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Objective To assess the long-term prevalence, natural history, progression, and incidence of radiographic first metatarsophalangeal (MTP) joint osteoarthritis (OA). Methods A longitudinal cohort design was used in which radiographic OA at the first MTP joint was investigated in participants from the Chingford 1,000 Women Study at year 6 (1995) and year 23 (2013-2015). Radiographic features of osteophytes (OPs) and/or joint space narrowing (JSN) at the first MTP joint were scored according to a validated foot atlas. Natural history was determined by the change in prevalence, incidence, progression, and worsening of OA in the first MTP joint. Results Complete case-matched foot radiographic data were available for 193 of the women currently enrolled in the study (mean ± SD age 75.7 ± 5.2 years [range 69-90 years]). At the level of the first MTP joint, prevalence of OA at year 6 was 21.76% in the left and 24.35% in the right; at year 23, it was 23.83% in the left and 32.64% in the right. Over the 19-year period, 13.5% of the women developed incident OA in the right first MTP joint and 8.3% in the left. Both progression and worsening of OA were more evident for OPs and in the right first MTP joints. Conclusion In this study of the natural history of radiographic first MTP joint OA, which to our knowledge is the longest study to date, the prevalence and incidence of first MTP joint OA increased over a 19-year period. Progression and/or worsening of OA at the first MTP joint over time appears to be driven by OP development rather than JSN, which suggests a biomechanical cause.

Animal models recapitulating features of chronic colitis, such as ulcerative colitis, Crohn’s disease, or HIV infection, are critical to study disease pathogenesis and test novel therapeutics. In this study, we used a proteomics approach to explore the molecular intestinal response in two rhesus macaque (RM) animal models of experimentally induced colitis using dextran sulfate sodium (DSS) and simian immunodeficiency virus (SIV) infection. Proteomic analysis detected more than 2500 proteins in colonic tissue collected from 30 RMs. Differential protein expression analysis revealed a protein expression pattern in DSS-treated RMs resembling the proteome of human ulcerative colitis. In a group of 12 DSS-treated RMs compared to 6 with no treatment, decrease in expression of proteins related to mitochondrial energy metabolism, including fatty acid metabolism was noted, while innate immune activation pathways, including complement and coagulation proteins were upregulated. SIV infection of RMs resulted in increased innate immune responses related to viral defense. Proteomic signatures of barrier damage were apparent in both DSS treatment or SIV infection. These results demonstrate that DSS treatment in a non-human primate model resembles features of human ulcerative colitis, making this a promising tool to study important immunological mechanisms in inflammatory bowel disease.

Vaccination and administration of monoclonal antibody cocktails are effective tools to control the progression of infectious diseases and to terminate pandemics such as COVID-19. However, the emergence of SARS-CoV-2 mutants with enhanced transmissibility and altered antigenicity requires broad-spectrum therapies. Here we developed a panel of SARS-CoV-2 specific mouse monoclonal antibodies (mAbs), and characterized them based on ELISA, Western immunoblot, isotyping, and virus neutralization. Six neutralizing mAbs that exhibited high-affinity binding to SARS-CoV-2 spike protein were identified, and their amino acid sequences were determined by mass spectrometry. Functional assays confirmed that three mAbs, F461G11, F461G15, and F461G16 neutralized four variants of concern (VOC): B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.2 (delta) These mAbs are promising candidates for COVID-19 therapy, and understanding their interactions with virus spike protein should support further vaccine and antibody development.

All cellular functions, ranging from regular cell maintenance and homeostasis, specialized functions specific to cellular types, or generating responses due to external stimulus, are mediated by proteins within the cell. Regulation of these proteins allows the cell to alter its behavior under different circumstances. A major mechanism of protein regulation is utilizing protein kinases and phosphatases; enzymes that catalyze the transfer of phosphates between substrates [1]. Proteins involved in phosphate signaling are well studied and include kinases and phosphatases that catalyze opposing reactions regulating both structure and function of the cell. Kinomics is the study of kinases, phosphatases and their targets, and has been used to study the functional changes in numerous diseases and infectious diseases with aims to delineate the cellular functions affected. Identifying the phosphate signaling pathways changed by certain diseases or infections can lead to novel therapeutic targets. However, a daunting 518 putative protein kinase genes have been identified [2], indicating that this protein family is very large and complex. Identifying which enzymes are specific to a particular disease can be a laborious task. In this review, we will provide information on large-scale systems biology methodologies that allow global screening of the kinome to more efficiently identify which kinase pathways are pertinent for further study.

