T cell immunity as a tool for studying epigenetic regulation of cellular differentiation

Cellular differentiation is regulated by the strict spatial and temporal control of gene expression. This is achieved, in part, by regulating changes in histone post-translational modifications (PTMs) and DNA methylation that in-turn, impact transcriptional activity. Further, histone PTMs and DNA methylation are often propagated faithfully at cell division (termed epigenetic propagation), and thus contribute to maintaining cellular identity in the absence of signals driving differentiation. Cardinal features of adaptive T cell immunity include the ability to differentiate in response to infection, resulting in acquisition of immune functions required for pathogen clearance; and the ability to maintain this functional capacity in the long-term, allowing more rapid and effective pathogen elimination following re-infection. These characteristics underpin vaccination strategies by effectively establishing a long-lived T cell population that contributes to an immunologically protective state (termed immunological memory). As we discuss in this review, epigenetic mechanisms provide attractive and powerful explanations for key aspects of T cell-mediated immunity - most obviously and notably, immunological memory, because of the capacity of epigenetic circuits to perpetuate cellular identities in the absence of the initial signals that drive differentiation. Indeed, T cell responses to infection are an ideal model system for studying how epigenetic factors shape cellular differentiation and development generally. This review will examine how epigenetic mechanisms regulate T cell function and differentiation, and how these model systems are providing general insights into the epigenetic regulation of gene transcription during cellular differentiation

Transcriptional Enhancers in the Regulation of T Cell Differentiation

The changes in phenotype and function that characterise the differentiation of naïve T cells to effector and memory states are underscored by large-scale, coordinated, and stable changes in gene expression. In turn, these changes are choreographed by the interplay between transcription factors and epigenetic regulators that act to restructure the genome, ultimately ensuring lineage-appropriate gene expression. Here, we focus on the mechanisms that control T cell differentiation, with a particular focus on the role of regulatory elements encoded within the genome, known as transcriptional enhancers. We discuss the central role of transcriptional enhancers in regulating T cell differentiation, both in health and disease

Turkey diseases : cause, prevention, and control

Cover title

Investigating Safety And Preliminary Efficacy Of Afm13 Plus Pembrolizumab In Patients With Relapsed/Refractory Hodgkin Lymphoma After Brentuximab Vedotin Failure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149522/1/hon134_2629.pd

A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/RHL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation

A protein functionalization platform based on selective reactions at methionine residues.

Nature has a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a marked increase in their functional diversity1. Inspired by this, chemical tools have been developed for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations that are suitable for effective protein functionalization is limited, because the stringent demands inherent to biological systems preclude the applicability of many potential processes2. These chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near-perfect conversion2-7. Although many bioconjugation methods exist at cysteine, lysine and tyrosine, a method targeting a less-explored amino acid would considerably expand the protein functionalization toolbox. Here we report the development of a multifaceted approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the electrophilic reactivity of a bespoke hypervalent iodine reagent, the S-Me group in the side chain of methionine can be targeted. The bioconjugation reaction is fast, selective, operates at low-micromolar concentrations and is complementary to existing bioconjugation strategies. Moreover, it produces a protein conjugate that is itself a high-energy intermediate with reactive properties and can serve as a platform for the development of secondary, visible-light-mediated bioorthogonal protein functionalization processes. The merger of these approaches provides a versatile platform for the development of distinct transformations that deliver information-rich protein conjugates directly from the native biomacromolecules

Recent advances in organic synthesis using light-mediated n-heterocyclic carbene catalysis

The combination of photocatalysis with other ground state catalytic systems have attracted much attention recently due to the enormous synthetic potential offered by a dual activation mode. The use of N-heterocyclic carbene (NHC) as organocatalysts emerged as an important synthetic tool. Its ability to harness umpolung reactivity by the formation of the Breslow intermediate has been employed in the synthesis of thousands of biologically important compounds. However, the available coupling partners are relatively restricted, and its combination with other catalytic systems might improve its synthetic versatility. Thus, merging photoredox and N-heterocyclic carbene (NHC) catalysis has emerged recently as a powerful strategy to develop new transformations and give access to a whole new branch of synthetic possibilities. This review compiles the NHC catalyzed methods mediated by light, either in the presence or absence of an external photocatalyst, that have been described so far, and aims to give an accurate overview of the potential of this activation modeL.M. acknowledges the Autonomous Community of Madrid (CAM) for the financial support (PEJD-2019-PRE/AMB-16640 and SI1/PJI/ 2019-00237) and for an “Atracción de Talento Investigador” contract (2017-T2/AMB-5037

The changing global distribution and prevalence of canine transmissible venereal tumour.

BACKGROUND: The canine transmissible venereal tumour (CTVT) is a contagious cancer that is naturally transmitted between dogs by the allogeneic transfer of living cancer cells during coitus. CTVT first arose several thousand years ago and has been reported in dog populations worldwide; however, its precise distribution patterns and prevalence remain unclear. RESULTS: We analysed historical literature and obtained CTVT prevalence information from 645 veterinarians and animal health workers in 109 countries in order to estimate CTVT's former and current global distribution and prevalence. This analysis confirmed that CTVT is endemic in at least 90 countries worldwide across all inhabited continents. CTVT is estimated to be present at a prevalence of one percent or more in dogs in at least 13 countries in South and Central America as well as in at least 11 countries in Africa and 8 countries in Asia. In the United States and Australia, CTVT was reported to be endemic only in remote indigenous communities. Comparison of current and historical reports of CTVT indicated that its prevalence has declined in Northern Europe, possibly due to changes in dog control laws during the nineteenth and twentieth centuries. Analysis of factors influencing CTVT prevalence showed that presence of free-roaming dogs was associated with increased CTVT prevalence, while dog spaying and neutering were associated with reduced CTVT prevalence. Our analysis indicated no gender bias for CTVT and we found no evidence that animals with CTVT frequently harbour concurrent infectious diseases. Vincristine was widely reported to be the most effective therapy for CTVT. CONCLUSIONS: Our results provide a survey of the current global distribution of CTVT, confirming that CTVT is endemic in at least 90 countries worldwide. Additionally, our analysis highlights factors that continue to modify CTVT's prevalence around the world and implicates free-roaming dogs as a reservoir for the disease. Our analysis also documents the disappearance of the disease from the United Kingdom during the twentieth century, which appears to have been an unintentional result of the introduction of dog control policies.This is the author's accepted manuscript. The final version of this article has been published by BioMed Central: http://www.biomedcentral.com/1746-6148/10/168