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Tumor-associated myeloid cells maintain immunosuppressive microenvironments within tumors. Identification of myeloid-specific receptors to modulate tumor-associated macrophage and myeloid-derived suppressor cell (MDSC) functions remains challenging. The leukocyte immunoglobulin-like receptor B (LILRB) family members are negative regulators of myeloid cell activation. We investigated how LILRB targeting could modulate tumor-associated myeloid cell function. LILRB2 antagonism inhibited receptor-mediated activation of SHP1/2 and enhanced proinflammatory responses. LILRB2 antagonism also inhibited AKT and STAT6 activation in the presence of M-CSF and IL-4. Transcriptome analysis revealed that LILRB2 antagonism altered genes involved in cell cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade effectively suppressed granulocytic MDSC and Treg infiltration and significantly promoted in vivo antitumor effects of T cell immune checkpoint inhibitors. Furthermore, LILRB2 blockade polarized tumor-infiltrating myeloid cells from non-small cell lung carcinoma tumor tissues toward an inflammatory phenotype. Our studies suggest that LILRB2 can potentially act as a myeloid immune checkpoint by reprogramming tumor-associated myeloid cells and provoking antitumor immunity.

Tumor-mediated regulation of the host immune system involves an intricate signaling network that results in the tumor's inherent survival benefit. Myeloid cells are central in orchestrating the mechanisms by which tumors escape immune detection and continue their proliferative programming. Myeloid cell activation has historically been classified using a dichotomous system of classical (M1-like) and alternative (M2-like) states, defining general pro- and anti-inflammatory functions, respectively. Explosions in bioinformatics analyses have rapidly expanded the definitions of myeloid cell pro- and anti-inflammatory states with different combinations of tissue- and disease-specific phenotypic and functional markers. These new definitions have allowed researchers to target specific subsets of disease-propagating myeloid cells in order to modify or arrest the natural progression of the associated disease, especially in the context of tumor-immune interactions. Here, we discuss the myeloid cell contribution to solid tumor initiation and maintenance, and strategies to reprogram their phenotypic and functional fate, thereby disabling the network that benefits tumor survival.

Tuberculosis is a leading cause of death in mankind due to infectious agents, and Mycobacterium tuberculosis (Mtb) infects and survives in macrophages (MФs). Although MФs are a major niche, myeloid-derived suppressor cells (MDSCs) are an alternative site for pathogen persistence. Both MФs and MDSCs express varying levels of leukocyte immunoglobulin-like receptor B (LILRB), which regulate the myeloid cell suppressive function. Herein, we demonstrate that antagonism of LILRB2 by a monoclonal antibody (mab) induced a switch of human MDSCs towards an M1-macrophage phenotype, increasing the killing of intracellular Mtb. Mab-mediated antagonism of LILRB2 alone and its combination with a pharmacological blockade of SHP1/2 phosphatase increased proinflammatory cytokine responses and phosphorylation of ERK1/2, p38 MAPK, and NF-kB in Mtb-infected MDSCs. LILRB2 antagonism also upregulated anti-mycobacterial iNOS gene expression and an increase in both nitric oxide and reactive oxygen species synthesis. Because genes associated with the anti-mycobacterial function of M1-MФs were enhanced in MDSCs following mab treatment, we propose that LILRB2 antagonism reprograms MDSCs from an immunosuppressive state towards a pro-inflammatory phenotype that kills Mtb. LILRB2 is therefore a novel therapeutic target for eradicating Mtb in MDSCs.

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Cancer is currently the second leading cause of death in the United States. Leukemia, a cancer of blood cells, is the most common form of cancer in children and is becoming increasingly more common as the population ages. Leukemia usually begins in blood cells in the bone marrow and is characterized as the infiltration of the bone marrow, blood, and other tissues with malignantly differentiated hematopoietic cells. Acute myeloid leukemia (AML) is cancer of myeloid cells and progresses rapidly in patients. Standard primary treatment involves chemotherapy with a combination of cytarabine (AraC) and an anthracycline such as daunorubicin to induce remission and may follow with hematopoietic stem cell transplant. Complete remission in patients under the age of 60 is approximately 60-85% with a 5-year disease free survival of 30%. In patients older than the age of 60, complete remission is markedly lower at 40-55% and 5-year disease free survival is drastically lower at 5-10%. The standard high dose intermittent AraC (HiDAC) or any other AraC regimen may be too toxic for some patients, especially those that are older and may cause cardiac disease in some patients. This prompts the need for alternative and new modalities of treatment. The identification of a myeloid cell surface specific receptor that regulates leukemia cell differentiation and increases drug sensitivity to lower the dose of chemotherapeutic drugs is crucial for the treatment success of hematological malignancies. The leukocyte immunoglobulin-like receptor type B (LILRB) family (LILRB1-5) originally found to be expressed in healthy myeloid cells can also be found expressed in AML cells. I hypothesize that the LILRB family of receptors, specifically LILRB3 is a novel target for leukemia treatment and that its blockade can inhibit proliferation of leukemia cells and tumor progression. In this study, I found that LILRB receptors can be further induced under stress and inflammatory conditions. LILRB3 blockade can synergistically inhibit leukemia cell proliferation and leukemia progression with chemotherapy or inflammatory stimulation. The myeloid lineage differentiation transcription factors, PU.1, C/EBPα, C/EBPβ, and IRF were upregulated upon treatment with LILRB3 blocking antibodies whereas phosphorylation of proliferation-related proteins, e.g. AKT, and Rb, were decreased. Transcriptome analysis predicts a decrease in EIF2 and mTOR signaling and downregulation in leukemia stemness signature genes which supports that LILRB3 blockade can inhibit leukemia progression. These results suggest potential novel mechanisms for transition from a proliferative malignant state to a more mature and differentiated state in leukemia cells, potentially rendering them more sensitive to chemotherapy.