Background: The prevalence of foot osteoarthritis (OA) is much less understood than hip, knee and hand OA. The foot is anatomically complex and different researchers have investigated different joints with lack of methodological standardisation across studies. The La Trobe Foot Atlas (LFA) is the first to address these issues in providing quantitative assessment of radiographic foot OA, but has not been tested externally. The aim of this study was to evaluate three different interpretive approaches to using the LFA for grading OA when scoring is difficult due to indistinct views of interosseous space and joint contour.Methods: Foot radiographs of all remaining participants (n=18) assessed in the Chingford Women Study 23year visit (mean (SD) for age: 75.5years (5.1)) were scored using the LFA defined protocol (Technique 1). Two revised scoring strategies were applied to the radiographs in addition to the standard LFA analyses. Technique 2 categorised joints that were difficult to grade as 'missing'. Technique 3 included joints that were difficult to grade as an over estimated score. Radiographic OA prevalence was defined for the foot both collectively and separately for individual joints.Results: When radiographs were scored using the LFA (Technique 1), radiographic foot OA was present in 89.9%. For Technique 2 the presence of radiographic foot OA was 83.5% and for Technique 3 it was 97.2%. At the individual joint level, using Technique 1, the presence of radiographic foot OA was higher with a wider range (18.3-74.3%) than Technique 2 (17.9-46.3%) and lower with a wider range (18.3-74.3%) than Technique 3 (39.9-79.4%).Conclusion: The three different ways of interpreting the LFA scoring system when grading of individual joints is technically difficult and result in very different estimates of foot OA prevalence at both the individual joint and global foot level. Agreement on the best strategy is required to improve comparability between studies.

Background: Ulnar collateral ligament (UCL) reconstruction of the elbow has become increasingly more frequent among elite overhead athletes. The purpose of this study was to conduct a systematic review comparing the clinical outcomes and biomechanical results of the Jobe, modified Jobe, docking, modified docking, Endobutton, and interference screw techniques for UCL reconstruction. Hypothesis: The docking technique will have significantly fewer complications and improved return-to-play rate. Study Design: Systematic review; Level of evidence, 4. Methods: Using the Medline PubMed, Cochrane, and EMBASE databases, a search was performed of all published articles, including randomized controlled trials, cohort studies, and case series, examining UCL reconstructions performed using one of the above noted techniques and excluding case reports and hybrid techniques. Statistical analysis was performed using a χ2 test of independence and 2-proportion Z test. Results: A total of 21 studies, 7 biomechanical and 14 clinical, met the inclusion criteria. There were 1368 patients. The overall complication rate was 18.6% (255/1368), further subdivided into 21 for the Jobe technique (29.2%), 203 for the modified Jobe technique (19.1%), 2 for the interference screw technique (10.0%), 2 (4.3%) for the modified docking technique, and 10 for the docking technique (6.0%). The most common complication across all studies was ulnar nerve neurapraxia in 176 patients (12.9%). The overall rate of return to play was 78.9%. Conclusion: Ulnar collateral ligament reconstruction utilizing the docking technique results in a significantly higher rate of return to play and a lower complication rate when compared with the Jobe and modified Jobe techniques. Clinical Relevance: A lower complication rate can lead to increased rates of return to play and better outcomes postoperatively.

Anterior cruciate ligament (ACL) reconstruction is one of the most extensively studied surgical procedures in orthopaedics. The importance of this ligament for knee function and stability has been widely studied. For athletes who participate in activities involving cutting, twisting, and running, surgical reconstruction of the ACL has become the standard of care. However, there is much debate regarding the techniques involved in ACL reconstruction, including graft choice, technique of drilling the femoral tunnel, and single- versus double-bundle reconstruction. In recent studies, ACL femoral tunnel drilling via a medial parapatellar or accessory anteromedial portal provides a more anatomic graft placement than transtibial femoral drilling. Long-term outcomes of these techniques have not been widely studied. This article details our technique for ACL reconstruction with bone-patellar tendon-bone autograft and a medial parapatellar portal.

