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NDORMS alumnus Dr Anand Segar has been awarded the Louis Barnett Prize 2015, presented to a young New Zealand surgeon or surgical trainee with the best research paper at the Royal Australasian College of Surgeons New Zealand Annual Meeting.
Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity
Abstract MCT-1 oncoprotein accelerates p53 degradation by means of the ubiquitin-dependent proteolysis. Our present data show that induction of MCT-1 increases chromosomal translocations and deregulated G2-M checkpoint in response to chemotherapeutic genotoxin. Remarkably, increases in chromosome copy number, multinucleation, and cytokinesis failure are also promoted while MCT-1 is induced in p53-deficient cells. In such a circumstance, the Ras–mitogen-activated protein kinase/extracellular signal-regulated kinase kinase–mitogen-activated protein kinase signaling activity and the expression of metastatic molecules are amplified. Given a p53-silencing background, MCT-1 malignantly transforms normal breast epithelial cells that are satisfactory for stimulating cell migration/adhesion and tumorigenesis. Detailed analyses of MCT-1 oncogenicity in H1299 p53-null lung cancer cells have shown that ectopically expressed MCT-1 advances xenograft tumorigenicity and angiogenesis, which cannot be completely suppressed by induction of p53. MCT-1 counteracts mutually with p53 at transcriptional levels. Clinical validations confirm that MCT-1 mRNA levels are differentially enriched in comparison between human lung cancer and nontumorigenic tissues. The levels of p53 mRNA are comparatively reduced in a subset of cancer specimens, which highly present MCT-1 mRNA. Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development. (Mol Cancer Res 2009;7(4):536–48)
The antagonism between MCT-1 and p53 affects the tumorigenic outcomes
Abstract Background MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes. Results MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation in vivo, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein. Conclusions The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.
Research prioritization in paediatric orthopaedics and the impact on funding
In 2017, the British Society for Children’s Orthopaedic Surgery engaged the profession and all relevant stakeholders in two formal research prioritization processes. In this editorial, we describe the impact of this prioritization on funding, and how research in children’s orthopaedics, which was until very recently a largely unfunded and under-investigated area, is now flourishing. Establishing research priorities was a crucial step in this process.Cite this article: Bone Joint J 2024;106-B(5):422–424.
Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL
Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
Reverse total shoulder replacement versus anatomical total shoulder replacement for osteoarthritis: population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England.
OBJECTIVES: To answer a national research priority by comparing the risk-benefit and costs associated with reverse total shoulder replacement (RTSR) and anatomical total shoulder replacement (TSR) in patients having elective primary shoulder replacement for osteoarthritis. DESIGN: Population based cohort study using data from the National Joint Registry and Hospital Episode Statistics for England. SETTING: Public hospitals and publicly funded procedures at private hospitals in England, 2012-20. PARTICIPANTS: Adults aged 60 years or older who underwent RTSR or TSR for osteoarthritis with intact rotator cuff tendons. Patients were identified from the National Joint Registry and linked to NHS Hospital Episode Statistics and civil registration mortality data. Propensity score matching and inverse probability of treatment weighting were used to balance the study groups. MAIN OUTCOME MEASURES: The main outcome measure was revision surgery. Secondary outcome measures included serious adverse events within 90 days, reoperations within 12 months, prolonged hospital stay (more than three nights), change in Oxford Shoulder Score (preoperative to six month postoperative), and lifetime costs to the healthcare service. RESULTS: The propensity score matched population comprised 7124 RTSR or TSR procedures (126 were revised), and the inverse probability of treatment weighted population comprised 12 968 procedures (294 were revised) with a maximum follow-up of 8.75 years. RTSR had a reduced hazard ratio of revision in the first three years (hazard ratio local minimum 0.33, 95% confidence interval 0.18 to 0.59) with no clinically important difference in revision-free restricted mean survival time, and a reduced relative risk of reoperations at 12 months (odds ratio 0.45, 95% confidence interval 0.25 to 0.83) with an absolute risk difference of -0.51% (95% confidence interval -0.89 to -0.13). Serious adverse events and prolonged hospital stay risks, change in Oxford Shoulder Score, and modelled mean lifetime costs were similar. Outcomes remained consistent after weighting. CONCLUSIONS: This study's findings provide reassurance that RTSR is an acceptable alternative to TSR for patients aged 60 years or older with osteoarthritis and intact rotator cuff tendons. Despite a significant difference in the risk profiles of revision surgery over time, no statistically significant and clinically important differences between RTSR and TSR were found in terms of long term revision surgery, serious adverse events, reoperations, prolonged hospital stay, or lifetime healthcare costs.
