Search

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provided long-lasting correction of reprogramming and broad disease phenotypes. These same control points worked directly in mouse and human basal ESC organoids. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury., Introduction Epithelial barriers maintain a fundamental responsibility to respond to injuries from the full range of environmental toxins and infectious agents. This role depends critically on carefully controlled growth and [...]

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge., Overview The HIV pandemic has claimed more than 40 million lives and has been a galvanizing force in research into the prevention, pathogenesis, and treatment of infectious diseases. It has [...]

Introduction Phenotypic plasticity is a hallmark of cancer (1-3). In advanced prostate cancer, up to 15%-20% of patients develop resistance to androgen receptor-directed (AR-directed) therapies through conversion from an androgen-driven [...], Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).

Various nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency., Author(s): Philip Newsholme [sup.1] Author Affiliations: (1) Curtin Medical School Faculty of Health Sciences and Curtin Health Innovation Research Institute, Curtin University, Perth, Australia Introduction The immune system protects the [...]

Background/Objectives Immune-mediated inflammatory diseases (IMIDs) are prevalent diseases. There is, however, a lack of understanding of the link between diet and IMIDs, how much dietary patterns vary between them and if there are food groups associated with a worsening of the disease. Subjects/Methods To answer these questions we analyzed a nation-wide cohort of n = 11,308 patients from six prevalent IMIDs and 2050 healthy controls. We compared their weekly intake of the major food categories, and used a Mendelian randomization approach to determine which dietary changes are caused by disease. Within each IMID, we analyzed the association between food frequency and disease severity. Results After quality control, n = 11,230 recruited individuals were used in this study. We found that diet is profoundly altered in all IMIDs: at least three food categories are significantly altered in each disease (P < 0.05). Inflammatory bowel diseases showed the largest differences compared to controls (n [greater than or equal to] 8 categories, P < 0.05). Mendelian randomization analysis supported that some of these dietary changes, like vegetable reduction in Crohn's Disease (P = 2.5 × 10.sup.-10, OR(95% CI) = 0.73(0.65, 0.80)), are caused by the disease. Except for Psoriatic Arthritis and Systemic Lupus Erythematosus, we have found [greater than or equal to]2 food groups significantly associated with disease severity in the other IMIDs (P < 0.05). Conclusions This cross-disease study demonstrates that prevalent IMIDs are associated to a significant change in the normal dietary patterns. This variation is highly disease-specific and, in some cases, it is caused by the disease itself. Severity in IMIDs is also associated with specific food groups. The results of this study underscore the importance of studying diet in IMIDs., Author(s): Antonio Julià [sup.1] , Sergio H. Martínez-Mateu [sup.1] , Eugeni Domènech [sup.2] [sup.3] , Juan D. Cañete [sup.4] , Carlos Ferrándiz [sup.2] , Jesús Tornero [sup.5] , Javier P. [...]

Genetic, neurobiological, neurochemical, environmental factors and their interactions contribute to autism phenotypes. Blood from 48 (age range: 4-17) autism spectrum disorder diagnosed patients (ASD) and 38 age- and gender-matched healthy control subjects was analyzed for numbers of neutrophils, lymphocytes, monocytes, albumin, serum Ischemia-Modified Albumin (IMA) levels and myeloperoxidase activity. The serum IMA levels, myeloperoxidase activity and peripheral blood mononuclear cells count were significantly higher in ASD cases than in the control subjects. There were no significant differences in albumin levels between the patient and control groups. These results suggest that the immune system, oxidative stress and myeloperoxidase activity may be activated in ASD. There is a clinical benefit from the early detection of ASD using myeloperoxidase activity, IMA levels and monocyte counts., Author(s): Mehmet Fatih Ceylan [sup.1] , Selma Tural Hesapcioglu [sup.1] , Cansu Pinar Yavas [sup.1] , Almila Senat [sup.2] , Ozcan Erel [sup.2] Author Affiliations: (1) grid.449874.2, 0000 0004 0454 [...]

To evaluate evidence for the role of probiotic supplementation in enhancing natural killer (NK) cell function in healthy elderly individuals. Five electronic databases were searched, and references of included articles and eligible reviews up to December 2019, with English language and human subject restrictions, were examined. Two independent reviewers identified randomized control trials (RCTs) of probiotic supplementation influencing NK cell function in healthy elderly individuals, assessed the quality of every article, and extracted data for subsequent meta-analysis. We identified six eligible trials including 364 healthy elderly subjects. Trials were heterogeneous in study design and probiotic supplementation (including genus, strain, dose, and duration). Five trials used Lactobacillus interventions alone or in combination with Bifidobacterium. Only one trial focused on Bacillus coagulans. The duration of supplementation ranged from 3 to 12 weeks, and the doses, from 1 × 10.sup.9 to 4 × 10.sup.10 colony-forming units. Pooling data of eligible trials showed that probiotics significantly (P < 0.05) increased NK cell activity in healthy elderly individuals (standardized mean difference = 0.777, 95% confidence interval: 0.187--1.366, P = 0.01, I.sup.2 = 84.6%). Although we obtained a significant outcome, the data do not provide convincing evidence for associations between probiotic supplementation and enhancement of NK cell function, given the small final number and very large heterogeneity. More RCTs with sufficient sample sizes and long-term follow-up are needed to focus on optimal probiotic dose, species, and duration of supplementation for healthy elderly individuals., Author(s): Qifeng Gui [sup.1] [sup.2] , Ange Wang [sup.1] [sup.2] , Xinxiu Zhao [sup.1] [sup.2] , Shunmei Huang [sup.1] [sup.2] , Zhongju Tan [sup.1] [sup.2] , Chi Xiao [sup.3] , [...]

