Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, et al. It was the first medicine approved with the FDAs Breakthrough Therapy Designation. Eur Urol. Nat Rev Immunol. Mao X, Yang X, Chen X, Yu S, Yu S, Zhang B, et al. Get the free daily newsletter read by industry experts. Google Scholar. [44] Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping. 2014;11(2):1636. Hypoventilation during sleep is determined by a thorough history of sleep disorder with an oximetry study and a capillary blood gas (see pulmonary function testing). The immuno-score is also associated with responses to different treatments [152], which emphasizes the essential role of the TIME in clinical applications. Other reviews have presented a detailed comparison of different computational approaches [131, 132]. Front Genet. [13] It becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates before age 13. [3] Most are unable to walk by the age of 12. DMD can be detected with about 95% accuracy by genetic studies performed during pregnancy. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Lavin Y, Kobayashi S, Leader A, Amir ED, Elefant N, Bigenwald C, et al. 2020;12(5):1307. The company is based on research by UPenn physician-scientist Saar Gill and is led by Phil Johnson, who was once chief scientific officer at The Childrens Hospital of Philadelphia. 17 The diversity of these approaches and the complexities of gene therapy mean that no single approach is likely to win. That situation will enable a rapid innovation cycle in which gene therapies are constantly being improved upon, which will offer new opportunities to leapfrog existing products. Patients who have the condition are often treated with drugs that replace the missing clotting protein, though they can still have breakthrough episodes. Table 1 compares the current major scRNA-seq technologies. Manage cookies/Do not sell my data we use in the preference centre. 2020;183(2):37794. Fricke I, Gabrilovich DI. Complications from treatment, such as mechanical ventilation and tracheotomy procedures, are also a concern. 18. 2021;10(1):1908010. 2019;16(12):128996. Combinatorial labeling of single cells for gene expression cytometry. Although this effect depends on the vector serotype used, and the clinical impact is still unclear, Other CD4+ T cells, including T helper 2 (Th2) cells and T helper 17 (Th17) cells, also facilitate immune responses in the tumour microenvironment [65, 66]. Cell. Prolactin levels also increase after epileptic seizures and after electroconvulsive therapy. University of Galway is an equal opportunities employer. scRNA-seq of fibroblasts in a genetically engineered mouse model of breast cancer further identified vascular CAFs (vCAFs), matrix CAFs (mCAFs), developmental CAFs (dCAFs), and cycling CAFs (cCAFs) [101]. Such cell-type- or tissue-specific regulatory elements (for example, promoters and enhancers) have become relatively common in viral-vector gene therapies. [3] Some may have intellectual disability. A comprehensive cellular atlas of the TIME has been drawn, providing a novel perspective for clinical application in various tumours. 2014;25(2):15265. Clinical-trial protocols have subsequently been revised to limit viral dosage, reflecting the tremendous importance of this issue. [6], DMD affects about one in 3,500 to 6,000 males at birth. [79][80], Researchers are working on a gene editing method to correct a mutation that leads to Duchenne muscular dystrophy (DMD). Today, a typical manufacturing run of an AAV-vector therapy using high-yield cell lines and large-capacity bioreactors might only produce approximately ten doses of a systemic gene therapy from a single batch at a cost of nearly $100,000 per dose (assuming approximately 1 10^17 vg per batch). Privacy 15. Among them, CellTalker utilizes differentially expressed genes, while CellPhoneDB includes the subunit architectures of ligands and receptors. Dendritic cells and tumor microenvironment: a dangerous liaison. The detailed features of these methods have been described in other reviews [57, 58]. NK cells that recruit cDC1 cells via the chemokine receptor X-C motif chemokine receptor 1 (XCR1) were identified and found to promote cancer immune control [140, 141]. Nat Methods. Cell. Probabilistic cell-type assignment of single-cell RNA-seq for tumor microenvironment profiling. The advent of SPLiT-seq reduced the cost of library construction for