Tumor-associated myeloid cells maintain immunosuppressive microenvironments within tumors. Identification of myeloid-specific receptors to modulate tumor-associated macrophage and myeloid-derived suppressor cell (MDSC) functions remains challenging. The leukocyte immunoglobulin-like receptor B (LILRB) family members are negative regulators of myeloid cell activation. We investigated how LILRB targeting could modulate tumor-associated myeloid cell function. LILRB2 antagonism inhibited receptor-mediated activation of SHP1/2 and enhanced proinflammatory responses. LILRB2 antagonism also inhibited AKT and STAT6 activation in the presence of M-CSF and IL-4. Transcriptome analysis revealed that LILRB2 antagonism altered genes involved in cell cytoskeleton remodeling, lipid/cholesterol metabolism, and endosomal sorting pathways, as well as changed differentiation gene networks associated with inflammatory myeloid cells as opposed to their alternatively activated phenotype. LILRB2 blockade effectively suppressed granulocytic MDSC and Treg infiltration and significantly promoted in vivo antitumor effects of T cell immune checkpoint inhibitors. Furthermore, LILRB2 blockade polarized tumor-infiltrating myeloid cells from non-small cell lung carcinoma tumor tissues toward an inflammatory phenotype. Our studies suggest that LILRB2 can potentially act as a myeloid immune checkpoint by reprogramming tumor-associated myeloid cells and provoking antitumor immunity.

Improving maternal nutrition practices during pregnancy is essential to save lives and improve health outcomes for both mothers and babies. This paper examines the maternal, household, and health service factors influencing maternal nutrition practices in the context of a large scale maternal, newborn, and child health (MNCH) program in Bangladesh. Data were from a household survey of pregnant (n = 600) and recently delivered women (n = 2,000). Multivariate linear and logistic regression analyses were used to examine the determinants of three outcomes: consumption of iron and folic acid (IFA) tablets, calcium tablets, and diverse diets. Women consumed 94 ± 68 IFA and 82 ± 66 calcium tablets (out of 180 as recommended) during pregnancy, and only half of them consumed an adequately diverse diet. Good nutrition knowledge was the key maternal factor associated with higher consumption of IFA (β = 32.5, 95% CI: 19.5, 45.6) and calcium tablets (β ~31.9, 95% CI: 20.9, 43.0) and diverse diet (OR = 1.8, 95% CI: 1.0-3.1), compared to poor knowledge. Women's self-efficacy in achieving the recommended practices and perception of enabling social norms were significantly associated with dietary diversity. At the household level, women who reported a high level of husband's support were more likely to consume IFA (β = 25.0, 95% CI: 18.0, 32.1) and calcium (β = 26.6, 95% CI: 19.4, 33.7) tablets and diverse diet (OR = 1.9, 95% CI: 1.2, 3.3), compared to those who received low support. Health service factors associated with higher intakes of IFA and calcium tablets were early and more prenatal care visits and receipt of free supplements. Combined exposure to several of these factors was attributed to the consumption of an additional 46 IFA and 53 calcium tablets and 17% higher proportions of women consuming diverse diets. Our study shows that improving knowledge, self-efficacy and perceptions of social norms among pregnant women, and increasing husbands' support, early registration in prenatal care, and provision of free supplements will largely improve maternal nutrition practices.

Limited evidence exists on the complex relationship among interventions, early initiation of breastfeeding (EIBF), prelacteal feeding and exclusive breastfeeding (EBF). We examined whether early breastfeeding practices are associated with EBF and how much improving EIBF and non‐prelacteal feeding contributes to increased prevalence of EBF. Survey data were collected in 2010 and 2014 as part of impact evaluations of Alive & Thrive (A&T) interventions to improve infant and young child feeding (IYCF) practices in Bangladesh, Vietnam and Ethiopia. Multivariable logistic regression analyses were used to examine effects of interventions and early breastfeeding practices on EBF. Structural equation modelling quantified the direct and indirect effects of interventions (via improving EIBF and non‐prelacteal feeding) on EBF. Although breastfeeding is nearly universal in all three countries (≥98%), delayed initiation of breastfeeding is prevalent (>60%) and prelacteal feeding is common. EIBF alone was not associated with EBF, whereas non‐prelacteal feeding was associated with 1.6–3.5 higher odds of EBF. Intervention exposure affected breastfeeding practices in all three countries; these impacts were amplified among those who practiced EIBF or non‐prelacteal feeding [odds ratio (OR) = 11 and 27.5 in Bangladesh and 6.5 and 11.5 in Vietnam, respectively]. The paths through EIBF and non‐prelacteal feeding explained 13%–18% of the effect of the interventions on EBF. Early breastfeeding practices influence EBF, but interventions aimed only at the initiation and early days of breastfeeding will be inadequate to promote EBF. Social and behaviour change interventions should simultaneously target EIBF, non‐prelacteal feeding and EBF to support optimal breastfeeding practices.

This paper draws on MacIntyre’s ethical thought to illuminate a hitherto underexplored religious context for business ethics, that of the Amish. It draws on an empirical study of Amish settlements in Holmes County, Ohio, and aims to deepen our understanding of Amish business ethics by bringing it into contact with an ethical theory that has had a significant impact within business ethics, that of Alasdair MacIntyre. It also aims to extend MacIntyrean thought by drawing on his neglected critique of modernity in the context of business ethics. The Amish context allows us to appreciate the relationship between MacIntyre’s critique of modernity, his conception of practices and communities, and his distinctive approach to the virtues. It also helps us to better understand how the ethical life is possible within our emotivist culture.