BACKGROUND. Immune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like [CD8.sup.+] T cells and whether they have prognostic relevance. METHODS. We analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). RESULTS. We show that senescent-like bone marrow [CD8.sup.+] T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival (OS). We defined what we believe to be new immune effector dysfunction (IED) signatures using 2 gene expression profiling platforms and reported that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes; these scores were a more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly shorter OS. CONCLUSION. The IED scores provided improved AML-risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit. TRIAL REGISTRATION. ClinicalTrials.gov; NCT02845297. FUNDING. John and Lucille van Geest Foundation, Nottingham Trent University's Health & Wellbeing Strategic Research Theme, NIH/NCI P01CA225618, Genentech-imCORE ML40354, Qatar National Research Fund (NPRP8-2297-3-494)., Introduction Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease (1). We recently identified BM microenvironmental transcriptomic profiles that stratify patients with newly diagnosed AML into immune-infiltrated and [...]

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-[alpha] is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-[alpha] in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR[beta] sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and [CD8.sup.+] T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of [CD8.sup.+] recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-[alpha] reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-[alpha] had costimulatory effects on TCR signaling. Our work supports the combination of IFN-[alpha] with TKI therapy, as IFN-[alpha] broadens the immune repertoire and restores immunological function., Introduction Currently, the ultimate therapeutic goal in patients with chronic-phase chronic myeloid leukemia (CP-CML) is to achieve deep molecular remission, which would allow the discontinuation of tyrosine kinase inhibitor (TKI) [...]

Introduction: HIV-controllers have the ability to spontaneously maintain viraemia at low or undetectable levels in the absence of antiretroviral treatment. Furthermore, HIV-controllers seem to have a superior capacity to spontaneously clear hepatitis C virus (HCV) compared to non HIV-controllers. Some of these subjects eventually lose HIV-controller status (transient controllers), whereas some HIV-controllers show a persistent natural HIV control (persistent controllers). We aimed to analyse whether persistent controllers have superior capacity to spontaneously clear HCV compared to transient controllers. Methods: We recruited HIV-controllers from January 1981 up to October 2016 with available antibodies to HCV (anti-HCV) data (n = 744). Factors associated with HIV spontaneous control in relation to HCV status were analysed in persistent and transient HIV-controllers with anti-HCV positive (n = 202 and n = 138 respectively) in comparison with 1700 HCV positive non HIV-controllers recruited from January 1981 up to March 2018, bivariate and multivariate analyses, following a logistic regression model, were applied. In addition, the factors related to the loss and time to lose HIV-controller status were explored (n = 744) using Log rank test and Kaplan-Meier curves, in this case the multivariate analysis consisted in a Cox regression model. Results: A higher frequency of HCV spontaneous clearance was found in persistent HIV-controllers (25.5%) compared to non-controllers (10.2%). After adjusting for potential confounders, as sex, age, HIV transmission risk, [CD4.sup.+] T-cell nadir and time of follow-up, HCV clearance was independently associated with persistent HIV spontaneous control (p = 0.002; OR (95% Cl) = 2.573 (1.428 to 4.633) ), but not with transient spontaneous control (p = 0.119; 1.589 (0.888 to 2.845) ). Furthermore, persistent HIV-controllers were more likely to spontaneously clear the HCV in comparison with transient controllers (p = 0.027; 0.377 (0.159 to 0.893). Finally not to lose or lengthen the time of losing this control was independently associated with HCV spontaneous clearance (p = 0.010; 0.503 (0.297 to 0.850). Conclusions: This study shows an association between spontaneous persistent HIV-control and HCV spontaneous clearance. The study findings support the idea of preserved immune mechanisms in persistent HIV control implicated in HCV spontaneous clearance. These results highlight persistent HIV-controllers but not transient controllers as a good model of functional HIV cure. Keywords: HIV; HCV; HIV-controllers; persistent; transient; HCV spontaneous clearance Additional information may be found under the Supporting Information tab for this article., 1 | INTRODUCTION HIV-controllers are a small group of subjects ( On the other hand, HIV-controllers as a whole seem to have a higher capacity to spontaneously clear hepatitis C [...]