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Uterine transplantation
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Our research preparations in the UTx area span more than a decade (9,10) and follow the innovation, development, exploration, assessment, long-term follow-up (IDEAL) concept (11), which emphasizes a structured and research-based introduction of any novel, major surgical procedure. This approach minimizes the risks for the patients, but also accumulates important scientific data during its clinical introduction. This approach is important for further improvement of any surgical procedure, but also in order to temporarily close any further introduction of the procedure if it proves to carry a substantial risk for the patients or if it fails to deliver its ultimate goal. Currently, UTx is in the D (development) phase of IDEAL with our observational study, including nine patients, that commenced in 2013 (5). Similar observational studies will most likely start in a number of centers in 2016–2017. The international UTx community has initiated the formation of an international registry, to follow all patients (donor, recipient, and child) lifelong to, also from this initial stage, accumulate data to explore the L (long-term follow-up) phase of the IDEAL concept. It should be mentioned that the International Federation of Gynecology and Obstetrics (FIGO) launched ethics principles of UTx in 2009 (12), and these emphasize that animal experiments, including research in nonhuman primates, should be used in preparation for clinical introduction of UTx as an experimental procedure.
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
RNAi inhibition of expression of the utx-1 gene encoding an H3K27me3 demethylase in young adult C. elegans extends the mean life span by approximately 30% [46,47]. Thus, H3K27me3 may be a regulatory mark in aging. Compared with control worms, utx-1 RNAi worms were more resistant to heat (35°C), DNA damage (UV), and oxidative (paraquat) stresses [47]. By an analysis of utx-1 RNAi effects on mutant backgrounds, the life span extension was shown to be mediated by activity of the insulin/IGF-1 signaling (IIS) pathway genes [46,47]. The exact target of utx-1 regulation seems to be the daf-2 gene, encoding an insulin-like growth factor receptor (IGF1R). The expression level of daf-2 increases dramatically, lagging behind the increase in utx-1 expression during the aging time course [47]. Apparently, this transcriptional regulation of the daf-2 gene might be through its H3K27me3-demethylation. UTX-1 regulation of the IIS pathway genes and the life span may well be relevant to mammals, since both UTX and IIS are highly conserved from invertebrates to mammals. Indeed, when the UTX mRNA in 3T3-L1 cells was downregulated by a complementary shRNA, a remarkable decrease in Igf1r and downstream genes expression was detected [47]. Thus, utx-1 regulation of the IIS pathway is conserved between worms and mice. A significant decrease in the IGF1R-associated H3K27me3 levels was observed in macaque muscle during aging. Interestingly, a genome-wide decrease in the promoter H3K27me3 levels with age has been observed that can be restored by utx-1 RNAi. In synchronized worms, H3K27me3 levels were not significantly affected between youth and middle age (up to D11), but drastically dropped to almost undetectable levels in older worms (D14-20) [46]. Thus, increased H3K27me3 seems to be associated with youthfulness. Obviously, utx-1 deficiency extends life span by maintaining high levels of H3K27me3, perhaps allowing a better control of chromatin repression. Therefore, UTX-1 may not specifically target IIS genes, but instead IIS genes may serve as sensors for the global changes in epigenetic status and tune downstream cell growth and stress resistance functions accordingly [47].
Epigenetic regulation of T cell development
Published in International Reviews of Immunology, 2023
Avik Dutta, Harini Venkataganesh, Paul E. Love
Several reports suggest that polycomb group (PcG) proteins govern the H3K27 methylation mark [25] and that Polycomb repressor complex (PRC) maintains the repressive state. There are three groups of PRCs: PRC1, PRC2, and Polycomb Repressive-Deubiquitinase (PR-DUB) complex [26, 27]. Each group has individual ways of remodeling chromatin, contributing to the epigenetic repression of genes important for cell development and proliferation. The PRC1 complex, which consists of several proteins including BMI-1, Ring1, and HPH proteins, recognizes and trimethylates K27 of histone 3 (H3K27me3) and helps to maintain the repressive state. The PRC2 complex includes EZH1 (enhancer of zeste homolog 1), EZH2, EED and SUV12 and initiates early gene repression with the help of histone deacetylases (HDACs) and DNMTs [25]. The discovery of histone demethylase LSD1 (Lysine-specific histone demethylase 1 A; encoded by the KDM1A gene) advanced the field as previously it was thought that histone methylation is permanent. This discovery has contributed to a dynamic view of chromatin remodeling [23, 28]. LSD1 demethylates H3K4 and H3K9 and is found to be upregulated in many cancers including T cell acute lymphoblastic leukemia (T-ALL) [29]. Several reports have also shown that the histone H3 K27 demethylases, KDM6A (Utx) and KDM6B (Jmjd3), help to shape the chromatin architecture and regulate gene expression by removing repressive histone modifications [30].
Uterus transplantation—questions and answers about the procedure that is expanding the field of solid organ transplantation
Published in Baylor University Medical Center Proceedings, 2021
Anji E. Wall, Giuliano Testa, David Axelrod, Liza Johannesson
Absolute uterine-factor infertility (AUFI) affects 3% to 5% of reproductive-aged infertile women worldwide and is attributed to congenital causes (e.g., Mayer-Rokitansky-Küster-Hauser syndrome) and acquired causes (e.g., previous hysterectomy).1 Uterus transplantation (UTx) has emerged as the only treatment for women with AUFI who desire to carry their own pregnancies. The first live births after UTx from living and deceased donors occurred in 20142 and 2017,3 respectively. The first live birth in the US after UTx was in 2017 at Baylor University Medical Center (BUMC).4 To date, more than 60 UTx procedures have been reported, with at least 18 live births.2–7 There are three active UTx programs in the United States, which make up the US Uterus Transplant Consortium: BUMC, Cleveland Clinic, and the University of Pennsylvania.8 Given the rapid growth and clinical success of UTx, it is important for members of the medical community to be knowledgeable about this procedure. This article provides answers to several common questions asked about UTx.
Allocating Uterus Transplants—Who Gets to Be a Gestational Mother?
Published in The American Journal of Bioethics, 2018
In 2014 a Swedish team demonstrated that live birth after uterine transplantation (UTx) was medically feasible. Clinical trials for UTx are now underway internationally and in the United States. Much as for face transplantation, the ethics of even performing the procedure have been debated extensively in the literature. Bruno and Arora’s (2018) article shifts the conversation forward to assess the allocation of donor uteruses for UTx. All organ transplantations raise questions about the eligibility of recipients and the allocation of scarce organs between possible recipients. Uterine transplants, as the authors correctly identify, raise unique allocation questions stemming from the reproductive intention and implication of the procedure. Despite the potential reproductive consequences, it is misplaced to overemphasize parental fitness in the context of UTx. From a regulatory standpoint, uterine allocation policies should model traditional organ allocation policies, not adoption policies.