Publications by authors named "Matthew J Anderson"

72 Publications

Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries.

Chem Sci 2021 Jul 22;12(27):9475-9484. Epub 2021 Jun 22.

Cancer Research UK Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Newcastle University Bedson Building Newcastle upon Tyne NE1 7RU UK

DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs.
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http://dx.doi.org/10.1039/d1sc03007hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278914PMC
July 2021

A Systematic Assessment of YouTube Content on Femoroacetabular Impingement: An Updated Review.

Orthop J Sports Med 2021 Jun 29;9(6):23259671211016340. Epub 2021 Jun 29.

Columbia University Irving Medical Center, New York, New York, USA.

Background: Online video-sharing platforms such as YouTube have become popular sources of medical information for patients. However, concern exists regarding the quality of such non-peer reviewed content. In fact, a previous investigation found the majority of YouTube information related to femoroacetabular impingement (FAI) to be of poor quality.

Purpose: To provide an updated assessment of the quality of FAI-related videos available on YouTube.

Study Design: Cross-sectional study.

Methods: The terms , , and were searched on YouTube, and exclusion criteria were applied to the first 100 results for each term. The diagnostic and treatment content of each video was graded and assigned a quality assessment rating based on a previously used rubric. Video characteristics (e.g. duration, views, "likes") were compared using both quality assessment rating and video source.

Results: A total of 142 videos were included in the final analysis. The most common video source was educational (48.6%), followed by physician-sponsored (30.3%). The majority of videos were graded as "somewhat useful" for both diagnostic and treatment content (59.4% and 61.6%, respectively); however, treatment content was rated "not useful" more often than diagnostic information (20.3% vs. 8.7%, respectively). Videos rated as "somewhat useful" received the most views per day on average, while educational videos were the most viewed by source (views and views per day). Educational videos had more views and likes on average than physician-sponsored videos ( < .05), but all other comparisons of video characteristics by source were not significant. Video duration was the only characteristic found to vary significantly by quality assessment rating ( < .001 for both diagnostic and treatment analyses), with higher-quality videos tending to be longer. Videos rated as "excellent" and "very useful" had mean durations >30 minutes but were viewed the least.

Conclusion: The overall quality of FAI-related content on YouTube remains low. Clinicians should be familiar with medical information available to patients on the internet, as it can influence patients' perspectives and shared decision-making processes. This review substantiates the need for more publicly available, high-quality video content regarding the diagnosis and treatment of FAI.
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http://dx.doi.org/10.1177/23259671211016340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246525PMC
June 2021

Using machine learning methods to predict nonhome discharge after elective total shoulder arthroplasty.

JSES Int 2021 Jul 20;5(4):692-698. Epub 2021 Apr 20.

New York-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

Background: Machine learning has shown potential in accurately predicting outcomes after orthopedic surgery, thereby allowing for improved patient selection, risk stratification, and preoperative planning. This study sought to develop machine learning models to predict nonhome discharge after total shoulder arthroplasty (TSA).

Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent elective TSA from 2012 to 2018. Boosted decision tree and artificial neural networks (ANN) machine learning models were developed to predict non-home discharge and 30-day postoperative complications. Model performance was measured using the area under the receiver operating characteristic curve (AUC) and overall accuracy (%). Multivariate binary logistic regression analyses were used to identify variables that were significantly associated with the predicted outcomes.

Results: There were 21,544 elective TSA cases identified in the National Surgical Quality Improvement Program registry from 2012 to 2018 that met inclusion criteria. Multivariate logistic regression identified several variables associated with increased risk of nonhome discharge including female sex (odds ratio [OR] = 2.83; 95% confidence interval [CI] = 2.53-3.17;  < .001), age older than 70 years (OR = 3.19; 95% CI = 2.86-3.57;  < .001), American Society of Anesthesiologists classification 3 or greater (OR = 2.70; 95% CI = 2.41-2.03;  < .001), prolonged operative time (OR = 1.38; 95% CI = 1.20-1.58;  < .001), as well as history of diabetes (OR = 1.56; 95% CI = 1.38-1.75;  < .001), chronic obstructive pulmonary disease (OR = 1.71; 95% CI = 1.46-2.01;  < .001), congestive heart failure (OR = 2.65; 95% CI = 1.72-4.01;  < .001), hypertension (OR = 1.35; 95% CI = 1.20-1.52;  = .004), dialysis (OR = 3.58; 95% CI = 2.01-6.39;  = .002), wound infection (OR = 5.67; 95% CI = 3.46-9.29;  < .001), steroid use (OR = 1.43; 95% CI = 1.18-1.74;  = .010), and bleeding disorder (OR = 1.84; 95% CI = 1.45-2.34;  < .001). The boosted decision tree model for predicting nonhome discharge had an AUC of 0.788 and an overall accuracy of 90.3%. The ANN model for predicting nonhome discharge had an AUC of 0.851 and an overall accuracy of 89.9%. For predicting the occurrence of 1 or more postoperative complications, the boosted decision tree model had an AUC of 0.795 and an overall accuracy of 95.5%. The ANN model yielded an AUC of 0.788 and an overall accuracy of 92.5%.

Conclusions: Both the boosted decision tree and ANN models performed well in predicting nonhome discharge with similar overall accuracy, but the ANN had higher discriminative ability. Based on the findings of this study, machine learning has the potential to accurately predict nonhome discharge after elective TSA. Surgeons can use such tools to guide patient expectations and to improve preoperative discharge planning, with the ultimate goal of decreasing hospital length of stay and improving cost-efficiency.
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http://dx.doi.org/10.1016/j.jseint.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245980PMC
July 2021

Return-to-Competition Criteria After Ulnar Collateral Ligament Reconstruction: A Systematic Review and Meta-analysis.

Am J Sports Med 2021 Jun 28:3635465211016839. Epub 2021 Jun 28.

Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, New York, USA.

