Purpose VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. Experimental design To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusion These findings provide a new understanding of the mechanisms underlying the modest efficacy of current anti-angiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers.

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SUMMARY Angiogenesis inhibitors are important for cancer therapy, but clinically approved anti-angiogenic agents have shown only modest efficacy and can compromise wound healing. This necessitates development of novel anti-angiogenesis therapies. Here, we show significantly increased EGFL6 expression in tumor- versus wound or normal endothelial cells. Using a series of in vitro and in vivo studies with orthotopic and genetically engineered mouse models, we demonstrate the mechanisms by which EGFL6 stimulates tumor angiogenesis. In contrast to its antagonistic effects on tumor angiogenesis, EGFL6 blockage did not affect normal wound healing. These findings have significant implications for development of anti-angiogenesis therapies.

CD8+ T cells become functionally impaired or “exhausted” in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)–15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells. MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFβ signaling enhanced IL-15 production and antiviral CD8+ T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.

Aim: The present study aimed to examine the correlation between high-sensitivity CRP to albumin ratio (CAR) and in-hospital and short-term major adverse cardiac events (MACEs) in patients with acute coronary syndrome (ACS). Materials & methods: We analyzed 652 consecutive patients who had been hospitalized for ACS. The MACEs were defined as cardiogenic shock, reinfarction, acute heart failure and all-cause death. Results: The incidence rate of MACEs was significantly higher in the high CAR (≥0.114) group than in the low CAR (<0.114) group. Multivariate analysis revealed that CAR, hs-CRP and albumin were independent predictors for increased risk for MACEs. Conclusion: The CAR was independently correlated with in-hospital and short-term MACEs and can be used for risk stratification in patients with ACS.

Three ice core samples were collected from the Malan ice core drilled from the Tibetan Plateau, and three 16S rDNA clone libraries by direct amplification from the ice-melted water were established. Ninety-four clones containing bacterial 16S rDNA inserts were selected. According to restriction fragment-length polymorphism analysis, 11 clones were unique in the library from which they were obtained and used for partial sequence and phylogenetic analysis, and compared with 8 reported sequences from the same ice core at depth 70 m. Differences among the samples were apparent in clone libraries. The phylotypes were dominated by the Proteobacteria group, Acinetobacter sp. and Cytophaga-Flavobacterium-Bacteroides (CFB) group. They accounted for 92.5% (Proteobacteria), 100% (Acinetobacter sp.), 34.4% (CFB) and 100% (beta-Proteobacteria) in the clone libraries from the samples at ice depths 35, 64, 70, and 82 m, respectively. The Acinetobacter sp. was only found in the deposition at ice depth 82 m and closely clustered with gamma-Proteobateria. Two members (Malan A-21 and 101) of alpha-Proteobacteria from the sample of 35 m and two (Malan B-26 and 48) of beta-Proteobacteria of 64 m were loosely clustered (< 95% similarity) with known bacteria, represented new genera in ice bacteria.

PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.

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