PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity.

PARP7 is a monoPARP that catalyzes the transfer of single units of ADP-ribose onto substrates to change their function. Here, we identify PARP7 as a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 restores type I interferon (IFN) signaling responses to nucleic acids in tumor models. Restored signaling can directly inhibit cell proliferation and activate the immune system, both of which contribute to tumor regression. Oral dosing of the PARP7 small-molecule inhibitor, RBN-2397, results in complete tumor regression in a lung cancer xenograft and induces tumor-specific adaptive immune memory in an immunocompetent mouse cancer model, dependent on inducing type I IFN signaling in tumor cells. PARP7 is a therapeutic target whose inhibition induces both cancer cell-autonomous and immune stimulatory effects via enhanced IFN signaling. These data support the targeting of a monoPARP in cancer and introduce a potent and selective PARP7 inhibitor to enter clinical development.

Rhesus macaques as a tractable physiological model of human ageing.

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population. This article is part of the theme issue 'Evolution of the primate ageing process'.

Synthesis of stable isotope-labelled firocoxib.

Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[13 C6 ] in an overall yield of 35% from the commercially available bromobenzene-[13 C6 ]. The synthetic route involved the preparation of the key intermediate phenyl-13 C6 -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[13 C,2 H3 ] via the sulfinic acid derivative of firocoxib and methyl iodide-[13 C,2 H3 ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.

Atrial natriuretic peptide-Fc, ANP-Fc, fusion proteins: semisynthesis, in vitro activity and pharmacokinetics in rats.

Atrial natriuretic peptide (ANP) may be a useful molecule for the treatment of cardiovascular diseases due to its potent natriuretic effects. In an effort to prolong the short in vivo half-life of ANP, fusions of the peptide to the Fc domain of IgG were generated using a semisynthetic methodology. Synthetic ANP peptides were synthesized with thioesters at either the N- or C-termini of the peptide and subsequently linked to the N-terminus of recombinantly expressed Fc using native chemical ligation. The linker length between the ANP and Fc moieties was varied among 2, 11, or 16 amino acids. In addition, either one ("monomeric") or two ("dimeric") ANP peptides were linked to Fc to study whether this modification had an effect on in vitro activity and/or in vivo half-life. The various constructs were studied for in vitro activity using a cell-based cGMP assay. The ANP-Fc fusion constructs were between 16- and ∼375-fold weaker than unconjugated ANP in this assay, and a trend was observed where the most potent conjugates were those with longer linkers and in the dimeric configuration. The pharmacokinetics of several constructs were assessed in rats, and the half-life of the ANP-Fc's were found to be approximately 2 orders of magnitude longer than that of the unconjugated peptide. There was no significant difference in terminal half-life between the monomeric and dimeric constructs (2.8-5.5 h), but a trend was observed where the C(max) of the monomeric constructs was approximately 3-fold higher than that of the dimeric constructs, although the origin of this effect is not understood. These novel ANP-Fc fusion constructs hold promise for future therapeutic application in the treatment of cardiovascular diseases.