[Research Articles] The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemic...
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Jones, B. E., Brown-Augsburger, P. L., Corbett, K. S., Westendorf, K., Davies, J., Cujec, T. P., Wiethoff, C. M., Blackbourne, J. L., Heinz, B. A., Foster, D., Higgs, R. E., Balasubramaniam, D., Wang, L., Zhang, Y., Yang, E. S., Bidshahri, R., Kraft, L., Tags: Research Articles Source Type: research
[Technical Comments] Comment on "Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI"
The nuclear pregnane X receptor may not protect against ischemia/reperfusion-induced acute kidney injury in mice. (Source: Science Translational Medicine)
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Luan, Z., Ming, W., Zhang, C., Huo, X., Zheng, F., Zhang, X., Guan, Y. Tags: Technical Comments Source Type: research
[Research Articles] Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset
Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. Mor...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Stelzer, I. A., Ghaemi, M. S., Han, X., Ando, K., Hedou, J. J., Feyaerts, D., Peterson, L. S., Rumer, K. K., Tsai, E. S., Ganio, E. A., Gaudilliere, D. K., Tsai, A. S., Choisy, B., Gaigne, L. P., Verdonk, F., Jacobsen, D., Gavasso, S., Traber, G. M., Elle Tags: Research Articles Source Type: research
[Research Articles] Exaggerated IL-17A activity in human in vivo recall responses discriminates active tuberculosis from latent infection and cured disease
Host immune responses at the site of Mycobacterium tuberculosis infection can mediate pathogenesis of tuberculosis (TB) and onward transmission of infection. We hypothesized that pathological immune responses would be enriched at the site of host-pathogen interactions modeled by a standardized tuberculin skin test (TST) challenge in patients with active TB compared to those without disease, and interrogated immune responses by genome-wide transcriptional profiling. We show exaggerated interleukin-17A (IL-17A) and T helper 17 (TH17) responses among 48 individuals with active TB compared to 191 with latent TB infection, asso...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Pollara, G., Turner, C. T., Rosenheim, J., Chandran, A., Bell, L. C. K., Khan, A., Patel, A., Peralta, L. F., Folino, A., Akarca, A., Venturini, C., Baker, T., Ecker, S., Ricciardolo, F. L. M., Marafioti, T., Ugarte-Gil, C., Moore, D. A. J., Chain, B. M., Tags: Research Articles Source Type: research
[Research Articles] A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells
About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a D...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Mukherjee, J., Pandita, A., Kamalakar, C., Johannessen, T.-C., Ohba, S., Tang, Y., Dalle-Ore, C. L., Bjerkvig, R., Pieper, R. O. Tags: Research Articles Source Type: research
[Research Articles] Hexachromatic bioinspired camera for image-guided cancer surgery
Cancer affects one in three people worldwide. Surgery remains the primary curative option for localized cancers, but good prognoses require complete removal of primary tumors and timely recognition of metastases. To expand surgical capabilities and enhance patient outcomes, we developed a six-channel color/near-infrared image sensor inspired by the mantis shrimp visual system that enabled near-infrared fluorescence image guidance during surgery. The mantis shrimp’s unique eye, which maximizes the number of photons contributing to and the amount of information contained in each glimpse of its surroundings, is recapitu...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Blair, S., Garcia, M., Davis, T., Zhu, Z., Liang, Z., Konopka, C., Kauffman, K., Colanceski, R., Ferati, I., Kondov, B., Stojanoski, S., Todorovska, M. B., Dimitrovska, N. T., Jakupi, N., Miladinova, D., Petrusevska, G., Kondov, G., Dobrucki, W. L., Nie, Tags: Research Articles Source Type: research
[Research Articles] iPSC-endothelial cell phenotypic drug screening and in silico analyses identify tyrphostin-AG1296 for pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a progressive disorder leading to occlusive vascular remodeling. Current PAH therapies improve quality of life but do not reverse structural abnormalities in the pulmonary vasculature. Here, we used high-throughput drug screening combined with in silico analyses of existing transcriptomic datasets to identify a promising lead compound to reverse PAH. Induced pluripotent stem cell–derived endothelial cells generated from six patients with PAH were exposed to 4500 compounds and assayed for improved cell survival after serum withdrawal using a chemiluminescent caspase assay. Subs...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Gu, M., Donato, M., Guo, M., Wary, N., Miao, Y., Mao, S., Saito, T., Otsuki, S., Wang, L., Harper, R. L., Sa, S., Khatri, P., Rabinovitch, M. Tags: Research Articles Source Type: research
[Research Articles] An RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia in mice
Achondroplasia is the most prevalent genetic form of dwarfism in humans and is caused by activating mutations in FGFR3 tyrosine kinase. The clinical need for a safe and effective inhibitor of FGFR3 is unmet, leaving achondroplasia currently incurable. Here, we evaluated RBM-007, an RNA aptamer previously developed to neutralize the FGFR3 ligand FGF2, for its activity against FGFR3. In cultured rat chondrocytes or mouse embryonal tibia organ culture, RBM-007 rescued the proliferation arrest, degradation of cartilaginous extracellular matrix, premature senescence, and impaired hypertrophic differentiation induced by FGFR3 si...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Kimura, T., Bosakova, M., Nonaka, Y., Hruba, E., Yasuda, K., Futakawa, S., Kubota, T., Fafilek, B., Gregor, T., Abraham, S. P., Gomolkova, R., Belaskova, S., Pesl, M., Csukasi, F., Duran, I., Fujiwara, M., Kavkova, M., Zikmund, T., Kaiser, J., Buchtova, M Tags: Research Articles Source Type: research
[Research Articles] A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma
In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αβ T cell receptor–expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8+ T cell populations (CD8+NK1.1+) revealed substantial up-regulation of granzymes, perforin, killer lectin-like r...
