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Wnt5a induces and maintains prostate cancer cells dormancy in bone
In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Further...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Ren, D., Dai, Y., Yang, Q., Zhang, X., Guo, W., Ye, L., Huang, S., Chen, X., Lai, Y., Du, H., Lin, C., Peng, X., Song, L. Tags: Solid Tumors Articles Source Type: research

Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer
PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a PIK3CA-characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with PIK3CA mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0.09–0.62) and overall survival (OS; hazard ratio 0.31, P = 0.0043, 95% CI 0.14–0.69) compared with nonr...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Hedberg, M. L., Peyser, N. D., Bauman, J. E., Gooding, W. E., Li, H., Bhola, N. E., Zhu, T. R., Zeng, Y., Brand, T. M., Kim, M.-O., Jordan, R. C. K., VandenBerg, S., Olivas, V., Bivona, T. G., Chiosea, S. I., Wang, L., Mills, G. B., Johnson, J. T., Duvvur Tags: Solid Tumors Articles Source Type: research

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly
In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Rodriguez-Laguna, L., Agra, N., Ibanez, K., Oliva-Molina, G., Gordo, G., Khurana, N., Hominick, D., Beato, M., Colmenero, I., Herranz, G., Torres Canizalez, J. M., Rodriguez Pena, R., Vallespin, E., Martin-Arenas, R., del Pozo, A., Villaverde, C., Bustama Tags: Cardiovascular Biology, Human Disease Genetics Articles Source Type: research

Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses
Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Franco, L. M., Gadkari, M., Howe, K. N., Sun, J., Kardava, L., Kumar, P., Kumari, S., Hu, Z., Fraser, I. D. C., Moir, S., Tsang, J. S., Germain, R. N. Tags: Innate Immunity and Inflammation Articles Source Type: research

Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Anzai, A., Mindur, J. E., Halle, L., Sano, S., Choi, J. L., He, S., McAlpine, C. S., Chan, C. T., Kahles, F., Valet, C., Fenn, A. M., Nairz, M., Rattik, S., Iwamoto, Y., Fairweather, D., Walsh, K., Libby, P., Nahrendorf, M., Swirski, F. K. Tags: Autoimmunity, Cardiovascular Biology, Innate Immunity and Inflammation Articles Source Type: research

Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis
Heart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces f...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Weckbach, L. T., Grabmaier, U., Uhl, A., Gess, S., Boehm, F., Zehrer, A., Pick, R., Salvermoser, M., Czermak, T., Pircher, J., Sorrelle, N., Migliorini, M., Strickland, D. K., Klingel, K., Brinkmann, V., Abu Abed, U., Eriksson, U., Massberg, S., Brunner, Tags: Cardiovascular Biology, Innate Immunity and Inflammation Articles Source Type: research

Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10
Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Xiao, P., Zhang, H., Zhang, Y., Zheng, M., Liu, R., Zhao, Y., Zhang, X., Cheng, H., Cao, Q., Ke, Y. Tags: Innate Immunity and Inflammation, Mucosal Immunology Articles Source Type: research

P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus
Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development ...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Faliti, C. E., Gualtierotti, R., Rottoli, E., Gerosa, M., Perruzza, L., Romagnani, A., Pellegrini, G., De Ponte Conti, B., Rossi, R. L., Idzko, M., Mazza, E. M. C., Bicciato, S., Traggiai, E., Meroni, P. L., Grassi, F. Tags: Autoimmunity Articles Source Type: research

Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies
Broadly neutralizing antibodies (Abs) that bind the influenza virus hemagglutinin (HA) stem may enable universal influenza vaccination. Here, we show that anti-stem Abs sterically inhibit viral neuraminidase (NA) activity against large substrates, with activity inversely proportional to the length of the fibrous NA stalk that supports the enzymatic domain. By modulating NA stalk length in recombinant IAVs, we show that anti-stem Abs inhibit virus release from infected cells by blocking NA, accounting for their in vitro neutralization activity. NA inhibition contributes to anti-stem Ab protection in influenza-infected mice,...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Kosik, I., Angeletti, D., Gibbs, J. S., Angel, M., Takeda, K., Kosikova, M., Nair, V., Hickman, H. D., Xie, H., Brooke, C. B., Yewdell, J. W. Tags: Infectious Disease and Host Defense Articles Source Type: research

Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus–mediated expression of the most pot...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Geisler, S., Huang, S. X., Strickland, A., Doan, R. A., Summers, D. W., Mao, X., Park, J., DiAntonio, A., Milbrandt, J. Tags: Neuroscience Brief Definitive Reports Source Type: research

3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice
3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer’s disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascu...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Lazic, D., Sagare, A. P., Nikolakopoulou, A. M., Griffin, J. H., Vassar, R., Zlokovic, B. V. Tags: Neuroscience Brief Definitive Reports Source Type: research

Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice
Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A, which represents a "second hit" that induces both neuroinfl...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Brenner, D., Sieverding, K., Bruno, C., Lüningschrör, P., Buck, E., Mungwa, S., Fischer, L., Brockmann, S. J., Ulmer, J., Bliederhäuser, C., Philibert, C. E., Satoh, T., Akira, S., Boillee, S., Mayer, B., Sendtner, M., Ludolph, A. Tags: Neuroinflammation, Human Disease Genetics, Neuroscience Brief Definitive Reports Source Type: research

Toward a better understanding of folate metabolism in health and disease
Folate metabolism is crucial for many biochemical processes, including purine and thymidine monophosphate (dTMP) biosynthesis, mitochondrial protein translation, and methionine regeneration. These biochemical processes in turn support critical cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. Not surprisingly, abnormal folate metabolism has been causally linked with a myriad of diseases. In this review, we provide a historical perspective, delve into folate chemistry that is often overlooked, and point out various missing links and underdeveloped areas in folate metabolism...
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Zheng, Y., Cantley, L. C. Tags: Metabolism Review Source Type: research

Inhibiting neuraminidase can make the difference
Immunogens inducing antibodies against the stem of influenza virus hemagglutinin are promising candidates for the development of universal vaccines. In this issue of JEM, Kosik et al. (https://doi.org/10.1084/jem.20181624) report that inhibition of neuraminidase by anti-stem antibodies contributes to their broadly neutralizing activity. (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - February 4, 2019 Category: Internal Medicine Authors: Rappuoli, R., Del Giudice, G. Tags: Infectious Disease and Host Defense Insights Source Type: research

Retraction: Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition
Vol. 210, No. 3, March 11, 2013. 10.1084/jem.20121486 The editors of the Journal of Experimental Medicine have been notified by Dr. Vivianne Malmström of the Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, that she and the other... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Amara, K., Steen, J., Murray, F., Morbach, H., Fernandez-Rodriguez, B. M., Joshua, V., Engström, M., Snir, O., Israelsson, L., Catrina, A. I., Wardemann, H., Corti, D., Meffre, E., Klareskog, L., Malmström, V. Tags: Retraction Source Type: research