Summary Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important tumor suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting miRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting miRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumor cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for those brain metastasis patients who are in dire need.

Based on the idea that the hardness of covalent crystal is intrinsic and equivalent to the sum of the resistance to the indenter of each bond per unit area, a semiempirical method for the evaluation of hardness of multicomponent crystals is presented. Applied to beta-BC2N crystal, the predicted value of hardness is in good agreement with the experimental value. It is found that bond density or electronic density, bond length, and degree of covalent bonding are three determinative factors for the hardness of a polar covalent crystal. Our method offers the advantage of applicability to a broad class of materials and initializes a link between macroscopic property and electronic structure from first principles calculation.

Abstract. Image segmentation is a fundamental problem in biomedical image analysis. Recent advances in deep learning have achieved promising results on many biomedical image segmentation benchmarks. However, due to large variations in biomedical images (different modalities, image settings, objects, noise, etc), to utilize deep learning on a new application, it usually needs a new set of training data. This can incur a great deal of annotation effort and cost, because only biomedical experts can annotate effectively, and often there are too many instances in images (e.g., cells) to annotate. In this paper, we aim to address the following question: With limited effort (e.g., time) for annotation, what instances should be annotated in order to attain the best performance? We present a deep active learning framework that combines fully convolutional network (FCN) and active learning to significantly reduce annotation effort by making judicious suggestions on the most effective annotation areas. We utilize uncertainty and similarity information provided by FCN and formulate a generalized version of the maximum set cover problem to determine the most representative and uncertain areas for annotation. Extensive experiments using the 2015 MICCAI Gland Challenge dataset and a lymph node ultrasound image segmentation dataset show that, using annotation suggestions by our method, state-of-the-art segmentation performance can be achieved by using only 50% of training data.

Conjugated side-chain-isolated D−A copolymers, based on the donor unit of benzodithiophene (BDT) with a thiophene-conjugated side chain, thiophene π bridge, and the acceptor unit of benzotriazole (BTA) with or without fluorine substitution (PBDT-FBTA and PBDT-HBTA), were designed and synthesized for elucidating their structure− property relationships. The copolymer films demonstrated well-defined absorption peaks with steep absorption edges, consistent with their rigid and ordered structures in the solid films. The substitution of a thiophene-conjugated side chain on the BDT unit in the copolymers aroused 15-nm red-shifted absorption in comparison with its polymer analogues with alkoxy side chains on the BDT unit. Compared to PBDT-HBTA, PBDT-FBTA with two-fluorine-atom substitution on the BTA unit demonstrated a lower highest occupied molecular orbital energy level, higher hole mobility, and significantly better photovoltaic performance. A polymer solar cell (PSC) based on PBDT-FBTA/PC 70 BM (1:2, w/w) with a 5% 1,8-diiodooctane additive displayed a power conversion efficiency (PCE) of 6.0% with a J sc of 11.9 mA cm −2 , a V OC of 0.75 V, and a fill factor of 67.2%, under the illumination of AM1.5G, 100 mW cm −2 . Even at a thicker active layer of 400 nm, the PSC still demonstrated a higher PCE of 4.74%. The results indicate that PBDT-FBTA is a promising polymer donor material for future application of large-area PSCs.

BackgroundThe macrophage, one of the several key immune cell types, is believed to be involved in tumorigenesis. However, the mechanism of macrophages promoting tumor progression is largely unknown.MethodsThe differentially secreted proteins of M1 and M2 macrophages were analyzed by mass spectrometry. We performed GST pull-down assay for the identification of cell-membrane receptors that interact with chitinase 3-like protein 1 (CHI3L1) protein. The mouse model was used to validate the function of CHI3L1 in cancer metastasis in vivo. Protein phosphorylation and gene expression were performed to study the signaling pathway activation of cancer cells after CHI3L1 treatment.ResultsM2 macrophage-secreted CHI3L1 promoted the metastasis of gastric and breast cancer cells in vitro and in vivo. The CHI3L1 protein functioned by interacting with interleukin-13 receptor α2 chain (IL-13Rα2) molecules on the plasma membranes of cancer cells. Activation of IL-13Rα2 by CHI3L1 triggered the activation of the mitogen-activated protein kinase signaling pathway, leading to the upregulated expression of matrix metalloproteinase genes, which promoted tumor metastasis. The results of this study indicated that the level of CHI3L1 protein in the sera of patients with gastric or breast cancer was significantly elevated compared with those of healthy donors.ConclusionsOur study revealed a novel aspect of macrophages with respect to cancer metastasis and showed that CHI3L1 could be a marker of metastatic gastric and breast cancer in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0408-0) contains supplementary material, which is available to authorized users.

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Sc-based III-nitride alloys were studied using Density Functional Theory with special quasi-random structures and were found to retain wide band gaps which stay direct up to x = 0.125 (Sc x Al 1-x N) and x = 0.375 (Sc x Ga 1-x N). Epitaxial strain stabilization prevents spinodal decomposition up to x = 0.3 (Scx Al 1-x N on GaN) and x = 0.24 (Sc x Ga 1-x N on GaN), with critical thicknesses for strain relaxation ranging from 3 nm to near-infinity. The increase in Sc content introduces compressive in-plane stress with respect to AlN and GaN, and leads to composition-and stress-tunable band gaps and polarization, and ultimately introduces ferroelectric functionality in Sc x Ga 1-x N at x ≈ 0.625.

miRNAs have emerged as post-transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Cdc42, one of the best characterized members of the Rho GTPase family, is found to be up-regulated in several types of human tumors and has been implicated in cancer initiation and progression. In the present study, we have identified miR-137 as a potential regulator of Cdc42 expression. A bioinformatics search revealed a putative target-site for miR-137 within the Cdc42 3 0 UTR at nt 792-798, which is highly conserved across different species. Expression of miR-137 in colorectal cancer cell lines was found inversely correlated with Cdc42 expression. miR-137 could significantly suppress Cdc42 3 0 UTR luciferase-reporter activity, and this effect was not detectable when the putative 3 0 UTR target-site was mutated. Consistent with the results of the reporter assay, ectopic expression of miR-137 reduced both mRNA and protein expression levels of Cdc42 and mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest, and blocking invasion of the colorectal cancer cells, whereas anti-miR-137 expression led to the opposite effect. Furthermore, expression of miR-137 suppressed the immediate downstream effector of Cdc42, PAK signaling. Our results suggest that miR-137 may have a tumor suppressor function by directly targeting Cdc42 to inhibit the proliferation and invasion activities of colorectal cancer cells. They raise an interesting possibility that Cdc42 activity and function can be controlled by miRNAs in addition to the classic regulators such as guanine nucleotide exchange factors and GTPase-activating proteins.