[Research Articles] TCR {beta} chain-directed bispecific antibodies for the treatment of T cell cancers
Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen–targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies direct...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Paul, S., Pearlman, A. H., Douglass, J., Mog, B. J., Hsiue, E. H.-C., Hwang, M. S., DiNapoli, S. R., Konig, M. F., Brown, P. A., Wright, K. M., Sur, S., Gabelli, S. B., Li, Y., Ghiaur, G., Pardoll, D. M., Papadopoulos, N., Bettegowda, C., Kinzler, K. W., Tags: Research Articles Source Type: research
[Research Articles] Epidemiological dynamics of enterovirus D68 in the United States and implications for acute flaccid myelitis
Acute flaccid myelitis (AFM) recently emerged in the United States as a rare but serious neurological condition since 2012. Enterovirus D68 (EV-D68) is thought to be a main causative agent, but limited surveillance of EV-D68 in the United States has hampered the ability to assess their causal relationship. Using surveillance data from the BioFire Syndromic Trends epidemiology network in the United States from January 2014 to September 2019, we characterized the epidemiological dynamics of EV-D68 and found latitudinal gradient in the mean timing of EV-D68 cases, which are likely climate driven. We also demonstrated a strong...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Park, S. W., Pons-Salort, M., Messacar, K., Cook, C., Meyers, L., Farrar, J., Grenfell, B. T. Tags: Research Articles Source Type: research
[Research Articles] Prosaposin mediates inflammation in atherosclerosis
Macrophages play a central role in the pathogenesis of atherosclerosis. The inflammatory properties of these cells are dictated by their metabolism, of which the mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator. Using myeloid cell–specific nanobiologics in apolipoprotein E–deficient (Apoe–/–) mice, we found that targeting the mTOR and ribosomal protein S6 kinase-1 (S6K1) signaling pathways rapidly diminished plaque macrophages’ inflammatory activity. By investigating transcriptome modifications, we identified Psap, a gene encoding the lysosomal protein prosaposin, as...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: van Leent, M. M. T., Beldman, T. J., Toner, Y. C., Lameijer, M. A., Rother, N., Bekkering, S., Teunissen, A. J. P., Zhou, X., van der Meel, R., Malkus, J., Nauta, S. A., Klein, E. D., Fay, F., Sanchez-Gaytan, B. L., Perez-Medina, C., Kluza, E., Ye, Y.-X., Tags: Research Articles Source Type: research
[Research Articles] Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates
Stem cell–derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-4...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Li, Q., Xu, Y., Lv, K., Wang, Y., Zhong, Z., Xiao, C., Zhu, K., Ni, C., Wang, K., Kong, M., Li, X., Fan, Y., Zhang, F., Chen, Q., Li, Y., Li, Q., Liu, C., Zhu, J., Zhong, S., Wang, J., Chen, Y., Zhao, J., Zhu, D., Wu, R., Chen, J., Zhu, W., Yu, H., Ardeha Tags: Research Articles Source Type: research
[Research Articles] Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals
We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Sims, E. K., Bundy, B. N., Stier, K., Serti, E., Lim, N., Long, S. A., Geyer, S. M., Moran, A., Greenbaum, C. J., Evans-Molina, C., Herold, K. C., Type 1 Diabetes TrialNet Study Group Tags: Research Articles Source Type: research
[Research Articles] Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome
Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MeCP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-s...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Shao, Y., Sztainberg, Y., Wang, Q., Bajikar, S. S., Trostle, A. J., Wan, Y.-W., Jafar-nejad, P., Rigo, F., Liu, Z., Tang, J., Zoghbi, H. Y. Tags: Research Articles Source Type: research
[Research Articles] Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity
