imaging and Clinical Outcome after Genicular Artery Embolization for Knee Osteoarthritis.

PURPOSE: To explore the association between baseline osteoarthritis (OA)-related magnetic resonance (MR) imaging features and pain reduction after genicular artery embolization (GAE) in patients with mild-to-moderate symptomatic knee OA resistant to conservative therapy. MATERIALS AND METHODS: This was a retrospective analysis of patients with mild-to-moderate symptomatic knee OA treated with GAE using imipenem-cilastatin sodium. The clinical outcome was scored at baseline and 6 months after treatment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). MR images were scored using the MR imaging osteoarthritis knee score. Linear regression was used to evaluate associations of before-treatment MR imaging scores with WOMACpain and WOMACtotal reduction after 6 months. RESULTS: Fifty-four patients (22.2% male; median age, 69.4 years; median WOMACpain at baseline, 12) were evaluated. Of all OA features scored, a higher cartilage full-thickness defect score showed the strongest association with less reduction of both WOMACpain (B,-0.63 [95% confidence interval (CI), -0.91 to -0.34]; P < .001) and WOMACtotal scores (B, -1.77 [95% CI, -2.87 to -0.67]; P < .001) following treatment. The presence of grade 2-3 effusion synovitis (B, -2.99 [95% CI, -5.39 to -0.60]) bone marrow lesions (B, -0.52 [95% CI, -0.86 to -0.19]), osteophytes (B, -0.21 [95% CI, -0.36 to -0.06]), and cartilage defect surface area score (B, -0.25 [95% CI -0.42 to -0.08]) all showed a significant association with less WOMACpain reduction (all P < .05). CONCLUSIONS: In patients with mild-to-moderate symptomatic knee OA treated with GAE, the presence and severity of full-thickness cartilage defects, effusion synovitis, bone marrow lesions, osteophytes, and cartilage surface area scores at baseline are associated with less favorable clinical outcomes at 6 months.

Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation.

Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration.

Routine Fracture Fixation for a Periprosthetic Hip Fracture Below Birmingham Hip Resurfacing: A Case Report.

CASE: We present a case of a 56-year-old man who sustained a basal cervical periprosthetic fracture around a well-fixed metal-on-metal hip resurfacing arthroplasty (MoMHRA). Although several fixation methods have been described, there seems to be no consensus about the optimal fixation method for fractures around MoMHRAs. This fracture could be regarded as a Vancouver type-B1 or -C periprosthetic fracture, so we successfully treated our patient in a standard way with a dynamic hip screw (DHS) and one cannulated hip screw. CONCLUSION: We describe DHS fixation as a successful treatment option for periprosthetic hip fractures around well-fixed MoMHRA.

Combining Cloud-Based Free-Energy Calculations, Synthetically Aware Enumerations, and Goal-Directed Generative Machine Learning for Rapid Large-Scale Chemical Exploration and Optimization.

The hit identification process usually involves the profiling of millions to more recently billions of compounds either via traditional experimental high-throughput screens (HTS) or computational virtual high-throughput screens (vHTS). We have previously demonstrated that, by coupling reaction-based enumeration, active learning, and free energy calculations, a similarly large-scale exploration of chemical space can be extended to the hit-to-lead process. In this work, we augment that approach by coupling large scale enumeration and cloud-based free energy perturbation (FEP) profiling with goal-directed generative machine learning, which results in a higher enrichment of potent ideas compared to large scale enumeration alone, while simultaneously staying within the bounds of predefined drug-like property space. We can achieve this by building the molecular distribution for generative machine learning from the PathFinder rules-based enumeration and optimizing for a weighted sum QSAR-based multiparameter optimization function. We examine the utility of this combined approach by designing potent inhibitors of cyclin-dependent kinase 2 (CDK2) and demonstrate a coupled workflow that can (1) provide a 6.4-fold enrichment improvement in identifying <10 nM compounds over random selection and a 1.5-fold enrichment in identifying <10 nM compounds over our previous method, (2) rapidly explore relevant chemical space outside the bounds of commercial reagents, (3) use generative ML approaches to "learn" the SAR from large scale in silico enumerations and generate novel idea molecules for a flexible receptor site that are both potent and within relevant physicochemical space, and (4) produce over 3 000 000 idea molecules and run 1935 FEP simulations, identifying 69 ideas with a predicted IC50 < 10 nM and 358 ideas with a predicted IC50 < 100 nM. The reported data suggest combining both reaction-based and generative machine learning for ideation results in a higher enrichment of potent compounds over previously described approaches and has the potential to rapidly accelerate the discovery of novel chemical matter within a predefined potency and property space.