Background: Injury to the ulnar collateral ligament of the elbow is common among overhead throwing athletes and can result in significant functional limitations. While surgical reconstruction offers high rates of return to competition, there are no validated or universally accepted guidelines for determining when an athlete can safely resume play.

Purpose: To assess the existing scientific literature for return-to-competition criteria utilized after ulnar collateral ligament reconstruction.

Study Design: Systematic review and meta-analysis; Level of evidence, 4.

Methods: The PubMed database was searched for clinical investigations of ulnar collateral ligament reconstruction in overhead throwing athletes published between January 2000 and June 2020. Only studies that had a minimum follow-up of 1 year and included at least 1 specific return-to-competition criterion were considered.

Results: A total of 15 studies were included in the final analysis, encompassing 1156 patients with an average age of 20.7 years (SD, 2.0 years). Baseball players composed 96.3% of patients for whom sport was specified, and 92.4% of baseball players were pitchers. The most common return-to-competition criterion, identified in 87% of studies, was completion of a return-to-throwing program, which started on average 16.7 weeks (range, 12-18 weeks) after surgery. A return-to-mound program was utilized in 53% of studies, starting on average 7.4 months (range, 6-9 months) postoperatively. Minimum time from surgery was used in 73% studies, with players waiting 7 to 12 months (mean, 9.7; SD, 1.4 months) after surgery before return-to-competition consideration. The overall rate of return to competition at the preinjury level or higher was 85.7% (SD, 8.5%) at an average of 12.2 months (SD, 0.6 months).

Conclusion: In general, we observed a paucity of literature describing the return-to-competition process after ulnar collateral ligament reconstruction in overhead throwing athletes. Only 3 explicit return-to-competition criteria were identified across all studies: completion of a return-to-throwing program, completion of a return-to-mound program for pitchers, and minimum time from surgery. Increased transparency regarding postoperative rehabilitation protocols and further research are necessary to identify and validate sport-specific return-to-competition criteria, which will ultimately help athletes return to play in a safe and timely fashion after ulnar collateral ligament reconstruction.
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http://dx.doi.org/10.1177/03635465211016839DOI Listing
June 2021

Case Report: Pentosan Polysulfate Sodium Maculopathy Originally Diagnosed as Pattern Macular Dystrophy.

Optom Vis Sci 2021 06;98(6):552-556

Department of Surgery, VA NIHCS Fort Wayne Campus, Fort Wayne, Indiana.

Significance: Pentosan polysulfate sodium (PPS) maculopathy is a clinical entity characterized by a pigmentary maculopathy in the setting of chronic exposure to PPS. Pentosan polysulfate sodium is indicated for discomfort related to interstitial cystitis/painful bladder syndrome. Given a reported interstitial cystitis/painful bladder syndrome prevalence up to 2%, recognition is critical to mitigate visual sequelae.

Purpose: We present an observational case report demonstrating typical findings of PPS maculopathy in a patient originally diagnosed with a pattern macular dystrophy. We demonstrate the importance of medical history, medication profile review, and multimodal imaging in the diagnosis and management. The patient provided written informed consent for medical information and images to be published.

Case Report: A 55-year-old White woman presented with a painless, bilateral loss of vision and bilateral pigmentary maculopathy that was initially diagnosed as pattern macular dystrophy. Detailed review of medical history, medication profile, and subsequent studies, including optical coherence tomography, near-infrared reflectance imaging, fundus autofluorescence, fluorescein angiography, and genetic studies, ultimately led to the diagnosis of PPS maculopathy. Pentosan polysulfate sodium was discontinued, and ongoing surveillance with multimodal imaging was encouraged.

Conclusions: Because toxic maculopathies are an uncommon diagnosis, screening and recognition of PPS maculopathy are critical in the primary eye care setting. Discontinuation of the insulting agent may be necessary to prevent potentially severe and irreversible vision loss in the at-risk population.
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http://dx.doi.org/10.1097/OPX.0000000000001702DOI Listing
June 2021

Epidemiology of Shoulder Instability in the National Football League.

Orthop J Sports Med 2021 May 4;9(5):23259671211007743. Epub 2021 May 4.

Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, New York, USA.

Background: Shoulder instability is a common and potentially debilitating injury among collision sport athletes that can lead to long-term damage of the glenohumeral joint. Limited data exist regarding instability among elite athletes in the National Football League (NFL).

Purpose: To describe the epidemiology of shoulder instability in the NFL from 2012 through 2017.

Study Design: Descriptive epidemiology study.

Methods: The NFL's injury database was reviewed for shoulder instability injuries resulting in missed time during the study inclusion dates. Injuries were classified by type and direction, as well as timing, setting, and mechanism. Median missed time was determined for the different types and directions of instability. Incidence rates for game-related injuries were calculated based on timing during the season and player position. Finally, the relationship between player position and instability direction was assessed.

Results: During the 6-year study period, 355 players sustained 403 missed-time shoulder instability injuries. Most injuries occurred during games (65%) via a contact mechanism (85%). The overall incidence rate of game-related instability was 3.6 injuries per 100,000 player-plays and was highest during the preseason (4.9 per 100,000 player-plays). The defensive secondary position accounted for the most injuries, but quarterbacks had the highest incidence rate in games (5.5 per 100,000 player-plays). Excluding unspecified events (n = 128; 32%), 70% (n = 192) of injuries were subluxations and 30% (n = 83) were dislocations; 75% of dislocations were anterior, while subluxations were more evenly distributed between the anterior and posterior directions (45% vs 52%, respectively). Players missed substantially more time after dislocation compared with subluxation (median, 47 days vs 13 days, respectively). When instability direction was known, the majority of instability events among quarterbacks and offensive linemen were posterior (73% and 53%, respectively), while anterior instability was most common for all other positions.

