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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

The rules governing the dimensions of the Javelin were substantially changed in 1986. It was considered that this new design guaranteed there was zero pitching moment at 0° angle of attack and that the pitching moment decreased (became negative) with increasing angle of attack. The objective of this study is to investigate if the pitching moment remains always negative (nose-down rotation). To measure accurate aerodynamic forces acting on a Javelin, the world’s largest 1 m magnetic suspension and balance system was used. The magnetic suspension and balance system was able to measure aerodynamic forces without support interference in the wind tunnel. In addition, computational fluid dynamics were carried out to estimate the pitching moment coefficients. It was found that the pitching moment coefficient of a commercially available Javelin becomes positive (nose-up rotation) at lower angles of attack, less than 12°. The pitching moment becomes positive if the upstream side of the center of gravity receives more inflow than the downstream side. This situation can be attained by, for example, increasing the thickness of the upstream side when compared with that of the downstream side.

Immunotherapies that target immune-checkpoint molecules such PD-1 have helped to achieve durable responses in melanoma treatment. However, 25% of melanoma patients who showed objective responses to PD-1 blockade develop resistance and suffer from disease progression and ultimately death, which necessitates the identification of related resistance mechanisms.IL-34 is a cytokine that controls the biology of myeloid cell lineage through binding to CSF-1R. IL-34 is importantly involved in the pathogenesis of various diseases. In cancer, the expression of IL-34 has been suggested to associate with tumor growth, metastasis, angiogenesis, and therapeutic resistance such as in lung cancers and malignant pleural mesotheliomas. In this study, we evaluate the possible involvement of IL-34 in immunotherapeutic resistance. Melanoma resection species were obtained from a patient who developed a refractory melanoma against immunotherapy with Nivolumab, and stained with anti-IL-34, anti-melanoma antigens and anti-CD163 antibody. Staining of these markers was compared between primary or metastatic refractory melanoma tissues. Immunohistochemistry staining of melanoma tissues showed an enhanced expression of IL-34 in metastatic refractory melanoma compared to primary melanoma tissues, which correlates with increased frequencies of CD163 macrophages. We introduce for the first time a clinical case of a patient with metastatic refractory melanoma that acquired resistance to anti-PD-1 immunotherapy, showing an enhanced expression of IL-34 in refractory melanoma tissues.

Interleukin (IL)-34 acts as an alternative ligand for the colony-stimulating factor-1 receptor and controls the biology of myeloid cells, including survival, proliferation, and differentiation. IL-34 has been reported to be expressed in cancer cells and to promote tumor progression and metastasis of certain cancers via the promotion of angiogenesis and immunosuppressive macrophage differentiation. We have shown in our previous reports that targeting IL-34 in chemo-resistant tumors in vitro resulted in a remarkable inhibition of tumor growth. Also, we reported poor prognosis in patients with IL-34-expressing tumor. Therefore, blocking of IL-34 is considered as a promising therapeutic strategy to suppress tumor progression. However, the molecular mechanisms that control IL-34 production are still largely unknown. IL-34 producing ovarian cancer cell line HM-1 was treated by bromodomain and extra terminal inhibitor JQ1. The mRNA and protein expression of IL-34 was evaluated after JQ1 treatment. Chromatin immunoprecipitation was performed to confirm the involvement of bromodomain-containing protein 4 (Brd4) in the regulation of the gene. Anti-tumor effect of JQ1 was evaluated in mouse tumor model. We identified Brd4 as one of the critical molecules that regulate expression in cancer cells. Consistent with this, we found that JQ1 is capable of efficiently suppressing the recruitment of Brd4 to the promotor region of gene. Additionally, JQ1 treatment of mice bearing IL-34-producing tumor inhibited the tumor growth along with decreasing expression in the tumor. The results unveiled for the first time the responsible molecule Brd4 that regulates expression in cancer cells and suggested its possibility as a treatment target.

We propose a new algorithm to detect the community structure in a network that utilizes both the network structure and vertex attribute data. Suppose we have the network structure together with the vertex attribute data, that is, the information assigned to each vertex associated with the community to which it belongs. The problem addressed this paper is the detection of the community structure from the information of both the network structure and the vertex attribute data. Our approach is based on the Bayesian approach that models the posterior probability distribution of the community labels. The detection of the community structure in our method is achieved by using belief propagation and an EM algorithm. We numerically verified the performance of our method using computer-generated networks and real-world networks.

