Sociodemographic factors affecting perceived stress during pregnancy and the association with immune-mediator concentrations

Objectives Determine which sociodemographic factors are most associated with increased maternal perceived stress during pregnancy. Evaluate the association between maternal stress and plasma immune-mediator concentrations (IMCs). Methods As part of a prospective, randomized clinical trial, 247 participants completed a Perceived Stress Scale survey (PSS-10) during each trimester of pregnancy. Blood samples were collected from participants and were analyzed for 25-hydroxyvitamin D (25(OH)D) concentration and for several IMCs: interferon-gamma, interleukins (IL-) IL-2, IL-4, IL-5, IL-10, vascular endothelial growth factor, c-reactive protein, and tumor necrosis factor alpha (TNF-α) (R&D Elisa). The potential associations between PSS-10 scores, sociodemographic factors, and IMCs were assessed. Results In bivariate analysis, participants who were not married and/or had high risk pregnancies were more likely to have increased PSS-10 scores (p<0.05). Increased PSS-10 scores were associated with higher serum concentrations of IL-2 and TNF-α, and decreased concentrations of IL-10 and 25(OH)D. In linear regression analysis, single marital status, high-risk pregnancy, IL-2, and TNF-α were independent predictors of PSS-10 scores. Conclusions This study identifies specific sociodemographic factors that are associated with increased perceived stress during pregnancy. This study also provides evidence that increased perceived stress is associated with physiological changes as measured by changes in circulating IL-2, TNF-α, IL-10, and 25(OH)D concentrations.

The Roadmap of RANKL/RANK Pathway in Cancer

The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma

Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 – 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.

Development and validation of a mouse model of contemporary cannabis smoke exposure

Cannabis is widely used for both recreational and medicinal purposes. Inhalation of combusted cannabis smoke is the most common mode of drug consumption, exposing the lungs to the pharmacologically active ingredients, including tetrahydrocannabinol (THC) and cannabidiol (CBD). While the relationship between cannabis smoke exposure and compromised respiratory health has yet to be sufficiently defined, previous investigations suggest that cannabis smoke may dysregulate pulmonary immunity. Presently, there exists few pre-clinical animal models that have been extensively validated for contemporary cannabis smoke exposure. To address this need, we developed a mouse model with readouts of total particular matter, serum cannabinoid and carboxyhemoglobin levels, lung cellular responses, and immune mediator production.Using a commercially available smoke exposure system and a cannabis source material of documented THC/CBD composition, we exposed mice to a total particulate matter of 698.89 (sd=66.09) µg·L−1 and demonstrate increases in serum cannabinoids and carboxyhemoglobin. We demonstrate that cannabis smoke modulates immune cell populations and mediators in both male and female BALB/c mice. This modulation is highlighted by increases in airway and lung tissue macrophage populations, including tissue-resident alveolar macrophages, monocyte-derived alveolar macrophages, and interstitial macrophage subpopulations. No changes in airway or lung tissue infiltration of neutrophils were observed. Immune mediator analysis indicated significant upregulation of MDC, TARC, and VEGF within the lung tissue of cannabis smoke exposed mice. This accessible and reproducible smoke exposure model provides a foundation to explore the impact of chronic cannabis exposures and/or co-exposures with pathogens of clinical relevance, such as influenza.

African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants

ObjectiveTo evaluate for racial differences in triggering receptor expressed on myeloid cells 2 (TREM2), a key immune mediator in Alzheimer disease, the levels of CSF soluble TREM2 (sTREM2), and the frequency of associated genetic variants were compared in groups of individuals who self-reported their race as African American (AA) or non-Hispanic White (NHW).MethodsCommunity-dwelling older research participants underwent measurement of CSF sTREM2 concentrations and genetic analyses.ResultsThe primary cohort included 91 AAs and 868 NHWs. CSF sTREM2 levels were lower in the AA compared with the NHW group (1,336 ± 470 vs 1,856 ± 624 pg/mL, p < 0.0001). AAs were more likely to carry TREM2 coding variants (15% vs 3%, p < 0.0001), which were associated with lower CSF sTREM2. AAs were less likely to carry the rs1582763 minor allele (8% vs 37%, p < 0.0001), located near MS4A4A, which was associated with higher CSF sTREM2. These findings were replicated in an independent cohort of 23 AAs and 917 NHWs: CSF sTREM2 levels were lower in the AA group (p = 0.03), AAs were more likely to carry coding TREM2 variants (22% vs 4%, p = 0.002), and AAs were less likely to carry the rs1582763 minor allele (16% vs 37%, p = 0.003).ConclusionsOn average, AAs had lower CSF sTREM2 levels compared with NHWs, potentially because AAs are more likely to carry genetic variants associated with lower CSF sTREM2 levels. Importantly, CSF sTREM2 reflects TREM2-mediated microglial activity, a critical step in the immune response to amyloid plaques. These findings suggest that race may be associated with risk for genetic variants that influence Alzheimer disease–related inflammation.

