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BACKGROUND: Corticosteroid injections (CSI) are commonly used for the treatment of shoulder pain in patients with osteoarthritis (OA) and rotator cuff arthropathy (RCA). These injections may increase the risk of infection following eventual shoulder arthroplasty. PURPOSE: The purpose of this study was to perform a systematic review and meta-analysis of existing data to explore the relationship between preoperative CSI's and postoperative periprosthetic joint infection (PJI) following shoulder arthroplasty. METHODS: A literature search was performed on PubMed, Embase, and Web of Science databases through September 29, 2023. Of the 4,221 retrieved, 7 studies including 136,233 patients were included for qualitative analysis. Studies describing patients receiving CSI prior to shoulder arthroplasty and the effect on postoperative infection risk were included in the systematic review and subsequent meta-analysis. Assessment of risk of bias was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. RESULTS: Receiving a corticosteroid injection prior to shoulder arthroplasty was found to have a statistically significant association with increased risk for PJI (OR: 1.13. 95%; CI: 1.06-1.19; p < 0.0001). The rate of PJI increased when injections were given closer to the time of surgery. Patients who received an injection at any time point before surgery had a 5.4% risk of PJI compared to 7.9% and 9.0% in patients receiving an injection within 3 months and 1 month of surgery respectively. This time dependent association however did not reach statistical significance: 1 month OR 1.48; 95% Cl: 0.86-2.53; p = 0.16, 3 months OR 1.95; 95% Cl: 0.95-4.00; p = 0.07. CONCLUSION: The results of this systematic review and meta-analysis demonstrate that patients receiving corticosteroid shoulder injections prior to shoulder arthroplasty may be at an increased risk for prosthetic joint infection postoperatively. While time dependent stratification did not reach statistical significance, our findings indicate a clear trend of increased risk for patients receiving injections closer to surgery.
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Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.
Assuntos
Amplificação de Genes , Genômica/métodos , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico/métodos , Análise Citogenética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , HumanosRESUMO
Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1-3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.
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Cromossomos/genética , DNA/genética , Amplificação de Genes/genética , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Cromatina/genética , HumanosRESUMO
Oncogene amplification is one of the most common drivers of genetic events in cancer, potently promoting tumor development, growth, and progression. The recent discovery that oncogene amplification commonly occurs on extrachromosomal DNA, driving intratumoral genetic heterogeneity and high copy number owing to its non-chromosomal mechanism of inheritance, raises important questions about how the subnuclear location of amplified oncogenes mediates tumor pathogenesis. Next-generation sequencing is powerful but does not provide spatial resolution for amplified oncogenes, and new approaches are needed for accurately quantifying oncogenes located on ecDNA. Here, we introduce ecSeg, an image analysis tool that integrates conventional microscopy with deep neural networks to accurately resolve ecDNA and oncogene amplification at the single cell level.
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Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.
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Amplificação de Genes , Neoplasias/genética , Algoritmos , Linhagem Celular , Linhagem Celular Tumoral , Duplicação Cromossômica , Cromossomos Humanos/genética , Computadores Moleculares , Fatores de Transcrição Forkhead/genética , Genes Virais , Humanos , Hibridização in Situ FluorescenteRESUMO
The integration of viral sequences into the host genome is an important driver of tumorigenesis in many viral mediated cancers, notably cervical cancer and hepatocellular carcinoma. We present ViFi, a computational method that combines phylogenetic methods with reference-based read mapping to detect viral integrations. In contrast with read-based reference mapping approaches, ViFi is faster, and shows high precision and sensitivity on both simulated and biological data, even when the integrated virus is a novel strain or highly mutated. We applied ViFi to matched genomic and mRNA data from 68 cervical cancer samples from TCGA and found high concordance between the two. Surprisingly, viral integration resulted in a dramatic transcriptional upregulation in all proximal elements, including LINEs and LTRs that are not normally transcribed. This upregulation is highly correlated with the presence of a viral gene fused with a downstream human element. Moreover, genomic rearrangements suggest the formation of apparent circular extrachromosomal (ecDNA) human-viral structures. Our results suggest the presence of apparent small circular fusion viral/human ecDNA, which correlates with indiscriminate and unregulated expression of proximal genomic elements, potentially contributing to the pathogenesis of HPV-associated cervical cancers. ViFi is available at https://github.com/namphuon/ViFi.
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DNA Circular/química , Papillomaviridae/genética , Neoplasias do Colo do Útero/genética , Integração Viral/genética , Biologia Computacional/instrumentação , DNA Circular/genética , DNA Viral/química , DNA Viral/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Elementos Nucleotídeos Longos e Dispersos/genética , Papillomaviridae/patogenicidade , RNA Mensageiro/química , RNA Mensageiro/genética , Sequências Repetidas Terminais/genética , Transcrição Gênica , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologiaRESUMO
Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.