Macrophages promote anti-androgen resistance in prostate cancer bone disease.

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Point Defects Stability, Hydrogen Diffusion, Electronic Structure, and Mechanical Properties of Defected Equiatomic γ(U,Zr) from First-Principles.

At present, many experimental fast reactors have adopted alloy nuclear fuels, for example, U-Zr alloy fuels. During the neutron irradiation process, vacancies and hydrogen (H) impurity atoms can both exist in U-Zr alloy fuels. Here, first-principles density functional theory (DFT) is employed to study the behaviors of vacancies and H atoms in disordered-γ(U,Zr) as well as their impacts on the electronic structure and mechanical properties. The formation energy of vacancies and hydrogen solution energy are calculated. The effect of vacancies on the migration barrier of hydrogen atoms is revealed. The effect of vacancies and hydrogen atom on densities of states and elastic constants are also presented. The results illustrate that U vacancy is easier to be formed than Zr vacancy. The H interstitial prefers the tetrahedral site. Besides, U vacancy shows H-trap ability and can raise the H migration barrier. Almost all the defects lead to decreases in electrical conductivity and bulk modulus. It is also found that the main effect of defects is on the U-5f orbitals. This work provides a theoretical understanding of the effect of defects on the electronic and mechanical properties of U-Zr alloys, which is an essential step toward tailoring their performance.

Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth.

Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C+CCR2+ inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis-associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.

Fluorogenic Trp(redBODIPY) cyclopeptide targeting keratin 1 for imaging of aggressive carcinomas.

Keratin 1 (KRT1) is overexpressed in squamous carcinomas and associated with aggressive pathologies in breast cancer. Herein we report the design and preparation of the first Trp-based red fluorogenic amino acid, which is synthetically accessible in a few steps and displays excellent photophysical properties, and its application in a minimally-disruptive labelling strategy to prepare a new fluorogenic cyclopeptide for imaging of KRT1+ cells in whole intact tumour tissues.

Improving the Level and Quality of Ethics Review in Chinese Medicine and Integrative Medicine.

Three features of ethics review in Chinese medicine (CM) and integrative medicine (IM) were put forward in this paper. It is consistent with the principles of ethical review in Western medicine; it has to be compliant with the laws of CM and IM; emphasis should be laid on the review of clinical practice facts and experience. Three problems were pointed out. The characteristics of CM and IM are not distinctive enough, operation procedures need to be refined and effectiveness remains to be improved. Based on the mentioned above, seven measures were proposed to improve the level and quality of ethics review in CM and IM, including better brand awareness, considerable tolerance, treatment based on disease differentiation and syndrome differentiation, scientific review and toxicity and side effects of CM, perfection of the ethics review system, reasonable procedures of ethics review and more specialized ethics review workers.

Macrophages and T lymphocytes are the predominant cells in intimal arteritis of resected renal allografts undergoing acute rejection.

BACKGROUND: In acute renal allograft rejection, T-cell-mediated processes have been generally regarded as dominant. Although there is recent evidence that macrophages play important roles in acute vascular rejection, less is known about the exact proportion of immunocytes in the intimal arteritis of renal allografts with unfavorable outcomes. METHODS: By immunohistochemical staining using nine primary antibodies, we classified the proportions of infiltrating immunocytes in intimal arteritis and glomerulitis in five allografts resected because of acute irreversible graft failure. RESULTS: All five allografts had features of antibody-mediated rejection based on criteria established by the Banff classification. In intimal arteritis, CD3+ T-lymphocytes accounted for 30.6±13.3% of the immunocytes and macrophages for 40.4±9.2%. 45.4% of the T-cells were CD8+ cytotoxic T-cells. Neutrophils were also present but accounted for a relatively low proportion of the cells (8.8±8.6%). B-cells and plasma cells all accounted for <5% of the immunocytes. NK cells were readily detected (4.2±4.2%). When we compared types of arteritis, the CD15+ neutrophils accounted for as many as 27.8±15.1% of immunocytes in V3 vasculitis and only 1.0±1.4% in V2 vasculitis. CD3+ T-lymphocytes accounted for 25.8±7.3% of immunocytes in V3 vasculitis and 41.5±7.9% in V2 vasculitis. In glomerulitis, the immunocytes were mainly macrophages (53.1±9.1%) and neutrophils (34.6±9.9%). CONCLUSION: Macrophages and T-lymphocytes accounted for the highest percentage of immunocytes in the intimal arteritis of irreversible renal failure associated with antibody-mediated rejection. 45.4% of the T-cells were CD8+ cytotoxic T-cells. Neutrophils and NK cells were also present in these lesions. The proportion of neutrophils in V3 vasculitis was much higher than in V2 vasculitis. These observations suggest that besides macrophages and T-lymphocytes, neutrophils may also play a role in the more severe arterial lesion. To our knowledge this is the first report of this observation. Macrophages and neutrophils were the main inflammatory cells in the glomerulitis of acute rejection.