Quantitative subchondral bone perfusion imaging in knee osteoarthritis using dynamic contrast enhanced MRI.

OBJECTIVE: Subchondral bone changes, characterized by increased bone turnover and vascularity, are believed to stimulate progression and pain in knee osteoarthritis (OA). The objective of this study was to evaluate the bone perfusion in knee OA using quantitative dynamic contrast enhanced MRI (DCE-MRI). DESIGN: Unicompartmental knee OA patients were included and underwent 3 Tesla DCE-MRI and T2-weighted MRI. Quantitative DCE-MRI analysis of Ktrans and Kep, representing perfusion parameters, was performed to evaluate differences between the most and least affected knee compartment. First, DCE-MRI parameter differences between epimetaphyseal and subchondral bone in both femur and tibia were assessed. Second, DCE-MRI parameters in subchondral bone marrow lesions (BMLs) were compared to surrounding subchondral bone without BMLs. RESULTS: Twenty-three patients were analyzed. Median Ktrans and Kep in epimetaphyseal bone were significantly higher (p < 0.05) in the most affected (Ktrans: 0.014; Kep: 0.054 min-1) compared to least affected (Ktrans: 0.010; Kep: 0.016 min-1) compartment. For subchondral bone, DCE-MRI parameters were significantly higher (p < 0.05) in the most affected (Ktrans: 0.019; Kep: 0.091 min-1) compared to least affected (Ktrans: 0.014; Kep: 0.058 min-1) compartment as well. Subchondral BMLs detected on fat-saturated T2-weighted images were present in all patients. Median Ktrans (0.091 vs 0.000 min-1) and Kep (0.258 vs 0.000 min-1) were significantly higher within subchondral BMLs compared to surrounding subchondral bone without BMLs (p < 0.001). CONCLUSIONS: Increased perfusion parameters in epimetaphyseal bone, subchondral bone and BMLs are observed in unicompartmental knee OA. BMLs likely account for most of the effect of the higher bone perfusion in knee OA.

Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.

Disease-causing mutations in many neurodegenerative disorders lead to proteinopathies that trigger endoplasmic reticulum (ER) stress. However, few therapeutic options exist for patients with these diseases. Using an in vitro screening platform to identify compounds that protect human motor neurons from ER stress-mediated degeneration, we discovered that compounds targeting the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family are neuroprotective. The kinase inhibitor URMC-099 (compound 1) stood out as a promising lead compound for further optimization. We coupled structure-based compound design with functional activity testing in neurons subjected to ER stress to develop a series of analogs with improved MAP4K inhibition and concomitant increases in potency and efficacy. Further structural modifications were performed to enhance the pharmacokinetic profiles of the compound 1 derivatives. Prostetin/12k emerged as an exceptionally potent, metabolically stable, and blood-brain barrier-penetrant compound that is well suited for future testing in animal models of neurodegeneration.

Reaction-Based Enumeration, Active Learning, and Free Energy Calculations To Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin-Dependent Kinase 2 Inhibitors.

