clinicaltrials.gov Identifier: NCT00848900.

Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation.

The torsional mode may provide more effective lens removal with a lower level of phacoemulsification time and energy.

Highlights d A distinct B cell subset emerges in tumors after chemotherapy d B cells elicit anti-tumor T cell immunity by ICOSL d Complement signals initiated by immunogenic cell death shape B cell phenotypes d Tumor CD55 expression determines the opposite effects of B cells in tumors

The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.

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The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.

Purpose We sought to evaluate visual performance and satisfaction with ready-made spectacles (RMS) in Chinese school-aged children with uncorrected refractive error. Design Randomized, double-blind, clinical trial. Participants Junior high school students from urban Guangzhou, China, aged approximately 12 to 15 years with ≥1 diopter (D) of uncorrected spherical equivalent (SE) refractive error. Students were excluded with ≥2.00 D astigmatism, ≥2 D myopic anisometropia, and ≥1 D hyperopic anisometropia and ocular disease affecting vision. Methods Refractive error was determined by cycloplegic subjective refraction. Students were randomly assigned to receive RMS or custom spectacles (CS) and assessed after 1 month of use. We required 175 students to complete in each arm to be able to measure a 15% difference in compliance. Main Outcome Measures Compliance with spectacles lens wear, patterns of use, vision, symptoms, and perceived value. Results Screening identified 965 of 4607 (20.9%) students with reduced distance vision; 212 of the 965 (22.0%) refused evaluation and 187 of the 965 (20.8%) had <1 D of SE refractive error. Sixty-one (6.3%) were referred for further evaluation and the remaining 495 (51.3%) participated. Social, demographic, and ocular parameters were similar in the 2 groups. Average SE refractive error was −2.57±1.31 (mean value ± standard deviation [SD]). Spectacle vision (Snellen acuity, mean ± SD) was worse with RMS in the eye with lower SE (20/25−0.5±0.9 lines vs 20/25+1±0.7 lines; P = 0.004) and higher SE (20/25−2±1.2 lines vs 20/25+1±0.8; P<0.001). There were no differences (P>0.05) in the rate of use (94.3% vs 92.2%), wearing to the 1-month visit (46.9% vs 51.5%), planned use (93.3% vs 93.7%), value (89.5% vs 91.7% “moderate or high value or most valued possession”), or symptoms (blur, 21.1% vs 19.4% [P = 0.8] and other symptoms [P>0.2]). Conclusions Although visual acuity was better with CS, no difference was found in acceptability in this population of students with predominantly simple myopic refractive error. This study supports the use of RMS in a school-based refractive services program, saving costs and improving the logistics of service delivery.