Microporous titanium and hydroxyapatite improve fixation of the tibial wall in unicompartmental knee replacement.
PURPOSE: Cementless Oxford unicompartmental knee replacement (OUKR) is associated with less pain than cemented OUKR 5 years postoperatively. This may be due to improved fixation at the tibial wall, which transmits tension and reduces stress in the bone below the tibial component. This study compares tibial wall fixation with three different types of fixation: cemented, cementless with hydroxyapatite (HA) and cementless with a microporous titanium coat and HA (HA + MPC). METHODS: Three consecutive cohorts were identified (n = 221 cemented in 2005-2007, n = 118 HA in 2014-2015, n = 125 HA + MPC in 2016-2017). Analysis was performed on anterior-posterior radiographs aligned on the tibial component taken 1-2 years postoperatively. Aligned radiographs are needed to see narrow radiolucencies adjacent to the wall. Alignment was assessed with rotation ratio (RR = wall width/internal wall height). Perfect RR is 0.3, and a maximum threshold of 0.5 was used. Quality of fixation to the wall was assessed with fixation ratio (FR = bone wall contact height/total wall height). Notable radiographic features at the tibial wall were also recorded. RESULTS: A total of 33 knees with cement, 37 knees with cementless with HA and 57 knees cementless with HA + MPC had adequately aligned radiographs. Fixation was significantly better with HA compared with cement (55% vs. 25%, p = 0.0016). The microporous coat further improved fixation (81% vs. 55%, p 80% was achieved in 3% of the cemented implants, 32% of HA and 68% of HA + MPC. In cementless cohorts, features suggestive of a layer of bone that had delaminated from the wall were seen in 8 (22%) HA and 3 (5%) HA + MPC knees. CONCLUSION: Radiographic tibial wall fixation in OUKR is poor with cement. It improves with an HA coating and improves further with an intermediary MPC. Improved tibial wall fixation may explain the lower levels of pain observed with cementless rather than cemented fixation described in the literature, but further clinical correlation is needed. LEVEL OF EVIDENCE: Level III, retrospective cohort study.
Polyethylene bearing wear is comparable for cemented and cementless Oxford unicompartmental knee replacements: Ten-year results of a randomized controlled trial.
PURPOSE: There is concern that using cementless components may increase polyethylene wear of the Oxford unicompartmental knee replacement (OUKR). Therefore, this study aimed to measure bearing wear at 10 years in patients from a randomized trial comparing Phase 3 cemented and cementless OUKRs and to investigate factors that may affect wear. It was hypothesized that there would be no difference in wear rate between cemented and cementless OUKRs. METHODS: Bearing thickness was determined using radiostereometric analysis at postoperative, 3-month, 6-month, 1-year, 2-year, 5-year and 10-year timepoints. As creep occurs early, wear rate was calculated using linear regression between 6 months and 10 years for 39 knees (20 cemented, 19 cementless). Associations between wear and implant, surgical and patient factors were analysed. RESULTS: The linear wear rate of the Phase 3 OUKR was 0.06 mm/year with no significant difference (p = 0.18) between cemented (0.054 mm/year) and cementless (0.063 mm/year) implants. Age, Oxford Knee Score, component size and bearing thickness had no correlation with wear. A body mass index ≥ 30 was associated with a significantly lower wear rate (p = 0.007) as was having ≥80% femoral component contact area on the bearing (p = 0.003). Bearings positioned ≥1.5 mm from the tibial wall had a significantly higher wear rate (p = 0.002). CONCLUSIONS: At 10 years, the Phase 3 OUKR linear wear rate is low and not associated with the fixation method. To minimize the risk of wear-related bearing fracture in the very long-term surgeons should consider using 4 mm bearings in very young active patients and ensure that components are appropriately positioned, which is facilitated by the current instrumentation. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
hadge: a comprehensive pipeline for donor deconvolution in single-cell studies.
