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Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice
Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. B...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Chen, G., Zuo, S., Tang, J., Zuo, C., Jia, D., Liu, Q., Liu, G., Zhu, Q., Wang, Y., Zhang, J., Shen, Y., Chen, D., Yuan, P., Qin, Z., Ruan, C., Ye, J., Wang, X.-J., Zhou, Y., Gao, P., Zhang, P., Liu, J., Jing, Z.-C., Lu, A., Yu, Y. Tags: Cardiovascular Biology Articles Source Type: research

ICAM-1 controls development and function of ILC2
Group 2 innate lymphoid cells (ILC2s) are emerging as key players in the pathogenesis of allergic airway inflammation. The mechanisms regulating ILC2, however, are not fully understood. Here, we found that ICAM-1 is required for the development and function of ILC2. ICAM-1–deficient (ICAM-1–/–) mice displayed significantly lower levels of ILC2s in the bone marrow and peripheral tissues than wild-type controls. CLP transfer and in vitro culture assays revealed that the regulation of ILC2 by ICAM-1 is cell intrinsic. Furthermore, ILC2s from ICAM-1–/– mice were functionally impaired, as indicated...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Lei, A.-H., Xiao, Q., Liu, G.-Y., Shi, K., Yang, Q., Li, X., Liu, Y.-F., Wang, H.-K., Cai, W.-P., Guan, Y.-J., Gabrilovich, D. I., Zhou, J. Tags: Innate Immunity and Inflammation Articles Source Type: research

Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma
Ewing sarcoma is a pediatric cancer driven by EWS-ETS transcription factor fusion oncoproteins in an otherwise stable genomic background. The majority of tumors express wild-type TP53, and thus, therapies targeting the p53 pathway would benefit most patients. To discover targets specific for TP53 wild-type Ewing sarcoma, we used a genome-scale CRISPR-Cas9 screening approach and identified and validated MDM2, MDM4, USP7, and PPM1D as druggable dependencies. The stapled peptide inhibitor of MDM2 and MDM4, ATSP-7041, showed anti-tumor efficacy in vitro and in multiple mouse models. The USP7 inhibitor, P5091, and the Wip1/PPM1...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Stolte, B., Iniguez, A. B., Dharia, N. V., Robichaud, A. L., Conway, A. S., Morgan, A. M., Alexe, G., Schauer, N. J., Liu, X., Bird, G. H., Tsherniak, A., Vazquez, F., Buhrlage, S. J., Walensky, L. D., Stegmaier, K. Tags: Solid Tumors Articles Source Type: research

miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 sign...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Meyer, S. E., Muench, D. E., Rogers, A. M., Newkold, T. J., Orr, E., OBrien, E., Perentesis, J. P., Doench, J. G., Lal, A., Morris, P. J., Thomas, C. J., Lieberman, J., McGlinn, E., Aronow, B. J., Salomonis, N., Grimes, H. L. Tags: Leukemia & Lymphoma, Stem Cells & Regeneration, Hematopoiesis Articles Source Type: research

Ca2+-mitochondria axis drives cell division in hematopoietic stem cells
Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (m). In contrast, upon stress hematopoiesis, HSCs actively start to divide. However, the underlying mechanism for the initiation of HSC division still remains unclear. To elucidate the mechanism underlying the transition of cell cycle state in HSCs, we analyzed the change of mitochondria in HSCs after BM suppression induced by 5-fluoruracil (5-FU). We found that HSCs initiate cell division after exhibiting enhanced m as a result of increased intracellular Ca2+ level. Although further acti...
Source: The Journal of Experimental Medicine - August 6, 2018 Category: Internal Medicine Authors: Umemoto, T., Hashimoto, M., Matsumura, T., Nakamura-Ishizu, A., Suda, T. Tags: Stem Cells & Regeneration Articles Source Type: research