The hit-to-lead and lead optimization processes usually involve the design, synthesis, and profiling of thousands of analogs prior to clinical candidate nomination. A hit finding campaign may begin with a virtual screen that explores millions of compounds, if not more. However, this scale of computational profiling is not frequently performed in the hit-to-lead or lead optimization phases of drug discovery. This is likely due to the lack of appropriate computational tools to generate synthetically tractable lead-like compounds in silico, and a lack of computational methods to accurately profile compounds prospectively on a large scale. Recent advances in computational power and methods provide the ability to profile much larger libraries of ligands than previously possible. Herein, we report a new computational technique, referred to as "PathFinder", that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. In this work, the integration of PathFinder-driven compound generation, cloud-based FEP simulations, and active learning are used to rapidly optimize R-groups, and generate new cores for inhibitors of cyclin-dependent kinase 2 (CDK2). Using this approach, we explored >300 000 ideas, performed >5000 FEP simulations, and identified >100 ligands with a predicted IC50 < 100 nM, including four unique cores. To our knowledge, this is the largest set of FEP calculations disclosed in the literature to date. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

K-RasG12D Has a Potential Allosteric Small Molecule Binding Site.

KRAS is the most commonly mutated oncogene in human cancer, with particularly high mutation frequencies in pancreatic cancers, colorectal cancers, and lung cancers [Ostrem, J. M., and Shokat, K. M. (2016) Nat. Rev. Drug Discovery 15, 771-785]. The high prevalence of KRAS mutations and its essential role in many cancers make it a potentially attractive drug target; however, it has been difficult to create small molecule inhibitors of mutant K-Ras proteins. Here, we identified a putative small molecule binding site on K-RasG12D using computational analyses of the protein structure and then used a combination of computational and biochemical approaches to discover small molecules that may bind to this pocket, which we have termed the P110 site, due to its adjacency to proline 110. We confirmed that one compound, named K-Ras allosteric ligand KAL-21404358, bound to K-RasG12D, as measured by microscale thermophoresis, a thermal shift assay, and nuclear magnetic resonance spectroscopy. KAL-21404358 did not bind to four mutants in the P110 site, supporting our hypothesis that KAL-21404358 binds to the P110 site of K-RasG12D. This compound impaired the interaction of K-RasG12D with B-Raf and disrupted the RAF-MEK-ERK and PI3K-AKT signaling pathways. We synthesized additional compounds, based on the KAL-21404358 scaffold with more potent binding and greater aqueous solubility. In summary, these findings suggest that the P110 site is a potential site for binding of small molecule allosteric inhibitors of K-RasG12D.

The effectiveness of high molecular weight hyaluronic acid for knee osteoarthritis in patients in the working age: a randomised controlled trial.

BACKGROUND: High molecular weight (HMW) hyaluronic acid (HA) is a treatment option for knee osteoarthritis (OA). The efficacy of HMW-HA in knee OA is investigated extensively, but the effectiveness in patients in the working age is unknown. Nevertheless, the number knee OA patients in the working age is increasing. Surgical treatment options are less eligible in these patients and productivity losses are high. In this study the effectiveness of intra-articular HMW-HA added to regular non-surgical usual care in everyday clinical practice (UC) compared to UC over 52 weeks in symptomatic knee OA patients in the working age was investigated. METHODS: In this open labelled randomized controlled trial, subjects aged between 18 and 65 years with symptomatic knee OA (Kellgren and Lawrence I-III) were enrolled and randomized to UC + 3 weekly injections with HMW-HA (intervention) or UC only (control). The primary outcome was the between group difference in responders to therapy according to OMERACT-OARSI criteria after 52 weeks. These criteria include the domains pain, knee related function and patient's global assessment (PGA). Function was evaluated with the KOOS questionnaire. Pain was assessed with the Numeric Rating Scale. Secondary outcome comprised the between group difference on the individual responder domains, as analysed with a random effects model. Odds Ratios (OR) were calculated by logistic regression analysis. Sensitivity analyses were performed. RESULTS: In total, 156 subjects were included (intervention group 77, control group 79). Subjects in the intervention group (HMW-HA + UC) were more often responder compared to the controls (UC). Depending on whether pain during rest or pain during activity was included in the responder domains, 57.1% versus 34.2% (p = 0.006) and 54.5% versus 34.2% (p = 0.015) was responder to therapy respectively. The results of the secondary outcome analyses show that scores on individual responder domains over all follow-up moments were statistically significant in favour of the intervention group in the domains pain during rest (δ 0.8, 95%CI 0.2; 1.4, p = 0.010), knee related function (δ - 6.8, 95%CI -11.9; - 1.7, p = 0.010) and PGA (δ - 0.7, 95%CI -0.9; - 0.4, p < 0.0001). CONCLUSIONS: Intra-articular HMW-HA added to usual care is effective for knee OA in patients in the working age. TRIAL REGISTRATION: www.trialregister.nl , NTR1651, registered 2009-3-3.