sequencing to $0.01 for each cell. Different approaches have been proposed, such as principal component analysis (PCA) [54], nonnegative matrix factorization (NMF) [55], and deep neural networks [56]. Stewart CA, Gay CM, Xi Y, Sivajothi S, Sivakamasundari V, Fujimoto J, et al. Tran HTN, Ang KS, Chevrier M, Zhang X, Lee NYS, Goh M, et al. [71] The compounds allow faulty parts of the dystrophin gene to be skipped when it is transcribed to RNA for protein production, permitting a still-truncated but more functional version of the protein to be produced. Integrating single-cell and spatial transcriptomics helps us explore cell communications at a new level [145, 146]. In 2016, Netflix released The Fundamentals of Caring, a film based on the novel. The TIME is composed of noncellular components (vessels, extracellular matrix, signaling molecules, etc.) Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. 2020;15(4):1484506. Terms and Conditions, Genome Biol. Subscribe to the BioPharma Dive free daily newsletter, Subscribe to BioPharma Dive for top news, trends & analysis, The free newsletter covering the top industry headlines, Vivera Welcomes Healthcare Founder and CEO Lea Ramirez to its Advisory Board, SpectronRx Completes Critical Step in Path to Supplying Europe With Life-Saving Radiopharmaceu, Syntegra and the Institute for Health Metrics Expand Strategic Partnership to Bring Privacy-Gu, BioIVT Opens New Blood Donor Center in Glasgow, Scotland. Many analytical tools for investigating ligand-receptor interactions based on scRNA-seq data have been developed (Fig. gRide, Genentech's employee commuting program, has saved 100 million miles of driving since the program's inception began in late 2006. The advent of single-cell RNA sequencing (scRNA-seq) has provided insight into the tumour immune microenvironment (TIME). 2021;374(6574):abe6474. CXCL12/CXCR4 pathway orchestrates CSC-like properties by CAF recruited tumor associated macrophage in OSCC. Clustering and annotation are essential in interpreting scRNA-seq data and exploring the TIME. Oncoimmunology. The advent of single-cell RNA sequencing (scRNA-seq) has provided insight into the tumour immune microenvironment (TIME). Exp Cell Res. For example, recent gene therapies for Duchenne muscular dystrophy (DMD) that aim to correct mutations in muscle cells throughout the body have delivered up to approximately 10^16 (ten-thousand trillion) viral particles in a single dose (for example, a dose of 3 10^14 vector genomes [vg] per kilogram [kg], assuming a 30-kg child), 1 It was the first medicine approved with the FDAs Breakthrough Therapy Designation. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. 2021;39(1):4358. Picelli S, Bjrklund K, Faridani OR, Sagasser S, Winberg G, Sandberg R. Smart-seq2 for sensitive full-length transcriptome profiling in single cells. The technology has long drawn interest for its potential advantages over traditional modalities. 2019;37(7):77382. 9. T cells have also been found to undergo exhaustion, constructing an immunosuppressive tumour microenvironment [124]. Hyperprolactinaemia, a commonly encountered adverse effect of antipsychotic medication, used to be regarded as an inevitable consequence of the treatment and ignored (Reference Bostwick, Guthrie and Ellingrod Bostwick 2009).However, it has now been established that 10/11/2022. scRNA-seq of gastric cancer revealed a novel DCs cluster expressing indoleamine 2,3-dioxygenase 1 (IDO1) and the chemokines CC motif chemokine ligand (CCL)22, CCL17, CCL19, and interleukin (IL)-32, which are involved in the recruitment of T cells [110]. In addition, the quality of scRNA-seq data obtained was similar to that obtained with Drop-seq and InDrop [44]. About Sangamo Therapeutics a Tumour-associated macrophages (TAMs) coexpressing M1 and M2 genes might evolve from M1 or M2 macrophages. Its still too early to determine the true impact of capsid engineering, as most engineered capsids are still in preclinical development. 