Conclusion: Shoulder instability is a common injury in the NFL and can result in considerable missed time. Dislocations occur less frequently than subluxations but lead to greater time lost. While most dislocations are anterior, more than half of subluxations are posterior, which is likely the result of repetitive microtrauma to the posterior capsulolabral complex sustained during sport-specific motions such as blocking. The risk of instability varies by player position, and position may also influence instability direction.
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http://dx.doi.org/10.1177/23259671211007743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113962PMC
May 2021

Debate Update: Surgery After 48 Hours of Admission for Geriatric Hip Fracture Patients Is Associated With Increase in Mortality and Complication Rate: A Study of 27,058 Patients Using the National Trauma Data Bank.

J Orthop Trauma 2021 Oct;35(10):535-541

Department of Orthopaedic Surgery, Columbia University Irving Medical Center, New York, NY.

Objective: To determine the association between surgical timing and short-term morbidity and mortality in elderly patients who sustain hip fractures using a national trauma database (OTA/AO 31A1-3, 31B1-3).

Design: Retrospective cohort study.

Setting: Level I-IV trauma centers in the United States.

Patients/participants: All patients ≥65 years of age who underwent surgery for hip fracture from 2011 to 2013.

Intervention: Time to surgery of <24, 24-48, and >48 hours from admission.

Main Outcome Measurements: Primary outcome was mortality by hospital discharge. Secondary outcomes were complications of myocardial infarction, cardiac arrest, acute respiratory distress syndrome (ARDS), unplanned reintubation, pneumonia, stroke, severe sepsis, and intensive care unit length of stay.

Results: Twenty-seven thousand fifty-eight patients were included in the study. Relative to the <24 hours cohort, patients in the >48 hours cohort were at increased risk for mortality (OR 1.89, 95% CI 1.52-2.33, P < 0.001), ARDS (OR 2.57, 95% CI 1.94-3.39, P < 0.001 for ARDS), myocardial infarction (OR 2.19, 95% CI 1.64-2.94, P < 0.0001), pneumonia (OR 2.04, 95% CI 1.71-2.44, P < 0.001), severe sepsis (OR 2.34, 95% CI 1.52-3.58, P = 0.003), and intensive care unit stay (OR 2.48, 95% CI 2.25-2.74, P < 0.0001). A subgroup analysis showed that healthier patients (modified Charlson Comorbidity Index less than 5) who had surgery >48 hours were not at increased risk of mortality.

Conclusions: For elderly patients with hip fractures, delaying surgery for more than 48 hours may be associated with increased short-term morbidity and mortality. This association may be pronounced for patients with more medical comorbidities.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.1097/BOT.0000000000002075DOI Listing
October 2021

Cognitive Training in Orthopaedic Surgery.

J Am Acad Orthop Surg Glob Res Rev 2021 03 10;5(3). Epub 2021 Mar 10.

From the Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, NY.

Introduction: Over the past two decades, various factors have led to fewer opportunities for hands-on learning in the operating room among orthopaedic surgery trainees. Innovative training platforms using anatomic models, cadaveric specimens, and augmented reality have been devised to address this deficiency in surgical training, but such training tools are often costly with limited accessibility. Cognitive training is a low-cost training technique that improves physical performance by refining the way in which information is mentally processed and has long been used by professional athletes and world-class musicians. More recently, cognitive training tools have been developed for several orthopaedic surgery procedures, but the overall utility of cognitive training in orthopaedic surgery remains unknown.

Methods: The purpose of this study was to review the existing literature regarding the use of cognitive training in orthopaedic surgery and to summarize the results of investigations comparing cognitive training tools with other methods of learning. To that effect, the PubMed and Embase databases were systematically reviewed for articles related to cognitive training in orthopaedic surgery.

Results: Eleven publications met the inclusion criteria, including six randomized controlled trials. Cognitive task analysis and mental rehearsal were the most common forms of cognitive training identified. All 11 publications supported the use of cognitive training in orthopaedic surgery training. In the six randomized controlled trials, the utilization of cognitive training was associated with notably improved surgical performance and increased knowledge compared with traditional methods of learning.

Discussion: Based on the limited evidence presented in this review, cognitive training represents a promising, low-cost adjunct to traditional orthopaedic surgery training. Further efforts should be directed at developing and evaluating additional cognitive training tools for orthopaedic surgery trainees.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-21-00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954369PMC
March 2021

Is Required for the Migration and Survival of a Subpopulation of Trigeminal Cranial Neural Crest Cells.

J Dev Biol 2020 Dec 11;8(4). Epub 2020 Dec 11.

Division of Sciences and Mathematics, University of the District of Columbia, Washington, DC 20008, USA.

The development of key structures within the mature vertebrate hindbrain requires the migration of neural crest (NC) cells and motor neurons to their appropriate target sites. Functional analyses in multiple species have revealed a requirement for the transcription factor gastrulation-brain-homeobox 2 (Gbx2) in NC cell migration and positioning of motor neurons in the developing hindbrain. In addition, loss of function studies in mutant mouse embryos, , demonstrate a requirement for for the development of NC-derived sensory neurons and axons constituting the mandibular branch of the trigeminal nerve (CNV). Our recent GBX2 target gene identification study identified multiple genes required for the migration and survival of NC cells (e.g., ). In this report, we performed loss-of-function analyses using mutant embryos, to improve our understanding of the molecular and genetic mechanisms regulated by during anterior hindbrain and CNV development. Analysis of expression in the hindbrain of homozygotes revealed a severely truncated rhombomere (r)2. Our data also provide evidence demonstrating a requirement for in the temporal regulation of expression in r3. Lastly, we show that is required for the expression of in a subpopulation of trigeminal NC cells, and correct migration and survival of cranial NC cells that populate the trigeminal ganglion. Taken together, these findings provide additional insight into molecular and genetic mechanisms regulated by that underlie NC migration, trigeminal ganglion assembly, and, more broadly, anterior hindbrain development.
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http://dx.doi.org/10.3390/jdb8040033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768483PMC
December 2020

Inter- and Intraobserver Reliability Between Orthopaedic Surgeons for Reparability of the Anterior Cruciate Ligament Using MRI.