Osteosarcoma is the most common primary bone malignancy, with a high propensity for local invasion, early metastasis and relapse. While the molecular mechanisms behind osteosarcoma development and metastasis have not yet been fully elucidated, research has highlighted an important role for Wnt signaling. Several Wnt ligands, receptors and coreceptors are highly expressed in osteosarcoma cell lines, while Wnt inhibitors are downregulated. As a result, research has begun to identify mechanisms with which to inhibit Wnt signaling. The use of Wnt pathway inhibitors and the targeting of c-Met, a Wnt regulated proto-oncogene, may be two possible mechanisms for treatment of osteosarcoma. In addition, as the Wnt signaling pathway is a regulator of stem cells, reagents that function as Wnt inhibitors are currently under investigation as inhibitors of cancer stem cell proliferation. Research involving the Wnt signaling pathway and cancer stem cells holds promise for novel treatment options in the future.

The mucosal surface of the female genital tract contains physiological, immunological, and microbial components that collectively comprise a functioning "mucosal system" that is critical for reproductive health. Alterations or imbalances to any of these components can have significant consequences for susceptibility to sexually transmitted infections, such as HIV. In recent years the advent of advanced systems biology technologies, such as metaproteomics, has provided new toolsets to studying mucosal systems. Studies have linked an altered mucosal proteome to many HIV risk factors including mucosal inflammation, bacterial vaginosis, hormonal contraceptives, and reduced efficacy of antiretroviral drugs for HIV prevention. Herein we will discuss how metaproteomics has been used to study mucosal system components, including epithelial barriers, inflammation, and the microbiome, with a focus on what alterations may contribute to increased HIV transmission risk in women.

Background: Musculoskeletal (MSK) disease is the major cause of years lived with disability in the UK. The UK is behind other comparable countries in confronting consequences of long-term diseases. One potentially effective approach is by educating people to become more health literate. Early life interventions relating to exercise and good MSK health practices may be an effective addition to traditional approaches. LifeLab is a science-based approach to improving teenagers’ health-related attitudes and behaviour. The LifeLab approach was developed at the University of Southampton and combines educationalists, scientists, clinical researchers and school children and has been effective in improving young peoples’ understanding of the nature of diseases and reasoning about health issues. However, no specific MSK health education components have previously been included in LifeLab. Methods: In 2014 the first MSK LifeLab workshop was designed with educationalists and researchers in biomechanics, occupational therapy, podiatry, and physiotherapy from the MSK Research Cluster at Southampton for year 8 (age 12-13) school students. The workshops aimed to promote young peoples’ health literacy in musculoskeletal health and integrated experiential learning using 3D motion analysis, real-time ultrasound scanning of muscles contracting; radiographs of normal and osteoarthritis foot joints; anatomy models and hand and hip joint implants. The workshops covered a) the impact of osteoarthritis joint disease on daily life b) capturing and illustrating joint movement using state of the art 3D motion analysis technology and c) an in-depth look at muscles using ultrasound imaging. Learning objectives included students being able to: 1. Identify key components of active healthy living for bones, muscles and joints 2. Observe patterns in how healthy joints can move and contrast patterns with injured joint movement 3. Discover what role muscles play in healthy joints 4. Compare healthy joint structures with arthritic joint structures Results: 58 students from 3 state secondary schools, attended a university widening participation outreach day within which the MSK LifeLab workshop was run. On the same day the students also attended workshops in Humanities and Oceanography. When asked which workshop of the outreach day was their favourite 43 % of the students identified the MSK workshops. Feedback on why the workshops were enjoyable included; “I enjoyed biomechanics because I like looking at how things work and move”; “Ostioarphritus. I'm into sports & find the body interesting”; “The bones because you got to find out about the body”. The interactive nature of the workshop with teenagers having hands on learning was also well received “My favourite was bones because they made it fun”; “The bones experiments because the technology involved was awesome.” Conclusions: Using interactive MSK workshops as part of LifeLab presents an exciting health literacy approach to encourage young people to start to engage in understanding their MSK health. Acknowledgements: These are not included in the abstract but will appear if we get a paper accepted. LifeLab, has been developed as a joint initiative, involving, in addition to the University of Southampton and the University Hospital Southampton NHS Foundation Trust; the MRC Lifecourse Epidemiology Unit, the University of Southampton (UoS) Faculty of Medicine and Southampton Education School, the Mathematics and Science Learning Centre (MSLC), the NIHR Southampton Biomedical Research Centre and the Garfield Weston Foundation. KWT is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre Some facilities and personnel in the MSK Research Cluster are funded by Arthritis Research UK.