2018;36(5):4217. With respiratory assistance, the median survival age can reach up to 40. Cytotoxic CD8+ T cells, which recognize specific antigens on tumour cells and subsequently eliminate them, are the most common and effective immune cells in the TIME [63]. Excitement around viral-vector gene therapies is evident. Multiple myeloma cell therapies like Bristol Myers Squibbs Abecma, by comparison, consist of T cell hunters seeking a protein called BCMA.. Once these engineered CAR-T cells are infused, they search for and During tumour progression, malignant cells lead to the recruitment and dysfunction of immune cells, which reciprocally influence tumorigenesis and the evolution of malignant cells [133], forming a vicious cycle (Fig. Exploring tissue architecture using spatial transcriptomics. Oncostatin M (OSM) derived from TAMs also interacts with its receptor on malignant cells to activate signal transducer and activator of transcription 3 (STAT3) [136]. Pfizer Disclosure Notice Landscape and fynamics of single immune cells in hepatocellular carcinoma. Get the latest celebrity news and hot celeb gossip with exclusive stories and pictures from Us Weekly. Sangamo Therapeutics is a clinical-stage biopharmaceutical company with a robust genomic medicines pipeline. [R]egulatory agencies tend to think more alike than differently, Schwartz wrote in an Oct. 12 note to clients. Please help update this article to reflect recent events or newly available information. To recognize flu symptoms, remember Flu F.A.C.T.S. Wei J, Zhou T, Zhang X, Tian T. DTFLOW: inference and visualization of single-cell pseudotime trajectory using diffusion propagation. 17. Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. 2016. https://doi.org/10.1101/079509. and cellular components (T cells, myeloid cells, fibroblasts, etc.) Genome Biol. Google Scholar. COVID-19: Briefing note #98, March 30, 2022 One of COVID-19s health effects is the transformation of healthcare. Statistics or biology: the zero-inflation controversy about scRNA-seq data. Compared with conventional methods, scRNA-seq can be utilized to identify novel cellular types and corresponding cellular states, deepening our understanding of TIME [24]. et al. Read press releases and learn about our presence at ASH this year. 2017;14(5):63750. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response, US Food and Drug Administration, December 19, 2019, fda.gov. Recent developments in application of single-cell RNA sequencing in the tumour immune microenvironment and cancer therapy. Once these engineered CAR-T cells are infused, they search for and destroy cancer cells expressing their target proteins, sometimes driving an immune response so strong it can be life-threatening. A branching point represents a significant divergence in cellular differentiation. SCORPIUS improves trajectory inference and identifies novel modules in dendritic cell development. On March 18, 2019, the FDA approved Genentechs immunotherapy, in combination with chemotherapy (carboplatin and etoposide), for the initial (first-line) treatment of adults with extensive-stage small cell lung cancer. Nearly all gene therapies currently available use one of three vector types: adeno-associated-virus (AAV) vectors, adenovirus vectors, or lentivirus vectors (Exhibit 1). PubMed Arun Srivastava, AAV vectors: Are they safe? Human Gene Therapy, July 2020, Volume 31, Number 1314, pp. 2018;9(1):5150. [3] Scoliosis is also common. scRNA-seq of the skin and blood of a patient with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) identified central memory CD4+ T cells enriched in human herpesvirus 6b DNA and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway as potential targets. University of Galway reserves the right to readvertise or extend the closing date for this post. Single-cell separation and capture are essential procedures for scRNA-seq in different approaches. A novel intercellular communication-associated gene signature for prognostic prediction and clinical value in patients with lung adenocarcinoma. Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics. Liu X, Li L, Si F, Huang L, Zhao Y, Zhang C, et al. CAS 2018;9:2425. Dive Insight: While gene therapy holds the promise of a permanent fix for genetic conditions like hemophilia, regulators are treading carefully with the technology and the many questions it raises. Han Luo or Jihwan Park. [3] About two thirds of cases are inherited from a person's mother, while one third of cases are due to a new mutation. apCAFs uniquely express major histocompatibility complex (MHC) class II genes, including CD74, which activates CD4+ T cells [99]. Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism. Science. Pseudotime trajectory analysis confirmed that TAMs transition continuously between M1 and M2 phenotypes (Fig. Shum EY, Walczak EM, Chang C, Fan HC. Vistain LF, Tay S. Single-cell proteomics. 