Orthop J Sports Med 2020 Nov 19;8(11):2325967120964608. Epub 2020 Nov 19.

Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, New York, USA.

Background: Anterior cruciate ligament (ACL) reconstruction is the standard of care for patients after an ACL tear, as poor historical outcomes were observed after primary ACL repair. Certain subgroups of patients, however, have been shown to have outcomes equivalent to reconstruction after undergoing ACL repair and therefore may benefit from the potential advantages offered by avoiding reconstruction. It is important to accurately and consistently identify and indicate these candidates for ACL repair.

Purpose/hypothesis: The purpose of this study was to determine the inter- and intraobserver reliability of magnetic resonance imaging (MRI) evaluation for the reparability of ACL tears and to identify imaging factors that may lead to surgeon uncertainty or disagreement in decision making. Our hypothesis was that the orthopaedic surgeons surveyed would not be able to reliably agree on the reparability of an ACL using MRI scans alone.

Study Design: Cohort study (diagnosis); Level of evidence, 3.

Methods: We administered 2 surveys to 6 fellowship-trained orthopaedic sports medicine surgeons. Each surgeon reviewed preoperative MRI scans for 20 patients and answered a series of questions, ultimately determining whether they would choose an ACL reconstruction or repair for the patient based on the imaging alone. The same survey was repeated 6 weeks later. Kappa values for inter- and intraobserver reliability of their decision making were then calculated.

Results: The average kappa for interobserver reliability in the 2 surveys was 0.22, and the average kappa for intraobserver reliability was 0.34. Interobserver reliability among the surgeons in this group was poor to moderate; intraobserver reliability was slightly better. The choice for ACL repair was significantly correlated with proximal tear locations ( = 0.854; < .001), good-quality ACL tissue remnant ( = 0.929; < .001), and how many surgeons believed that the tear only involved a single bundle ( = 0.590; = .006).

Conclusion: The surgeons surveyed in this study did not consistently agree on candidates for ACL repair using MRI alone.
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http://dx.doi.org/10.1177/2325967120964608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686628PMC
November 2020

maintains levels critical for normal somite segmentation clock function.

Elife 2020 11 19;9. Epub 2020 Nov 19.

Genetics of Vertebrate Development Section, Cancer and Developmental Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, United States.

During vertebrate development, the presomitic mesoderm (PSM) periodically segments into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. Here, we examined mouse mutants lacking only or , which we previously demonstrated act redundantly to prevent PSM differentiation. is not required for somitogenesis, but mutants display a range of vertebral defects. We analyzed mutants by quantifying mRNAs fluorescently labeled by hybridization chain reaction within Imaris-based volumetric tissue subsets. These data indicate that FGF4 maintains levels and normal oscillatory patterns. To support our hypothesis that FGF4 regulates somitogenesis through , we demonstrate genetic synergy between and , but not with . Our data indicate that is potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations.
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http://dx.doi.org/10.7554/eLife.55608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717904PMC
November 2020

C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development.

Biomed Pharmacother 2020 Dec 28;132:110856. Epub 2020 Oct 28.

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, 200080, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, 200080, China; National Clinical Research Center for Eye Diseases, Shanghai, 20080, China; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 20080, China. Electronic address:

Purpose: The incidence of retinopathy of prematurity (ROP) has increased continuously in recent years. However, the therapeutic effects of current treatments still remain undesired. This study aims to investigate the role of C-CBL in retinal angiogenesis in ROP and its potential as a therapeutic target.

Methods: Mouse retina microvascular endothelial cells (mRMECs) and induced experimental ROP/ oxygen-induced retinopathy (OIR) mice were employed to investigate the role of C-CBL in angiogenesis with combined molecular and cellular approaches, and histopathology methods. OIR mouse pups at postnatal day 12 (P12) were either injected intravitreally with adenovirus overexpressing c-Cbl or c-Cbl siRNA. Retinal neovascularization and avascular status were evaluated by retinal immunofluorescence (IF) staining, whole-mounts and hematoxylin and eosin (H&E) staining.

Results: C-CBL inhibits neovascularization by negatively regulating JAK2/STAT3/VEGF signaling axis in a ubiquitination-dependent manner. Knockdown of c-Cbl by siRNA reduced ubiquitin-mediated JAK2 degradation and increased levels of p-JAK2, p-STAT3, VEGF, and neovascularization in mRMECs, which can be reversed by JAK2 inhibitor treatment. While knockdown of c-Cbl significantly increased neovascular (NV) zone in the retinas, c-Cbl overexpression inhibited neovascularization in the retinal tissues in OIR mice.

Conclusion: We found that C-CBL is required for anti-neovascularization process in ROP development by inhibiting JAK2/STAT3-dependent angiogenesis. Thus, our finding strongly suggest that C-CBL may be a potential novel therapeutic target for treating ROP.
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http://dx.doi.org/10.1016/j.biopha.2020.110856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336301PMC
December 2020

Trends in total shoulder arthroplasty from 2005 to 2018: lower complications rates and shorter lengths of stay despite patients with more comorbidities.

JSES Int 2020 Sep 7;4(3):657-661. Epub 2020 Jun 7.

Department of Orthopaedic Surgery, Columbia University Medical Center, New York, NY, USA.

Background: Total shoulder arthroplasty (TSA) is an increasingly common procedure. This study looked at trends in TSA using a nationwide registry, with a focus on patient demographics, comorbidities, and complications.

Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent TSA from 2005 to 2018. Cohorts were created based on year of surgery: 2005-2010 (N = 1116), 2011-2014 (N = 5920), and 2015-2018 (N = 16,717). Patient demographics, comorbidities, operative time, hospital length of stay, discharge location, and complications within 30 days of surgery were compared between cohorts using bivariate and multivariate analysis.