Combination of the Probiotics Lacticaseibacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis, BB-12 Has Limited Effect on Biomarkers of Immunity and Inflammation in Older People Resident in Care Homes: Results From the Probiotics to Reduce Infections iN CarE home reSidentS Randomized, Controlled Trial

Aging is associated with a decline in many components of the immune system (immunosenescence). Probiotics may improve the immune response in older people. The objective was to determine the effect of the combination of two probiotic organisms [Lacticaseibacillus (previously known as Lactobacillus) rhamnosus GG (LGG) and Bifidobacterium animalis subsp. lactis, BB-12 (BB-12)] on a range of immune biomarkers measured in the blood of older people resident in care homes in the UK. In a randomized controlled trial, older people [aged 67–97 (mean 86) years] resident in care homes received the combination of LGG+BB-12 (1.3–1.6 × 109 CFU per day) or placebo for up to 12 months. Full blood count, blood immune cell phenotypes, plasma immune mediator concentrations, phagocytosis, and blood culture responses to immune stimulation were all measured. Response to seasonal influenza vaccination was measured in a subset of participants. Paired samples (i.e., before and after intervention) were available for 30 participants per group. LGG and BB-12 were more likely to be present in feces in the probiotic group and were present at higher numbers. There was no significant effect of the probiotics on components of the full blood count, blood immune cell phenotypes, plasma immune mediator concentrations, phagocytosis by neutrophils and monocytes, and blood culture responses to immune stimulation. There was an indication that the probiotics improved the response to seasonal influenza vaccination with significantly (p = 0.04) higher seroconversion to the A/Michigan/2015 vaccine strain in the probiotic group than in the placebo group (47 vs. 15%).

Development and validation of a mouse model of contemporary cannabis smoke exposure

ABSTRACTCannabis is widely used for both recreational and medicinal purposes. Inhalation of combusted cannabis smoke is the most common mode of drug consumption, exposing the lungs to the pharmacologically active ingredients, including tetrahydrocannabinol (THC) and cannabidiol (CBD). While the relationship between cannabis smoke exposure and compromised respiratory health has yet to be sufficiently defined, previous investigations suggest that cannabis smoke may dysregulate pulmonary immunity. Presently, there exists few pre-clinical animal models that have been extensively validated for contemporary cannabis smoke exposure. To address this need, we developed a mouse model with readouts of total particular matter, serum cannabinoid and carboxyhemoglobin levels, lung cellular responses, and immune mediator production.Using a commercially available smoke exposure system and a cannabis source material of documented THC/CBD composition, we exposed mice to a total particulate matter of 698.89 (SD = 66.09) µg/L and demonstrate increases in serum cannabinoids and carboxyhemoglobin. We demonstrate that cannabis smoke modulates immune cell populations and mediators in both male and female BALB/c mice. This modulation is highlighted by increases in airway and lung tissue macrophage populations, including tissue-resident alveolar macrophages, monocyte-derived alveolar macrophages, and interstitial macrophage subpopulations. No changes in airway or lung tissue infiltration of neutrophils were observed. Immune mediator analysis indicated significant upregulation of MDC, TARC, and VEGF within the lung tissue of cannabis smoke exposed mice. This accessible and reproducible smoke exposure model provides a foundation to explore the impact of chronic cannabis exposures and/or co-exposures with pathogens of clinical relevance, such as influenza.

Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients

Introduction The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon-free direct-acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance. Objective Here, we aimed at evaluating the effects of direct-acting antiviral therapy-induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct-acting antiviral-mediated hepatitis C clearance in cirrhosis patients was investigated. Methods Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed post-treatment hepatocellular carcinoma and their respective negative controls, before and after direct-acting antiviral treatment. Results Elevated pre-therapy concentrations of specific soluble immune mediators including MCP-3, GDNF, CDCP1, IL-17C, IL-17A, SLAMF1, CCL11, FGF-5, LIF-R, IL10, IL-10RA, IL-15RA, beta NGF, CCL28, CCL25 and NT-3 distinguished patients who developed post-treatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF-5 and IL-15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pre-therapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the post-therapy carcinoma-free patients experienced significant ameliorations. Conclusions These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct-acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct-acting antiviral therapies would be superior to the risk of developing carcinoma.