2021;22(2):1592603. Cillo AR, Krten CHL, Tabib T, Qi Z, Onkar S, Wang T, et al. Sorry, you need to enable JavaScript to visit this website. 2012;12(4):23952. Pfizer presents initial clinical data on Phase 1B gene therapy study for Duchenne muscular dystrophy (DMD), Pfizer, June 28, 2019, pfizer.com. There are a large number of zero values in the scRNA-seq expression matrix. Use of fluorescence in situ hybridization (FISH) in diagnosis and tailored therapies in solid tumors. Military Medical Research Nat Biotechnol. Researchers discovered communications between CAFs and gastric cancer cells via integrin receptor interactions with collagen, fibronectin, thrombospondin 1 (THBS1) ligands, and leucine rich repeat containing G protein-coupled receptor 4 (LGR4)- R-spondin 3 (RSPO3), which regulate stemness [110]. This review focuses on the application of scRNA-seq in investigation of the TIME. If the vital capacity has dropped below 40% of normal, a volume ventilator/respirator may be used during sleeping hours, a time when the person is most likely to be underventilating (hypoventilating). Deep learning: new computational modelling techniques for genomics. Zolgensma data including patients with more severe SMA at baseline further demonstrate therapeutic benefit, including prolonged event-free survival, increased motor function and milestone movement, Novartis, October 1, 2020, novartis.com. Other tools, such as NicheNet, also consider the alterations in downstream pathways in receiver cells [130]. 14 Indeed, regulators have used reducing the empty-to-full capsid ratio as part of the rationale for lifting clinical holds on gene-therapy products with previous safety issues. 3a). Improving capsid properties could bring multiple immediate benefits. Concurrently, Kole et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. In addition, the capsid is largely responsible for the stability of the viral vector during the manufacturing process and can affect storage and distribution requirements. Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics. Thus, interrupting pre-exhausted T cells before exhaustion may be essential for cancer immunotherapy [123]. This release contains forward-looking information about an investigational hemophilia A therapy, giroctocogene fitelparvovec, including its potential benefits and the phase 3 AFFINE study, including anticipated timing of active trial sites, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. As TAMs and T cells represent the most abundant immune cell types in the TIME, we mainly focus on these two cell types. Eleven grand challenges in single-cell data science. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 2020;37(4):45670. Their aim is to:[48], Modern "volume ventilators/respirators", which deliver an adjustable volume (amount) of air to the person with each breath, are valuable in the treatment of people with muscular dystrophy-related respiratory problems. Many types of therapeutic agents (for example, enzymes, antibodies, and siRNAs) can be encoded in DNA sequences that can be rapidly designed and synthesized once a target is identified. Chen YP, Yin JH, Li WF, Li HJ, Chen DP, Zhang CJ, et al. For example, a twofold increase in a capsids cell-type specificity could enable a twofold decrease in the overall viral dose required, thereby improving safety and cost. Similarly, another study demonstrated that anaplastic thyroid cancer cells are derived from a subcluster of papillary thyroid cancer cells, where a distinct TIME was constructed, leading to significantly worse prognoses [125]. The common down-stream data analysis of scRNA-seq is shown in Fig. Picelli S. Single-cell RNA-sequencing: the future of genome biology is now. Adv Exp Med Biol. Physical therapy is helpful to maintain muscle strength, flexibility, and function. On March 21, 2014, the FDA approved a Genentech medicine for people 12 years of age and older for the treatment of chronic idiopathic urticaria (CIU), a form of chronic hives. Unraveling the immune systems intertwined responses to viral-vector gene therapies remains difficult. In addition, scRNA-seq of pancreatic ductal adenocarcinoma revealed interactions between TIGIT and hepatitis A virus cellular receptor 2 (HAVCR2) in T and NK cells, as well as their corresponding ligands PVR and LGALS9 in malignant cells, resulting in