The cross-talk between angiogenesis and immunity within the tumor microenvironment (TME) is critical for tumor prognosis. While pro-angiogenic and immunosuppressive TME promote tumor growth, anti-angiogenic and immune stimulatory TME inhibit tumor progression. Therefore, there is a great interest in achieving vascular normalization to improve drug delivery and enhance antitumor immunity. However, anti–vascular endothelial growth factor (VEGF) mechanisms to normalize tumor vessels have offered limited therapeutic efficacies for patients with cancer. Here, we report that Myct1, a direct target of ETV2, was nearly exclu...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Kabir, A. U., Subramanian, M., Lee, D. H., Wang, X., Krchma, K., Wu, J., Naismith, T., Halabi, C. M., Kim, J. Y., Pulous, F. E., Petrich, B. G., Kim, S., Park, H.-C., Hanson, P. I., Pan, H., Wickline, S. A., Fremont, D. H., Park, C., Choi, K. Tags: Research Articles Source Type: research
[Research Articles] Broad neutralization of H1 and H3 viruses by adjuvanted influenza HA stem vaccines in nonhuman primates
Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus–associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 vi...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Darricarrere, N., Qiu, Y., Kanekiyo, M., Creanga, A., Gillespie, R. A., Moin, S. M., Saleh, J., Sancho, J., Chou, T.-H., Zhou, Y., Zhang, R., Dai, S., Moody, A., Saunders, K. O., Crank, M. C., Mascola, J. R., Graham, B. S., Wei, C.-J., Nabel, G. J. Tags: Research Articles Source Type: research
[Reports] APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer’s disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., Milo, B., Graziosi, A., Baru, V., Lewis, C. A., Kellis, M., Sabatini, D. M., Tsai, L.-H., Lindquist, S. Tags: Reports Source Type: research
[Research Articles] BMPR1A maintains skeletal stem cell properties in craniofacial development and craniosynostosis
This study advances our knowledge base of congenital deformity and regenerative medicine mediated by skeletal stem cells. (Source: Science Translational Medicine)
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Maruyama, T., Stevens, R., Boka, A., DiRienzo, L., Chang, C., Yu, H.-M. I., Nishimori, K., Morrison, C., Hsu, W. Tags: Research Articles Source Type: research
[Research Articles] Characterization of initial key steps of IL-17 receptor B oncogenic signaling for targeted therapy of pancreatic cancer
The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphor...
Source: Science Translational Medicine - March 3, 2021 Category: Biomedical Science Authors: Wu, H.-H., Tsai, L.-H., Huang, C.-K., Hsu, P.-H., Chen, M.-Y., Chen, Y.-I., Hu, C.-M., Shen, C.-N., Lee, C.-C., Chang, M.-C., Chang, Y.-T., Tien, Y.-W., Jeng, Y.-M., Lee, E. Y.- H. P., Lee, W.-H. Tags: Research Articles Source Type: research
[Research Articles] Mechanism and reversal of drug-induced nephrotoxicity on a chip
The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Cohen, A., Ioannidis, K., Ehrlich, A., Regenbaum, S., Cohen, M., Ayyash, M., Tikva, S. S., Nahmias, Y. Tags: Research Articles Source Type: research
[Research Articles] Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries
Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation o...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Wang, T., Wagner, A., Gehwolf, R., Yan, W., Passini, F. S., Thien, C., Weissenbacher, N., Lin, Z., Lehner, C., Teng, H., Wittner, C., Zheng, Q., Dai, J., Ni, M., Wang, A., Papadimitriou, J., Leys, T., Tuan, R. S., Senck, S., Snedeker, J. G., Tempfer, H., Tags: Research Articles Source Type: research
[Research Articles] Transitional B cell cytokines predict renal allograft outcomes
Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical reje...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Cherukuri, A., Salama, A. D., Mehta, R., Mohib, K., Zheng, L., Magee, C., Harber, M., Stauss, H., Baker, R. J., Tevar, A., Landsittel, D., Lakkis, F. G., Hariharan, S., Rothstein, D. M. Tags: Research Articles Source Type: research
[Research Articles] Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia
This study not only functionally established two distinctive origins of human LSCs for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell–associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Zeisig, B. B., Fung, T. K., Zarowiecki, M., Tsai, C. T., Luo, H., Stanojevic, B., Lynn, C., Leung, A. Y. H., Zuna, J., Zaliova, M., Bornhauser, M., von Bonin, M., Lenhard, B., Huang, S., Mufti, G. J., So, C. W. E. Tags: Research Articles Source Type: research