Quality of life and health status after Girdlestone resection arthroplasty in patients with an infected total hip prosthesis.

Introduction: The Girdlestone resection arthroplasty (GRA) is a salvage procedure for a recurrent or persistent prosthetic joint infection of the hip. This procedure negatively impacts the functional outcome and presumably also diminishes health status (HS) and quality of life (QOL). However, studies investigating the QOL after GRA are lacking. This cross-sectional study compares patients with a Girdlestone situation after an infected total hip prosthesis with a normative population with regard to HS and QOL. Methods: Patients with a permanent GRA were suitable to be enrolled in the study. Subjects completed the World Health Organization Quality of life (WHOQOL-BREF) and the EuroQol 5 dimension 3 level version (EQ-5D-3L). Scores were compared with data from the normal population, from patients with a lower limb amputations and data from patients with a myocardial infarction. Results: Sixty-three patients who underwent GRA between January 2000 and March 2017 completed the questionnaire. The median time between the GRA and competing the questionnaire was 48 months (4 -436). All WHOQOL-BREF domain scores were significantly lower in GRA patients compared to the normative data (p<0.001), patients with myocardial infarction or lower limb amputation. EQ-5D-3L results showed that HS was significantly impaired in GRA patients when compared to normative data (p<0.001) and also impaired when compared to data from lower limb amputations and myocardial infarctions. Conclusion: HS and QOL scores in patients with a permanent Girdlestone situation after an infected hip prosthesis are significantly lower than Dutch normative scores. Patients with a permanent Girdlestone situation scored even lower on HS than patients with a lower limb amputation or a myocardial infarction.

Bone Marrow-Harvesting Technique Influences Functional Heterogeneity of Mesenchymal Stem/Stromal Cells and Cartilage Regeneration.

BACKGROUND: Connective tissue progenitors (CTPs) from native bone marrow (BM) or their culture-expanded progeny, often referred to as mesenchymal stem/stromal cells, represents a promising strategy for treatment of cartilage injuries. But the cartilage regeneration capacity of these cells remains unpredictable because of cell heterogeneity. HYPOTHESIS: The harvest technique of BM may highly influence stem cell heterogeneity and, thus, cartilage formation because these cells have distinct spatial localization within BM from the same bone. STUDY DESIGN: Controlled laboratory study. METHODS: CTPs obtained from the femur of patients undergoing total hip replacement by 2 harvest techniques-BM aspiration and BM collection-after bone rasping were immunophenotyped by flow cytometry and evaluated for chondrogenic ability. The spatial localization of different CTP subsets in BM was verified by immunohistochemistry. RESULTS: Cells from the BM after rasping were significantly more chondrogenic than the donor-matched aspirate, whereas no notable difference in their osteogenic or adipogenic potential was observed. The authors then assessed whether distinct immunophenotypically defined CTP subsets were responsible for the different chondrogenic capacity. Cells directly isolated from BM after rasping contained a higher percentage (mean, 7.2-fold) of CD45-CD271+CD56+ CTPs as compared with BM aspirates. The presence of this subset in the harvested BM strongly correlated with chondrogenic ability, showing that CD271+CD56+ cells are enriched in chondroprogenitors. Furthermore, evaluation of these CTP subsets in BM revealed that CD271+CD56+ cells were localized in the bone-lining regions whereas CD271+CD56- cells were found in the perivascular regions. Since the iliac crest remains a frequent site of BM harvest for musculoskeletal regeneration, the authors also compared the spatial distribution of these subsets in trabeculae of femoral head and iliac crest and found CD271+CD56+ bone-lining cells in both tissues. CONCLUSION: Chondrogenically distinct CTP subsets have distinct spatial localization in BM; hence, the harvest technique of BM determines the efficiency of cartilage formation. CLINICAL RELEVANCE: The harvest technique of BM may be of major importance in determining the clinical success of BM mesenchymal stem/stromal cells in cartilage repair.