Results: Bivariate analysis revealed significantly more comorbidities among patients in the 2015-2018 cohort compared with the 2005-2010 cohort, specifically American Society of Anesthesiologist class III or IV (57.0% vs. 44.3%, < .001), morbid obesity (10.8% vs. 7.8%, < .001), diabetes (17.8% vs. 12.1%, < .001), and chronic obstructive pulmonary disease (6.7% vs. 4.1%,  = .003). The use of regional anesthesia has decreased (5.6% in 2005-2010 vs. 2.8% in 2015-2018, < .001), as has operative time (▵: -16 minutes, < .001) and length of stay (▵: -0.6 days, < .001). There were also significant decreased rates of perioperative blood transfusion (OR [odds ratio], 0.46), non-home discharge (OR, 0.79), urinary tract infection (OR, 0.47), and sepsis (OR, 0.17), ( < .001 for all comparisons) between the 2005-2010 and 2015-2018 cohorts.

Conclusions: Between 2005 and 2018, patients undergoing TSA had increasingly more comorbidities but experienced lower rates of short-term complications, in the context of shorter hospitalizations and more frequent discharge to home.
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http://dx.doi.org/10.1016/j.jseint.2020.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479025PMC
September 2020

The Fgf8 subfamily (Fgf8, Fgf17 and Fgf18) is required for closure of the embryonic ventral body wall.

Development 2020 10 19;147(21). Epub 2020 Oct 19.

Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA

The closure of the embryonic ventral body wall in amniotes is an important morphogenetic event and is essential for life. Defects in human ventral wall closure are a major class of birth defect and a significant health burden. Despite this, very little is understood about how the ventral body wall is formed. Here, we show that fibroblast growth factor (FGF) ligands FGF8, FGF17 and FGF18 are essential for this process. Conditional mouse mutants for these genes display subtle migratory defects in the abdominal muscles of the ventral body wall and an enlarged umbilical ring, through which the internal organs are extruded. By refining where and when these genes are required using different Cre lines, we show that and are required in the presomitic mesoderm, whereas is required in the somites. This study identifies complex and multifactorial origins of ventral wall defects and has important implications for understanding their origins during embryonic development.
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http://dx.doi.org/10.1242/dev.189506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595690PMC
October 2020

Team Approach: Developmental Dysplasia of the Hip.

JBJS Rev 2020 09;8(9):e20.00030

Division of Orthopedic Surgery, Albany Medical Center, Albany, New York.

Developmental dysplasia of the hip (DDH) encompasses a wide spectrum of hip disorders, including neonatal instability, acetabular dysplasia, hip subluxation, and frank dislocation of the hip. It is a common disorder, with a reported incidence of between 0.1% and >10% of live births. Coordinated, interdisciplinary care is important to achieving successful outcomes. This starts with accurate assessment of risk factors in the prenatal period, thorough clinical examination by the primary care provider at all well-child visits, and early referral to a pediatric orthopaedic surgeon for prompt diagnosis and treatment. Early diagnosis and prompt treatment is critical for an excellent outcome. Ongoing, open communication between clinicians is essential for the effective coordination of care. Treatment options vary depending on the age of presentation. A Pavlik harness (dynamic hip abduction orthosis) is used for children up to 6 months of age. A more rigid abduction orthosis may be used if treatment with a Pavlik harness is unsuccessful, with a closed reduction and spica cast being the next step if needed for children up to 18 months of age. Finally, open reduction with possible concomitant femoral and/or pelvic osteotomies is the surgical option in an older child, when necessary. In general, the later the child is diagnosed with and treated for DDH, the greater the risk of a nonoptimal outcome. Depending on the severity of the condition, children with DDH may need to be followed closely until skeletal maturity so as not to miss the diagnosis of asymptomatic residual hip dysplasia, which can predispose patients to early hip arthritis.
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http://dx.doi.org/10.2106/JBJS.RVW.20.00030DOI Listing
September 2020

Recent trends in Medicare utilization and surgeon reimbursement for shoulder arthroplasty.

J Shoulder Elbow Surg 2021 Jan 9;30(1):120-126. Epub 2020 Jun 9.

Department of Orthopedic Surgery, Columbia University Irving Medical Center, New York, NY, USA.

Background: Recent efforts to contain health care costs and move toward value-based health care have intensified, with a continued focus on Medicare expenditures, especially for high-volume procedures. As total shoulder arthroplasty (TSA) volume continues to increase, especially within the Medicare population, it is important for orthopedic surgeons to understand recent trends in the allocation of health care expenditures and potential effects on reimbursements. The purpose of this study was to evaluate trends in annual Medicare utilization and provider reimbursement rates for shoulder arthroplasty procedures between 2012 and 2017.

Methods: This study tracked annual Medicare claims and payments to shoulder arthroplasty surgeons via publicly available databases and aggregated data at the county level. Descriptive statistics were used to evaluate trends in procedure volume, utilization rate (per 10,000 Medicare beneficiaries), and reimbursement rate. We used adjusted multiple linear regression models to examine associations between county-specific variables (ie, urban or rural, average household income, poverty rate, percentage Medicare population, and race and ethnicity demographics) and procedure volume, utilization rate, and reimbursement rate.

Results: Between 2012 and 2017, there was an 81.3% increase in primary TSA volume and 55.5% increase in primary TSA utilization. The Midwest and South had higher utilization rates than the Northeast and West (P < .001). TSA utilization rates in metropolitan areas were significantly higher than in rural areas (P < .001). Utilization rates for primary TSA procedures also had a significant negative association with poverty rate (P < .001). Regarding reimbursements, the Medicare payment per TSA case decreased from 2012 to 2017, with overall inflation-adjusted decreases of 7.1% and 11.8% for primary and revision cases, respectively. TSAs performed in metropolitan areas received significantly higher reimbursements per case than TSAs performed in rural areas ($1108.05 and $1066.40, respectively; P = .002). Furthermore, reimbursements per case were on average higher in the Northeast and West than in the South and Midwest (P < .001).

