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Introduction. Doxazosin, a selective α1-adrenoreceptor antagonist widely used in the management of benign prostatic hyperplasia (BPH), has been shown to induce apoptosis in androgen-independent (AI) and PTEN (phosphatases and tensin homolog)-negative prostate cancer (PC) cells. The objective of this study was to assess the effects of doxazosin on the growth of PC cells with a functional PTEN/PI3K/Akt pathway in relation to cell androgen sensitivity and Bcl-2 expression. Material and methods. The DU145 cell line and two derivatives: 1) DKC9 [DU145 (Bcl2 +/+)] and 2) DAR19 [DU145 (AR+/+)] were used. The effect of doxazosin on i) cell proliferation and ii) Akt phosphorylation was measured using the MTT assay and Western blotting, respectively. Results. Doxazosin caused significant concentration, but not time-dependent, decrease in cell viability. The threshold of sensitivity to the compound differed between the cell lines and was the lowest in the parental cell line. In DAR 19 cells, AR-mediated signaling further increased cell resistance to doxazosin. In all cell lines, doxazosin-induced apoptosis was rescued by EGF stimulation and, in DAR19 cells, by AR activation. Doxazosin reduced basal and EGF-/DHT-induced Akt phosphorylation. Conclusions. This study demonstrates that doxazosin induces apoptosis in PTEN-positive AI PC cells, at least partially, via Akt deactivation and that over-expression of Bcl-2 or AR increases cell resistance to the drug. These results imply that translational potential of doxazosin depends on phenotypic characteristics of PC cells and provide evidence for limitations to its application in hormone refractory tumors. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) elicits a potent T-cell response in humans that appears to protect the host from virus-associated disease. Despite facing strong host defense mechanisms, CMV remains as a lifelong infection that may reactivate and cause life-threatening disease in immunocompromised individuals. This persistence is probably assisted by expression of immune subversion proteins of the virus encoded by genes belonging to the US gene family. These proteins modulate major histocompatibility complex expression in infected cells and bias in vitro experiments toward the detection of only certain specificities. We have combined the use of recombinant CMV, lacking the US2 to US11 region genes, and cytoplasmic gamma interferon staining to define a more accurate assessment of CMV-specific responses in vivo. Recombinant CMV stimulation reveals a CD8 response much larger than that of parental virus in all donors tested. In some cases, this represented up to 10-fold increases in the number of cells detected. Responses were directed mainly against pp65, IE-1, and pp50 in the majority of donors. In addition, previously unreported IE-2-specific T-cell responses could be detected in a minority of cases. Furthermore, we observed a less marked increase in the response to mutant CMV by CD4 T cells in some donors. This suggests that a much broader T-cell response to CMV exists in vivo than is revealed by restimulation with wild-type virus and adds to the evidence that the efficacy of immune evasion strategies may not be as absolute as previously believed. [ABSTRACT FROM AUTHOR]

Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals. [ABSTRACT FROM AUTHOR]

VIVALDI (ISRCTN14447421) is a government-funded longitudinal open observational cohort study of staff and residents in care homes for older people in England. The study aimed to describe epidemiology (including seroprevalence) and immune responses to COVID-19 in a subset of care homes, in the context of extremely high mortality in this setting, in the first 12-18 months of the pandemic. Data linkage to routine health data was undertaken for all staff and residents and a subset of individuals who consented to sequential blood sampling to investigate SARS-CoV-2 immunity. This paper aims to describe the samples stored within the VIVALDI biobank and associated linked data, available for use by researchers. Over 70,000 individuals from 346 care homes were included in the data linkage cohort (1 st March 2020-31 st March 2023). 4971 samples from 2264 individuals (1415 staff, 827 residents) collected between 29 th October 2020 and 10 th March 2023 are stored. Amongst these samples, there was a maximum of seven per participant however, 217 (26.2%) residents and 551 (38.9%) staff participated in one round only. Key study findings include high COVID-19 seroprevalence among surviving residents, exceeding rates in community-dwelling peers. COVID-19 vaccinations generated robust immune responses in staff and residents which waned, supporting the need for booster vaccination, particularly in response to new variants. Prior infection significantly improved vaccine-induced immune responses, however protection from infection declined following Omicron variant emergence. This is a unique cohort of pre- and post-infection samples linked to data on COVID-19 infections, vaccinations, and outcomes. The cohort spans host immune response evolution to infection and vaccination in this rarely sampled population of frail older care home residents who are especially vulnerable to infection and severe outcomes. These samples can be used to investigate biological mechanisms behind disparate infection responses in older people and make a valuable contribution to research into ageing., Competing Interests: Competing interests: LS, AC, AH, and OS report grants from the Department of Health & Social Care and the UK Health Security Agency (UKHSA) during the conduct of the study and LS is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. AH reports funding from the COVID Core Studies Programme and is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health and Environmental Modelling Group of the Scientific Advisory Group for Emergencies. No other competing interests were disclosed., (Copyright: © 2024 Krutikov M et al.)