We present a theory of the high-spin generalization of topological insulators and their doped superconducting states. The higher-spin topological insulators involve a pair ofJ=3/2bands with opposite parity and are characterized by their band inversion. The low-energy effective theory reveals that the topological insulators host four different phases characterized by mirror Chern numbers, at which boundaries two different patterns of bulk Dirac points appear. For the carrier-doped case, it is shown that the system may host unique unconventional superconductivity because of its high-spin nature and additional orbital degrees of freedom intrinsic to topological insulators. The superconducting critical temperature is evaluated by using density-density pairing interactions, and odd-parity Cooper pairs are shown to be naturally realized in the presence of interorbital pairing interaction. It is observed that even the simplest spin-0 odd-parity pairing state exhibits a novel class of topological superconductivity—high winding topological superconductivity. We also discuss the experimental signals of high winding topological superconductivity in the case of the antiperovskite superconductorSr3−xSnO.

C -Glycosides, in which a sugar moiety is linked via a carbon-carbon (C-C) bond to a non-sugar moiety (aglycone), are found in our food and medicine. The C-C bond is cleaved by intestinal microbes and the resulting aglycones exert various bioactivities. Although the enzymes responsible for the reactions have been identified, their catalytic mechanisms and the generality of the reactions in nature remain to be explored. Here, we present the identification and structural basis for the activation of xenobiotic C -glycosides by heterocomplex C -deglycosylation enzymes from intestinal and soil bacteria. They are found to be metal-dependent enzymes exhibiting broad substrate specificity toward C -glycosides. X-ray crystallographic and cryo-electron microscopic analyses, as well as structure-based mutagenesis, reveal the structural details of these enzymes and the detailed catalytic mechanisms of their remarkable C-C bond cleavage reactions. Furthermore, bioinformatic and biochemical analyses suggest that the C -deglycosylation enzymes are widely distributed in the gut, soil, and marine bacteria. In C-glycosides the sugar moiety is linked through a carbon-carbon bond to the non-sugar moiety, which can be cleaved by intestinal microbes. Here, the authors use bioinformatics analysis to identify C-glycoside deglycosidase enzymes in intestinal and soil bacteria, biochemically characterise them and determine their structures and probe catalytic important residues in mutagenesis experiments.

ObjectiveBleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC.DesignThis retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration.ResultsA prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01).ConclusionsIn this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.

To reveal the origin of the mini-starbursts in the Milky Way, we carried out large-scale CO observations toward the RCW 106 giant molecular cloud (GMC) complex using the NANTEN2 4 m radio telescope operated by Nagoya University. We also analyzed the Mopra Southern Galactic Plane CO survey and Herschel infrared continuum archival data. The RCW 106 GMC complex contains the radial velocity components of −68 km s−1 and −50 km s−1 reported by H. Nguyen et al. (2015). Focusing on the RCW 106 East and West region with the massive star formation having the bright infrared dust emission, we found that these regions have three different velocity components with ∼10 km s−1 differences. The two out of three velocity components show morphological correspondence with the infrared cold dust emission and connect with the bridge feature on a position–velocity diagram. Therefore, two molecular clouds with ∼10 km s−1 differences are likely to be physically associated with massive star-forming regions in the GMC complex. Based on these observational results, we argue that mini-starbursts and massive star/cluster formation in the RCW 106 GMC complex are induced by supersonic cloud–cloud collisions in an agglomerate of molecular gas on the Scutum–Centaurus arm.

Sesamin is one of the major lignans found in sesame oil. Although some microbial metabolites of sesamin have been identified, sesamin-metabolic pathways remain uncharacterized at both the enzyme and gene levels. Here, we isolated microorganisms growing on sesamin as a sole-carbon source. One microorganism showing significant sesamin-degrading activity was identified as Sinomonas sp. no. 22. A sesamin-metabolizing enzyme named SesA was purified from this strain and characterized. SesA catalyzed methylene group transfer from sesamin or sesamin monocatechol to tetrahydrofolate (THF) with ring cleavage, yielding sesamin mono- or di-catechol and 5,10-methylenetetrahydrofolate. The kinetic parameters of SesA were determined to be as follows: K m for sesamin = 0.032 ± 0.005 mM, V max = 9.3 ± 0.4 (μmol·min−1·mg−1), and k cat = 7.9 ± 0.3 s−1. Next, we investigated the substrate specificity. SesA also showed enzymatic activity toward (+)-episesamin, (−)-asarinin, sesaminol, (+)-sesamolin, and piperine. Growth studies with strain no. 22, and Western blot analysis revealed that SesA formation is inducible by sesamin. The deduced amino acid sequence of sesA exhibited weak overall sequence similarity to that of the protein family of glycine cleavage T-proteins (GcvTs), which catalyze glycine degradation in most bacteria, archaea, and all eukaryotes. Only SesA catalyzes C1 transfer to THF with ring cleavage reaction among GcvT family proteins. Moreover, SesA homolog genes are found in both Gram-positive and Gram-negative bacteria. Our findings provide new insights into microbial sesamin metabolism and the function of GcvT family proteins.