Conclusions: Our study confirms that although TSA volume and per capita utilization have increased dramatically since 2012, Medicare Part B reimbursements to surgeons have continued to fall even after the adoption of bundled-payment models for orthopedic procedures. Cost-containment efforts continue to focus on Medicare reimbursements to surgeons, although other expenditures such as hospital payments and operational and implant costs must also be evaluated as part of an overall transition to value-based health care.
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http://dx.doi.org/10.1016/j.jse.2020.04.030DOI Listing
January 2021

Orthopaedic Surgery Elicits a Systemic Anti-Inflammatory Signature.

J Clin Med 2020 Jul 6;9(7). Epub 2020 Jul 6.

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Little information is available on the functional activity of leukocytes after arthroplasty or the expansion of populations with immune suppressive properties during the acute post-operative period. Synovial fluid and matched pre- and post-surgical blood samples were collected from total hip and knee arthroplasty patients (THA and TKA, respectively) to examine the impact of surgery on peripheral blood leukocyte frequency, bactericidal activity, and inflammatory mediator expression. For spinal surgeries, inflammatory mediator production by peripheral blood mononuclear cells (PBMCs) pre- and post-surgery was examined. An expansion of immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) was observed following arthroplasty, which correlated with significantly increased serum interleukin-10 (IL-10) levels. Analysis of synovial fluid from THA and TKAs revealed reduced granulocyte colony-stimulating factor (G-CSF) and soluble CD40 ligand (sCD40L) and increased interleukin-6 (IL-6), monocyte chemoattractant protein 2 (CCL2) and Fms-like tyrosine kinase 3 ligand (Flt-3L) compared to pre- and post-surgical serum. For the spinal surgery cohort, stimulation of PBMCs isolated post-surgery with bacterial antigens produced significantly less pro-inflammatory (IL-1α, IL-1β, interleukin-1 receptor antagonist (IL-1RA), IL-12p40, growth-related oncogene-α/GRO-α (CXCL1) and 6Ckine (CCL21)) and more anti-inflammatory/tissue repair mediators (IL-10, G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)) compared to PBMCs recovered before surgery. The observed bias towards systemic anti-inflammatory changes without concomitant increases in pro-inflammatory responses may influence susceptibility to infection following orthopaedic surgery in the context of underlying co-morbidities or risk factors.
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http://dx.doi.org/10.3390/jcm9072123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408679PMC
July 2020

Proximo-distal positional information encoded by an Fgf-regulated gradient of homeodomain transcription factors in the vertebrate limb.

Sci Adv 2020 Jun 3;6(23):eaaz0742. Epub 2020 Jun 3.

Cardiovascular Development Program, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain.

The positional information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern. During development, morphogens and interpreter transcription factors provide this information. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal fibroblast growth factor (FGF). Elimination of Meis results in premature limb distalization and HoxA expression, proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.
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http://dx.doi.org/10.1126/sciadv.aaz0742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269661PMC
June 2020

Coordinated directional outgrowth and pattern formation by integration of Wnt5a and Fgf signaling in planar cell polarity.

Development 2018 04 13;145(8). Epub 2018 Apr 13.

Developmental Genetics Section, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA

Embryonic morphogenesis of a complex organism requires proper regulation of patterning and directional growth. Planar cell polarity (PCP) signaling is emerging as a crucial evolutionarily conserved mechanism whereby directional information is conveyed. PCP is thought to be established by global cues, and recent studies have revealed an instructive role of a Wnt signaling gradient in epithelial tissues of both invertebrates and vertebrates. However, it remains unclear whether Wnt/PCP signaling is regulated in a coordinated manner with embryonic patterning during morphogenesis. Here, in mouse developing limbs, we find that apical ectoderm ridge-derived Fgfs required for limb patterning regulate PCP along the proximal-distal axis in a Wnt5a-dependent manner. We demonstrate with genetic evidence that the Wnt5a gradient acts as a global cue that is instructive in establishing PCP in the limb mesenchyme, and that Wnt5a also plays a permissive role to allow Fgf signaling to orient PCP. Our results indicate that limb morphogenesis is regulated by coordination of directional growth and patterning through integration of Wnt5a and Fgf signaling.
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http://dx.doi.org/10.1242/dev.163824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964654PMC
April 2018

Lateral asymmetry in the freely occurring behaviour of budgerigars (Melopsittacus undulatus) and its relation to cognitive performance.

Laterality 2018 May 22;23(3):344-363. Epub 2017 Aug 22.

a Department of Psychology , Saint Joseph's University , Philadelphia , PA , USA.

Hemispheric laterality and its provision of potential fitness advantages to aves is a widespread topic of research in budgerigars and other parrot species [e.g., Magat, M. & Brown, C. (2009). Laterality enhances cognition in Australian parrots. Proceedings of the Royal Society B: Biological Sciences, 276, 4155-4162]. In the current study, lateral preferences were tracked for 11 captive-reared budgerigars that subsequently underwent 2 cognitive problem-solving tests: a tool-use problem and a dig-discrimination task. Two significant individual-level lateral preferences (a leftward unipedal support preference and a rightward preening side preference) and 1 significant population-level preference (a right-side preening preference) were obtained. Lateral preening side preference indices for individual subjects correlated with various measures of performance on the dig task, such that right-side preening preferences and stronger lateral preferences irrespective of direction were associated with enhanced dig task performance. The data generally support the idea that laterality in aves serves as a good predictor of increased cognitive capability, while also offering new evidence for population-level lateral preferences in the species.
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http://dx.doi.org/10.1080/1357650X.2017.1361964DOI Listing
May 2018

Do small changes in rotation affect measurements of lower extremity limb alignment?

J Orthop Surg Res 2017 May 22;12(1):77. Epub 2017 May 22.