immune cell dysfunction and pancreatic cancer progression [137]. We have been using different technological solutions to help those with hearing loss perceive sound, and these technologies have been advancing and improving in recent years. Giroctocogene fitelparvovec is currently being studied in the Phase 3 AFFINE study. Nat Methods. Bartoschek M, Oskolkov N, Bocci M, Lvrot J, Larsson C, Sommarin M, et al. 2022 Genentech, Inc. All rights reserved. Cell. All authors read and approved the final manuscript. Were not ready for it, Psychedelic magic mushroom drug may ease some depression, Extremely satisfying: Scientists insight powers new RSV vaccine for infants, Vaccine Trend Report: The Latest Challenges & Opportunities. On December 6, 2018, the FDA granted approval to a new immunotherapy combination for the initial treatment of people with metastatic non-squamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations. PubMed Central Get access to Genentech information and resources for stories in development. We believe that advances in technology and wide application of single-cell analysis can lead to the discovery of novel perspectives on cancer therapy and that scRNA-seq can subsequently be implemented more frequently in clinical practice. On the other hand, some interactions between immune cells can induce an antitumor TIME. For instance, TAMs were found to have decreased CXCL12- C-X-C motif chemokine receptor (CXCR)3 and CXCL12-CXCR4 interactions and enhanced CD86-CTLA-4 interactions between cytotoxic T cells and Tregs in nasopharyngeal carcinoma, resulting in a TIME that aggravates cancer progression [138]. Cell. 2 Although traditional genomic and transcriptomic analyses, such as CIBERSORTx and DWLS, also emphasize immune-related pathways and computational approaches and have been applied to predict immune cell components, technical limitations have confounded the precise characterization of the TIME [13, 14]. Eraslan G, Avsec , Gagneur J, Theis FJ. While only four in vivo viral-vector gene therapies are currently on the market, more than 100 gene-therapy assets are in clinical trials as of late 2020, with a far greater number in preclinical development.. 3. The current generation of viral-vector gene therapies represents the culmination of decades of biological and clinical research. In the short to medium termwhile technological challenges limit the scope of gene therapies to curative treatments for rare diseasesfast followers may find it difficult to be successful, even with improved technologies, as first entrants rapidly address prevalent populations. IL-6 secreted by vCAFs induces epigenetic alterations in ICC cells, which enhance malignancy [162]. We depict the major procedures of scRNA-seq in Fig. In addition to secreting antibodies, B cells also participate in cellular immunity through the production of cytokines that interact with T cells [79]. This could be severe, moderate, or mild hearing loss. - A Quest Article", "Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. 1. The person gradually will increase the amount of time using the ventilator/respirator during the day as needed. Greten FR, Grivennikov SI. 2020;177(7):147284. Patient dosing is expected to resume in October New York, NY, and Brisbane, California, September 22, 2022 - Pfizer and Sangamo Therapeutics announced that the Phase 3 AFFINE study evaluating giroctocogene fitelparvovec, an investigational gene therapy for patients with moderately severe to severe hemophilia A, has re-opened recruitment. Many of these assets have emerged from the steady stream of small- and midsize biotech companies and On June 8, 2018, the FDA approved a Genentech medicine for people with previously treated chronic lymphocytic leukemia. Like the capsid, the DNA sequence of the viral vector itself affects multiple aspects of a gene therapys performance, but engineering the vector can often be considerably easier, cheaper, and quicker. In addition to malignant cells, the tumour immune microenvironment (TIME) is an essential component of various tumours. Proc Natl Acad Sci USA. Comparative analysis of droplet-based ultra-high-throughput single-cell RNA-seq systems. On January 30, 2012, a Genentech medicine was approved by the FDA for the treatment of adults with a type of skin cancer, called basal cell carcinoma (BCC), that has spread to other parts of the body or that has come back after surgery or that their healthcare provider decides cannot be treated with surgery or radiation. Nature. Nickerson NK, Mill CP, Wu HJ, Riese DJ 2nd, Foley J. Autocrine-derived epidermal growth factor receptor ligands contribute to recruitment of tumor-associated macrophage and growth of basal breast cancer cells in vivo. Martelotto LG, Baslan T, Kendall J, Geyer FC, Burke KA, Spraggon L, et al. These technique improvements shed light on construction of large single-cell datasets with high resolution. 