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation.

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial.

OBJECTIVES: Guidelines recommend intra-articular glucocorticoid injection in patients with painful hip osteoarthritis. However, intra-articular hip injection is an invasive procedure. The efficacy of systemic glucocorticoid treatment for pain reduction in hip osteoarthritis is unknown. This randomised, double-blind, trial assessed effectiveness in hip pain reduction of an intramuscular glucocorticoid injection compared with a placebo injection in patients with hip osteoarthritis. METHODS: Patients with painful hip osteoarthritis were randomised to either 40 mg triamcinolone acetate or placebo with an intramuscular injection into the gluteus muscle. The primary outcomes were severity of hip pain at rest, during walking (0-10) and WOMAC pain at 2-week postinjection. We used linear mixed models for repeated measurements at 2, 4, 6 and 12 weeks for the intention-to-treat data analysis. RESULTS: Of the 107 patients randomised, 106 could be analysed (52 in the glucocorticoid group, 54 in the placebo group). At 2-week follow-up, compared with placebo injection, the intramuscular glucocorticoid injection showed a significant and clinically relevant difference in hip pain reduction at rest (difference -1.3, 95% CI -2.3 to -0.3). This effect persisted for the entire 12-week follow-up. For hip pain during walking, the effect was present at 4-week, 6-week and 12-week follow-ups, and for WOMAC pain the effect was present at 6-week and 12-week follow-up. CONCLUSIONS: An intramuscular glucocorticoid injection showed effectiveness in patients with hip osteoarthritis on one of the three primary outcomes at 2-week postinjection. All primary outcomes showed effectiveness from 4 to 6 weeks, up to a 12-week follow-up. TRIAL REGISTRATION NUMBER: NTR2966.

Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells.

Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.

Characterization of Endothelial Cells Associated with Hematopoietic Niche Formation in Humans Identifies IL-33 As an Anabolic Factor.

Bone marrow formation requires an orchestrated interplay between osteogenesis, angiogenesis, and hematopoiesis that is thought to be mediated by endothelial cells. The nature of the endothelial cells and the molecular mechanisms underlying these events remain unclear in humans. Here, we identify a subset of endoglin-expressing endothelial cells enriched in human bone marrow during fetal ontogeny and upon regeneration after chemotherapeutic injury. Comprehensive transcriptional characterization by massive parallel RNA sequencing of these cells reveals a phenotypic and molecular similarity to murine type H endothelium and activation of angiocrine factors implicated in hematopoiesis, osteogenesis, and angiogenesis. Interleukin-33 (IL-33) was significantly overexpressed in these endothelial cells and promoted the expansion of distinct subsets of hematopoietic precursor cells, endothelial cells, as well as osteogenic differentiation. The identification and molecular characterization of these human regeneration-associated endothelial cells is thus anticipated to instruct the discovery of angiocrine factors driving bone marrow formation and recovery after injury.