Sutter Institute for Medical Research, 2801 Capitol Ave Suite 400, Sacramento, 95816, USA.

Background: The alignment of the lower extremity has important implications in the development of knee arthritis. The effect of incremental rotations of the limb on common parameters of alignment has not been studied. The purpose of the study was to (1) determine the standardized neutral position measurements of alignment and (2) determine the effect of rotation on commonly used measurements of alignment.

Methods: Eighty-seven full length CT angiography studies (49 males and 38 females, average age 66 years old) were included. Three-dimensional models were created using a rendering software program and placed on a virtual plane. An image of the extremity was obtained. Thirty scans were randomly selected, and those models were rotated in 3° intervals around the longitudinal axis and additional images were obtained.

Results: In the neutral position, the mechanical lateral distal femoral articular angle (mLDFA) was 85.6 ± 2.3°, medial proximal tibial angle (MPTA) was 86.1 ± 2.8°, and mechanical tibiofemoral angle (mTFA) was -0.7 ± 3.1°. Females had a more valgus alignment with a mTFA of 0.5 ± 2.9° while males had a more varus alignment with a mTFA of -1.7 ± 2.9°. The anatomic tibiofemoral angle (aTFA) was 4.8 ± 2.6°, the anatomic lateral distal femoral angle (aLDFA) measured 80.2 ± 2.2°, and the anatomical-mechanical angle (AMA) was 5.4 ± 0.7°. The prevalence of constitutional varus was 18%. The effect of rotation on the rotated scans led to statistically significant differences relative to the 0° measurement for all measurements. These effects may be small, and their clinical importance is unknown.

Conclusions: This study provides new information on standardized measures of lower extremity alignment and the relationship between discreet axial rotations of the entire lower extremity and these parameters.
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http://dx.doi.org/10.1186/s13018-017-0571-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441094PMC
May 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Personality types in Budgerigars, Melopsittacus undulatus.

Behav Processes 2017 May 11;138:34-40. Epub 2017 Feb 11.

Saint Joseph's University, Department of Psychology, 5600 City Ave., Philadelphia, PA, 19131, USA. Electronic address:

The current study further characterized personality types in Budgerigars, an avian model that only recently demonstrated individual consistencies in behavior (Callicrate et al., 2011). Several methodological techniques, commonly used in previous examinations of other animal models, were employed. Specifically, Phase I assessed the relationship between Budgerigar personality types and Hypothalamic-Pituitary-Adrenal (HPA) activity, while Phase II sought to examine the persistence of individual behavioral tendencies across varying testing contexts. In comparison to other species, our findings failed to illustrate a clear relationship between Budgerigar personality types and concentrations of corticosterone. However, results provided significant evidence for the consistency of personalities across multiple contexts. In sum, our investigation further defined the expression of personality in the Budgerigar and substantiated the claim for individual tendencies in this species.
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http://dx.doi.org/10.1016/j.beproc.2017.02.003DOI Listing
May 2017

Budgie in the mirror: An exploratory analysis of social behaviors and mirror use in the Budgerigar (Melopsittacus undulatus).

Behav Processes 2017 Feb 2;135:66-70. Epub 2016 Dec 2.

Saint Joseph's University, Department of Psychology, 5600 City Ave., Philadelphia, PA 19131, USA. Electronic address:

Despite their prevalent use amongst avian species, particularly in Budgerigars, the relationship between mirror use and social behaviors is in need of elucidation. After establishing social behavior measures (e.g., agonistic and pair-bond data) in a colony of Budgerigars, mirrors were introduced and subsequent use was documented. Results illustrated a significant relationship between mirror use and pair-bonds, such that mirror use increased with increasing pair-bond strength. The authors posit that individual differences in gregariousness may best account for the obtained results, with certain birds seeking more social stimulation than others, whether it be from a pair-bond or from its own reflected mirror image. Additionally, the trends observed within agonistic behaviors were consistent with previous avian literature such that those who initiated more encounters also won more encounters and that there was a preference to be closer to birds that win more encounters.
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http://dx.doi.org/10.1016/j.beproc.2016.11.015DOI Listing
February 2017

An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension.

PLoS Genet 2016 05 4;12(5):e1006018. Epub 2016 May 4.

Genetics of Vertebrate Development Section, Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States of America.

During vertebrate axis extension, adjacent tissue layers undergo profound morphological changes: within the neuroepithelium, neural tube closure and neural crest formation are occurring, while within the paraxial mesoderm somites are segmenting from the presomitic mesoderm (PSM). Little is known about the signals between these tissues that regulate their coordinated morphogenesis. Here, we analyze the posterior axis truncation of mouse Fgf3 null homozygotes and demonstrate that the earliest role of PSM-derived FGF3 is to regulate BMP signals in the adjacent neuroepithelium. FGF3 loss causes elevated BMP signals leading to increased neuroepithelium proliferation, delay in neural tube closure and premature neural crest specification. We demonstrate that elevated BMP4 depletes PSM progenitors in vitro, phenocopying the Fgf3 mutant, suggesting that excessive BMP signals cause the Fgf3 axis defect. To test this in vivo we increased BMP signaling in Fgf3 mutants by removing one copy of Noggin, which encodes a BMP antagonist. In such mutants, all parameters of the Fgf3 phenotype were exacerbated: neural tube closure delay, premature neural crest specification, and premature axis termination. Conversely, genetically decreasing BMP signaling in Fgf3 mutants, via loss of BMP receptor activity, alleviates morphological defects. Aberrant apoptosis is observed in the Fgf3 mutant tailbud. However, we demonstrate that cell death does not cause the Fgf3 phenotype: blocking apoptosis via deletion of pro-apoptotic genes surprisingly increases all Fgf3 defects including causing spina bifida. We demonstrate that this counterintuitive consequence of blocking apoptosis is caused by the increased survival of BMP-producing cells in the neuroepithelium. Thus, we show that FGF3 in the caudal vertebrate embryo regulates BMP signaling in the neuroepithelium, which in turn regulates neural tube closure, neural crest specification and axis termination. Uncovering this FGF3-BMP signaling axis is a major advance toward understanding how these tissue layers interact during axis extension with important implications in human disease.
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http://dx.doi.org/10.1371/journal.pgen.1006018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856314PMC
May 2016

Osteophyte formation after ACL rupture in mice is associated with joint restabilization and loss of range of motion.