Background To report a case series of failures of bioabsorbable interference screws with possible identification of a novel failure mechanism. Methods A retrospective review of ACL reconstructions by the senior author utilizing BioComposite™ Interference Screws (Arthrex, Inc., Naples, FL) was performed. Complications related to screw placement, including fracture, breakage or bending were examined. Our rate and methods of failure were compared to those quoted in the current literature. Results Eighty-seven patients of average age 23.8 years met inclusion criteria. There were eight screw failures in six patients, with femoral failure in seven and tibial failure in one. The femoral screw fractured halfway between the tip and head in five, while the head of the screw broke in one and the screw bent in another. In the case of tibial interference screw fracture, failure occurred halfway between the tip and head. The insertion device that was used was replaced after recognition of material deformation and considered a potential contributor to the breakage risk as no further screw failures have occurred since. Conclusions We demonstrate a unique failure mechanism of bio-absorbable interference screws. In each case, the reconstruction was salvaged. Regular inspection of materials and implants can ensure optimal outcomes and decrease complications intra-operatively.

Background Neuropilin 2 (NRP2) isa multi-functional co-receptor to many receptors, including VEGF receptor, c-Met and others. NRP2 has recently been implicated in tumor angiogenesis, growth, and metastasis of many other cancers. However, its role in osteosarcoma remains poorly understood. Results NRP2 was overexpressed in osteosarcoma cell lines and tissues, and associated with poor survival of osteosarcoma patients. Knockdown of NRP2 expression by short-hairpin (Sh) RNA resulted in reduced tumor growth, metastasis, and blood vessel formation of osteosarcoma. Knockdown of NRP2 expression by ShRNA also inhibited the recruitment of HUVEC cells to osteosarcoma cells. Inhibition of Wnt signaling by overexpression of secreted Wnt antagonists soluble LRP5, Frzb, and WIF1 markedly down-regulated mRNA and protein expression of NRP2 in osteosarcoma cell lines. Conclusions Regulation of NRP2 receptor expression may represent a novel approach for treatment of osteosarcoma through retarding osteosarcoma growth, metastasis and blood vessel formation. In addition, down-regulation of NRP2 expression can be achieved by expression of secreted Wnt antagonists. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0359-4) contains supplementary material, which is available to authorized users.

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Usingin vivoandin vitrostudies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector.In vitroexperiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.

Purpose of Study: To investigate the role of the Neuropilin-1 (NRP-1) in angiogenesis and regulation by Wnt-signaling pathway in osteosarcoma (OS) cell lines. Methods: In vitro tube formation assay using HUVEC cells to examine the effect of Frzb, WIF1, and DKK3 on angiogenesis. Microarray and real-time PCR to assess the mRNA level of NRP-1 in SaOS-2 cells transfected with Dominant Negative LRP5 (DNLRP5) and PcDNA vector control. Western blots were performed to evaluate the expression of NRP-1 in 8 OS cell lines and normal osteoblast (NHOst), as well as the effect of Wnt inhibitors (DNLPR5, Frzb, WIF-1, DKK3) on NRP-1 expression in OS cell lines (LM7, 143B, and 143.98.2) Results: In order to develop a new therapeutic target for OS, the most common primary malignant bone tumor, we examined the expression of NRP-1 and vascular endothelial growth factor (VEGF) in 8 established OS cell lines, as well as NHOst. Both VEGF and NRP-1 (a co-receptor of VEGF) were up-regulated in most OS cell lines compared with normal osteoblast, suggesting that VEGF and NRP-1 may be responsible for the excessive blood vessel formation in OS. Given our previous report that Wnt inhibitors Frzb, WIF1, DKK3, and DNLRP5, inhibited tumor growth and metastasis of OS, we hypothesize that one of the potential mechanisms may be through inhibition of tumor angiogenesis. When HUVEC assay was examined, DKK3, Frzb, WIF-1 condition medium significantly inhibited tube formation compared with control, suggesting that these Wnt inhibitors suppressed angiogenesis. Further microarray assay, real time PCR and western blots indicated that these Wnt inhibitors (DKK3, Frzb, WIF-1 and DNLRP5) dramatically down-regulated the expression of NRP-1, but VEGF level remained unchanged. These results show that inhibition of angiogenesis by Wnt signaling may be mediated by down-regulation of NRP-1 instead of VEGF. Discussion and Conclusions: Our study suggests that the Wnt-signaling reduces tumor growth and metastasis by inhibiting angiogenesis and by down-regulating NRP-1 expression in OS. We are further studying the role of NRP-1 in osteosarcoma by knockdown of NRP1 expression in OS cells to assess tumor proliferation, metastases and angiogenesis. This may represent a novel therapeutic strategy for osteosarcoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3963.