C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells.

CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance

Periprosthetic Joint Infection After Total Knee Arthroplasty With or Without Antibiotic Bone Cement.

IMPORTANCE Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. OBJECTIVE To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. DESIGN, SETTING, AND PARTICIPANTS This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. EXPOSURE Primary TKA with ALBC vs plain bone cement. MAIN OUTCOMES AND MEASURES The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. RESULTS Among 2 168 924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1 917 190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. CONCLUSIONS AND RELEVANCE In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries

Identification of differentially expressed genes in early inner ear development

Accession Number: GSE16918 Platform: GPL8764: Agilent-015068 Chicken Gene Expression Microarray 4x44k (Feature Number version) Organism: Gallus gallus Published on 2010-06-21 Summary: The first morphological evidence of the developing ear is a thickened disk of ectoderm known as the otic placode. However, signals for otogenesis are present even before the otic placode is physically apparent. Several inductive signals have been identified through candidate gene approaches, but there are still many gaps in the signaling cascade of otogenesis. Presently the candidate gene approach has largely exhausted known candidates. This project compares the pre-otic domain with a control region that is competent, but not specified to form otic placode. The purpose of this work is to identify genes that are differentially expressed in the pre-otic domain in order to generate a list of novel candidate genes for otic placode induction. Overall Design: Two condition experiment, pre-otic domain vs. rostral control (competent but not specificied to form otic placode); Biological replicates: 4 replicates for each condition consisting of pooled samples from 7 bi-lateral tissue microdissection; dye swap Contact: Name: Christian N. Paxton Organization: Christian Laboratory: Schoenwolf Deparment: Neurobiology and Anatomy Address: 2B-458 SOM, 30 N. 1900 E. Salt Lake City UT 84132 USA Email: [email protected] Phone: 801-581-6157 Organization: Agilent Technologies Address: Palo Alto CA 94304 USA Email: [email protected] Phone: 877-424-4536 Web-Link: www.agilent.co

Insect pollinators: linking research and policy. Workshop report.

EXECUTIVE SUMMARY Pollinators interact with plants to underpin wider biodiversity, ecosystem function, ecosystem services to agricultural crops and ultimately human nutrition. The conservation of pollinators is thus an important goal. Pollinators and pollination represent a tractable example of how biodiversity can be linked to an ecosystem service. This represents a case study for exploring the impacts of various policy instruments aiming to halt/reverse the loss of ecosystem services. There is a need to understand how multiple pressures (e.g. habitat loss, fragmentation and degradation, climate change, pests and diseases, invasive species and environmental chemicals) can combine or interact to affect diversity, abundance and health of different pollinator groups. Decision makers need to balance consideration of the effects of single pressures on pollinators against the suite of other pressures on pollinators. For instance, the threat from pesticide use (with its high public and media profile) also needs to be considered in the context of the other threats facing pollinators and balanced against the need for food security. An independent review of the balance of risks across pollinator groups from pesticide use would help synthesise current knowledge into an accessible form for decision makers. To manage or lessen these threats to pollinators (wild and managed) and pollination requires improved knowledge about their basic ecology. We still need to know where and in what numbers different pollinator species occur, how they use different environments, how they interact with each other through shared plants and diseases and how wild pollinator abundance is changing. Decision makers need clear factual evidence for i) the relative contribution of different managed and wild pollinator groups to wildflower and crop pollination and ii) how this varies across different land-uses, ecosystems and regions. Addressing these basic and applied questions will improve our ability to forecast impacts on pollination service delivery to agricultural crops arising from current and future environmental changes, pesticide use and emerging diseases. The development of a long-term, multi-scale monitoring scheme to monitor trends in pollinator (wild and managed) population size and delivery of pollination services (ideally tied to data collection on land-use, pesticide applications and disease incidence at relevant spatial scales) would provide the evidence base for developing the effectiveness of policy and management interventions over time. Such a monitoring scheme would benefit from including research council organisations (e.g. CEH), governmental departments (e.g. Fera), universities, museums and NGOs (e.g. BBKA,SBA, Bumblebee Conservation Trust etc) Insect Pollinators: linking research and policy Workshop Report | 5 In the context of agricultural intensification and conservation we need to establish what type, quality and quantity of interventions (e.g. agri-environment schemes, protected areas) are needed, where to place them and how they can sustain different pollinator populations and effective pollination services. Current monitoring of the risks from diseases and pesticides requires broadening to consider other insects aside from honey bees, unless we can demonstrate that honey bees are good surrogates for all other pollinators. There is a need to increase confidence in regulatory risk assessments pertaining to pathogens and pesticides by incorporating other pollinator species, investigating chronic exposure to multiple chemicals and using field relevant dosages (specific to regions, not using other data sources as surrogates). At present the effects of spatial, social and temporal scales on the benefits stakeholders receive from pollination services are only beginning to be understood. Economic valuation of pollination services can help optimise the cost-effectiveness of service management measures and offer new opportunities to incentivise action or raise awareness among stakeholders. Novel tools and instruments (e.g. education and training) are needed to translate broad international (e.g. CBD, EU Biodiversity Strategy) and national (e.g. England‟s Biodiversity Strategy) policies into local actor (e.g. beekeeper, farmer, citizen scientist) contributions to meet biodiversity commitments Refocusing some public funding to link basic science to development of practical solutions (e.g. better crop protection products, improved disease resistance or treatment) could help science deliver better-targeted evidence for pollinator protection. Scientists need to make more use of opportunities (e.g. POSTnotes1; practitioner guides) to transfer knowledge to a broad audience in order to better influence decision maker and practitioner behaviours. Improved knowledge exchange between scientists and decision makers is important to combating threats to pollination. Central to this is improved understanding of the respective positions of policy makers and scientists. For instance, policy-makers usually need to be presented with a range of options to balance against other areas of policy. Science does not always arrive at a consensus due to uncertainties in data or models. Policy-makers need to understand that scientists are communicating the “best available knowledge at present” and that consequently it is not always possible to give a definitive answer

Low MiR-187 Expression Promotes Resistance to Chemoradiation Therapy In Vitro and Correlates with Treatment Failure in Patients with Esophageal Adenocarcinoma

Abstract Esophageal adenocarcinoma (EAC) has a poor prognosis and is increasing in incidence in many Western populations. Neoadjuvant chemoradiation therapy (CRT) followed by surgery is increasingly the standard of care for locally advanced EAC; however, resistance to treatment is a significant clinical problem. The identification of both novel biomarkers predicting response to treatment and novel therapeutic targets to enhance the efficacy of CRT is key to improving survival rates in EAC. In this study, we performed global microRNA (miRNA) profiling of pretreatment EAC biopsies and identified 67 miRNAs significantly altered in patients who are resistant to CRT. One of these miRNAs, miR-187, was significantly decreased in pretreatment EAC tumors from patients having a poor response to neoadjuvant CRT, highlighting downregulation of miR-187 as a potential mediator of treatment resistance in EAC. In vitro, miR-187 was demonstrated to play a functional role in modulating sensitivity to X-ray radiation and cisplatin in EAC and its dysregulation was demonstrated to be due to chromosomal alterations. In vitro, miR-187 altered expression of a diverse array of pathways, including the immune regulator complement component 3 (C3), serum levels of which we have previously demonstrated to predict patient response to CRT. In vivo, expression of C3 was significantly increased in tumors from patients having a poor response to CRT. This study highlights for the first time a role for miR-187 as a novel biomarker of response to CRT and a potential therapeutic target for enhancing the efficacy of CRT in EAC