Effects of BCG vaccination on donor unrestricted T cells in two prospective cohort studies.

BACKGROUND: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1-restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. METHODS: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. FINDINGS: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of CD26+CD161+TRAV1-2- IFN-γ-expressing CD4+ T cells in infants. INTERPRETATION: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. FUNDING: Aeras, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

COPD in the time of COVID-19: an analysis of acute exacerbations and reported behavioural changes in patients with COPD.

INTRODUCTION: The impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and associated "lockdown" measures on acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is unknown. We aimed to evaluate the change in AECOPD treatment frequency during the first 6 weeks of lockdown in the UK compared with 2019 and assess changes in self-reported behaviour and wellbeing. METHODS: In this observational study in Leicestershire, UK, patients with COPD under a secondary care clinic were recruited. Exacerbation frequency in the first 6 weeks of COVID-19 lockdown was compared with the same period in 2019 using electronic health records. A telephone survey was used to assess changes in anxiety, inhaler adherence, physical activity and behaviour during the pre-lockdown and lockdown periods compared with normal. RESULTS: 160 participants were recruited (mean±sd age 67.3±8.1 years, 88 (55%) males, mean±sd forced expiratory volume in 1 s 34±13% pred). 140 (88%) reported at least one AECOPD in the previous year. Significantly more community managed exacerbations were observed in 2020 compared with 2019 (126 versus 99; p=0.026). The increase was a result of multiple courses of treatment, with a similar proportion of patients receiving at least one course (34.4% versus 33.8%). DISCUSSION: During lockdown participants reported significantly increased anxiety, adherence to their preventative inhalers and good adherence to shielding advice (all p<0.001). A significant reduction in self-reported physical activity and visitors was reported (both p<0.001). CONCLUSIONS: Treatment for AECOPD events increased during the first 6 weeks of the SARS-CoV-2 pandemic in the UK compared with 2019. This was associated with increased symptoms of anxiety and significant behavioural change.

Targeting the Nuclear Import Receptor Kpnß1 as an Anticancer Therapeutic.

Karyopherin beta 1 (Kpnß1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnß1 expression was found in certain cancers and Kpnß1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnß1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnß1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnß1 and known Kpnß1 cargoes NFAT, NFκB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpnß1. INI-43 treatment elicited a G2-M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpnß1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560-73. ©2016 AACR.