J Orthop Res 2017 03 13;35(3):466-473. Epub 2016 Apr 13.

Biomedical Engineering Graduate Group, University of California-Davis, Davis, California.

Osteophytes are a typical radiographic finding during osteoarthritis (OA). Osteophytes are thought to form in response to joint instability; however, the time course of osteophyte formation and joint stabilization following joint injury is not well understood. In this study, we investigated the time course of osteophyte formation and joint function following non-invasive knee injury in mice. We hypothesized that initial joint instability following knee injury would initiate osteophyte formation, which would in turn restabilize the joint and reduce range of motion (ROM). Mice were subjected to non-invasive anterior cruciate ligament (ACL) rupture. Anterior-posterior (AP) joint laxity, ROM, and chondro/osteophyte formation were measured immediately after injury, and 2, 4, 6, and 8 weeks post-injury. Chondrophyte areas at each time point were measured with histology, while mineralized osteophyte volume was determined using micro-computed tomography. Immediately after ACL rupture, AP joint laxity was increased twofold, while ROM was increased 11.7%. Chondrophytes appeared by 2 weeks post-injury, corresponding with a decrease in AP joint laxity and ROM. By 8 weeks post-injury, considerable osteophyte formation was observed around the joint, AP joint laxity returned to control levels, and joint ROM decreased to 61% of control values. These data support a role for chondro/osteophytes in joint restabilization after injury, and provide crucial insight into the time course and pathology of joint degeneration during OA development in the mouse. Statement of Clinical Significance: Results from this study increase understanding of conditions leading to osteophyte formation.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:466-473, 2017.
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http://dx.doi.org/10.1002/jor.23252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603200PMC
March 2017

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

BMPs are direct triggers of interdigital programmed cell death.

Dev Biol 2016 Mar 27;411(2):266-276. Epub 2016 Jan 27.

Genetics of Vertebrate Development Section, Cancer and Developmental Biology Lab, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. Electronic address:

During vertebrate embryogenesis the interdigital mesenchyme is removed by programmed cell death (PCD), except in species with webbed limbs. Although bone morphogenetic proteins (BMPs) have long been known to be players in this process, it is unclear if they play a direct role in the interdigital mesenchyme or if they only act indirectly, by affecting fibroblast growth factor (FGF) signaling. A series of genetic studies have shown that BMPs act indirectly by regulating the withdrawal of FGF activity from the apical ectodermal ridge (AER); this FGF activity acts as a cell survival factor for the underlying mesenchyme. Other studies using exogenous factors to inhibit BMP activity in explanted mouse limbs suggest that BMPs do not act directly in the mesenchyme. To address the question of whether BMPs act directly, we used an interdigit-specific Cre line to inactivate several genes that encode components of the BMP signaling pathway, without perturbing the normal downregulation of AER-FGF activity. Of three Bmps expressed in the interdigital mesenchyme, Bmp7 is necessary for PCD, but Bmp2 and Bmp4 both have redundant roles, with Bmp2 being the more prominent player. Removing BMP signals to the interdigit by deleting the receptor gene, Bmpr1a, causes a loss of PCD and syndactyly, thereby unequivocally proving that BMPs are direct triggers of PCD in this tissue. We present a model in which two events must occur for normal interdigital PCD: the presence of a BMP death trigger and the absence of an FGF survival activity. We demonstrate that neither event is required for formation of the interdigital vasculature, which is necessary for PCD. However, both events converge on the production of reactive oxygen species that activate PCD.
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http://dx.doi.org/10.1016/j.ydbio.2015.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028150PMC
March 2016

Contribution of mechanical unloading to trabecular bone loss following non-invasive knee injury in mice.

J Orthop Res 2016 10 10;34(10):1680-1687. Epub 2016 Feb 10.

Department of Orthopaedic Surgery, University of California-Davis Medical Center, 4635 2nd Ave, Suite 2000, Sacramento, California, 95817.

Development of osteoarthritis commonly involves degeneration of epiphyseal trabecular bone. In previous studies, we observed 30-44% loss of epiphyseal trabecular bone (BV/TV) from the distal femur within 1 week following non-invasive knee injury in mice. Mechanical unloading (disuse) may contribute to this bone loss; however, it is unclear to what extent the injured limb is unloaded following injury, and whether disuse can fully account for the observed magnitude of bone loss. In this study, we investigated the contribution of mechanical unloading to trabecular bone changes observed following non-invasive knee injury in mice (female C57BL/6N). We investigated changes in gait during treadmill walking, and changes in voluntary activity level using Open Field analysis at 4, 14, 28, and 42 days post-injury. We also quantified epiphyseal trabecular bone using μCT and weighed lower-limb muscles to quantify atrophy following knee injury in both ground control and hindlimb unloaded (HLU) mice. Gait analysis revealed a slightly altered stride pattern in the injured limb, with a decreased stance phase and increased swing phase. However, Open Field analysis revealed no differences in voluntary movement between injured and sham mice at any time point. Both knee injury and HLU resulted in comparable magnitudes of trabecular bone loss; however, HLU resulted in considerably more muscle loss than knee injury, suggesting another mechanism contributing to bone loss following injury. Altogether, these data suggest that mechanical unloading likely contributes to trabecular bone loss following non-invasive knee injury, but the magnitude of this bone loss cannot be fully explained by disuse. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1680-1687, 2016.
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http://dx.doi.org/10.1002/jor.23178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603199PMC
October 2016
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