2021;184(13):3559-72.e22. They have suboptimal properties, including little cell-type specificity, moderate efficiency of cell entry, and relatively high levels of preexisting immunity in humans. Ni J, Wang X, Stojanovic A, Zhang Q, Wincher M, Bhler L, et al. [59] In addition, patients with Duchenne muscular dystrophy also have elevated plasma lipoprotein levels, implying a primary state of dyslipidemia in patients. Various amplification methods can be used within microwell plates, including SMART-seq2, CEL-Seq, MARS-seq, and STRT-seq [37,38,39,40]. [10] There is general difficulty with motor skills, which can result in an awkward manner of walking, stepping, or running. This approach also provides high-quality gene expression readouts. Still, new biotech companies continue to emerge, as private investors have billions of available dollars to put to use. Ji Z, Ji H. TSCAN: pseudo-time reconstruction and evaluation in single-cell RNA-seq analysis. 10/11/2022. Cell communication in the TIME is related to tumour progression. Find recent and archived press releases. Cancer-associated fibroblasts (CAFs) recruit Tregs by secreting C-X-C motif chemokine ligand 12 (CXCL12) and are also correlated with M2 macrophages via periostin. CAFs cancer-associated fibroblasts, cCAFs cycling CAFs, dCAFs developmental CAFs, apCAFs antigen-presenting CAFs, iCAFs inflammatory CAFs, myCAFs myofibroblastic CAFs, mCAFs matrix CAFs, TAMs tumour-associated macrophages, DCs dendritic cells, cDC conventional DC, FCN1 ficolin 1, LAMP3 lysosomal associated membrane protein 3, SPP1 secreted phosphoprotein 1, FOLR2 folate receptor Beta, Tregs regulatory T cells, NK natural killer, CSG cell surface glycoprotein, GZMK granzyme K, CXCL13 C-X-C motif chemokine ligand 13, BHLHE40 basic helix-loop-helix family member E40, Th1 T helper 1, KIR killer cell immunoglobulin like receptor, LAYN layilin, TCF7 transcription factor 7, LAG3 lymphocyte activating 3. 10 Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. ImmunoScore signature: a prognostic and predictive tool in gastric cancer. In 2017, the commercial sequencing platform 10Genomics was successfully developed based on the above techniques, enabling a significant increase in cell throughput and a considerable reduction in single-cell sequencing costs [35]. In August, Microsoft said pulling Call of Duty from PlayStation would be unprofitable, and in this recent filing it claimed that Sony would still have a larger install base than Xbox if every single Call of Duty player on PlayStation switched to Microsofts ecosystem. Latest Explore all the latest news and information on Physics World; Research updates Keep track of the most exciting research breakthroughs and technology innovations; News Stay informed about the latest developments that affect scientists in all parts of the world; Features Take a deeper look at the emerging trends and key issues within the global scientific Something went wrong. In 2011, cancer cell therapy was closer to science project than treatment. CIPR: a web-based R/shiny app and R package to annotate cell clusters in single cell RNA sequencing experiments. October 14, 2022. 2020;21(1):191. However, there are also people with the disease in their 20s who have no need for a ventilator. Even though the application of scRNA-seq has made great progressions in TIME studies, the promotion and popularization of single-cell sequencing technology are limited by high sample quality requirements, limited throughput, inevitable technical errors and high costs [173]. Theyve also weighed on the commercial outlook of other ex vivo gene-based treatments for inherited diseases like sickle cell and beta thalassemia, which are made with similarly complex manufacturing processes. 2020;52(1):183-99.e9. IEEE Trans Neural Netw Learn Syst. Nat Biotechnol. The muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy. 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