Single-cell multiplexing techniques (cell hashing and genetic multiplexing) combine multiple samples, optimizing sample processing and reducing costs. Cell hashing conjugates antibody-tags or chemical-oligonucleotides to cell membranes, while genetic multiplexing allows to mix genetically diverse samples and relies on aggregation of RNA reads at known genomic coordinates. We develop hadge (hashing deconvolution combined with genotype information), a Nextflow pipeline that combines 12 methods to perform both hashing- and genotype-based deconvolution. We propose a joint deconvolution strategy combining best-performing methods and demonstrate how this approach leads to the recovery of previously discarded cells in a nuclei hashing of fresh-frozen brain tissue.
Bone erosions and joint damage caused by chikungunya virus: a systematic review.
BACKGROUND: Chikungunya fever is an emerging global infection transmitted by Aedes mosquitoes that manifests as an acute febrile illness with joint pain and can lead to chronic arthritis. The mechanism underlying chronic joint damage remains unclear; however, chronic chikungunya arthritis shares similarities with rheumatoid arthritis. Disease-modifying antirheumatic drugs have revolutionized rheumatoid arthritis treatment by preventing joint damage. However, the role of these therapies in chronic chikungunya arthritis has not been determined. We conducted a systematic review to evaluate the burden of joint structural damage in chronic chikungunya arthritis to help to define the role of disease-modifying therapy in this disease. METHODS: This systematic review included retrospective and prospective studies, trials, and case reports evaluating joint damage caused by chikungunya virus. Various databases were searched without any date or language restrictions. Study selection was conducted independently by two researchers, and data were extracted from the articles selected. RESULTS: A total of 108 studies were initially evaluated, with 8 meeting the inclusion criteria. Longitudinal studies have reported persistent joint pain from chikungunya infection and the progression of radiographic joint damage up to 13 years post-infection. Joint imaging revealed synovial inflammation, bone erosion, and cartilage destruction in patients with chronic chikungunya arthritis. CONCLUSIONS: Few studies have addressed chikungunya-induced joint damage, limiting our understanding of chronic chikungunya arthritis. Nevertheless, chronic chikungunya arthritis has similarities to rheumatoid arthritis. The success of early disease-modifying antirheumatic drug therapy in rheumatoid arthritis underscores the need for comprehensive research on its role in chikungunya arthritis.
The burden of schizophrenia in the Middle East and North Africa region, 1990-2019.
Schizophrenia ranks as the third-most common cause of disability among mental disorders globally. This study presents findings on the prevalence, incidence and years lived with disability (YLDs) as a result of schizophrenia in the Middle East and North Africa (MENA), stratified by age, sex and sociodemographic index (SDI). We collected publicly accessible data from the Global Burden of Disease (GBD) study 2019. This study reports the burden of schizophrenia, from 1990 to 2019, for the 21 countries that comprise MENA. In 2019, MENA exhibited an age-standardised point prevalence of 248.2, an incidence rate of 14.7 and an YLD rate of 158.7 per 100,000, which have not changed substantially between 1990 and 2019. In 2019, the age-standardised YLD rate was highest in Qatar and lowest in Afghanistan. No MENA countries demonstrated noteworthy changes in the burden of schizophrenia from 1990 to 2019. Furthermore, in 2019, the highest number of prevalent cases and the point prevalence were observed among those aged 35-39, with a higher prevalence among males in almost all age categories. Additionally, in 2019, the age-standardised YLD rates in MENA were below the worldwide average. Finally, there was a positive correlation between the burden of schizophrenia and the SDI from 1990 to 2019. The disease burden of schizophrenia has remained relatively stable over the past thirty years. Nevertheless, as the regional life-expectancy continues to increase, the burden of schizophrenia is also expected to rise. Therefore, early planning for the increase in the burden of the disease is urgently needed in the region.