Source: Science Translational Medicine - May 5, 2021 Category: Biomedical Science Authors: Konduri, V., Joseph, S. K., Byrd, T. T., Nawas, Z., Vazquez-Perez, J., Hofferek, C. J., Halpert, M. M., Liu, D., Liang, Z., Baig, Y., Salsman, V. S., Oyewole-Said, D., Tsimelzon, A., Burns, B. A., Chen, C., Levitt, J. M., Yao, Q., Ahmed, N. M., Hegde, M., Tags: Research Articles Source Type: research
[Research Articles] SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models
The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening "on-target/off-tumor" toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Hyrenius-Wittsten, A., Su, Y., Park, M., Garcia, J. M., Alavi, J., Perry, N., Montgomery, G., Liu, B., Roybal, K. T. Tags: Research Articles Source Type: research
[Research Articles] Robot-induced hallucinations in Parkinsons disease depend on altered sensorimotor processing in fronto-temporal network
We report a robotics-based approach applying conflicting sensorimotor stimulation, enabling the induction of presence hallucinations (PHs) and the characterization of a subgroup of patients with PD with enhanced sensitivity for conflicting sensorimotor stimulation and robot-induced PH. We next identify the fronto-temporal network of PH by combining MR-compatible robotics (and sensorimotor stimulation in healthy participants) and lesion network mapping (neurological patients without PD). This PH-network was selectively disrupted in an additional and independent cohort of patients with PD, predicted the presence of symptomat...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Bernasconi, F., Blondiaux, E., Potheegadoo, J., Stripeikyte, G., Pagonabarraga, J., Bejr-Kasem, H., Bassolino, M., Akselrod, M., Martinez-Horta, S., Sampedro, F., Hara, M., Horvath, J., Franza, M., Konik, S., Bereau, M., Ghika, J.-A., Burkhard, P. R., Van Tags: Research Articles Source Type: research
[Research Articles] SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glyc...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Choe, J. H., Watchmaker, P. B., Simic, M. S., Gilbert, R. D., Li, A. W., Krasnow, N. A., Downey, K. M., Yu, W., Carrera, D. A., Celli, A., Cho, J., Briones, J. D., Duecker, J. M., Goretsky, Y. E., Dannenfelser, R., Cardarelli, L., Troyanskaya, O., Sidhu, Tags: Research Articles Source Type: research
[Research Articles] SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations
Insulin resistance is a key event in type 2 diabetes onset and a major comorbidity of obesity. It results from a combination of fat excess–triggered defects, including lipotoxicity and metaflammation, but the causal mechanisms remain difficult to identify. Here, we report that hyperactivation of the tyrosine phosphatase SHP2 found in Noonan syndrome (NS) led to an unsuspected insulin resistance profile uncoupled from altered lipid management (for example, obesity or ectopic lipid deposits) in both patients and mice. Functional exploration of an NS mouse model revealed this insulin resistance phenotype correlated with...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Paccoud, R., Saint-Laurent, C., Piccolo, E., Tajan, M., Dortignac, A., Pereira, O., Le Gonidec, S., Baba, I., Gelineau, A., Askia, H., Branchereau, M., Charpentier, J., Personnaz, J., Branka, S., Auriau, J., Deleruyelle, S., Canouil, M., Beton, N., Salles Tags: Research Articles Source Type: research
[Research Articles] Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3
Acute lung injury (ALI) causes high mortality and lacks any pharmacological intervention. Here, we found that pazopanib ameliorated ALI manifestations and reduced mortality in mouse ALI models and reduced edema in human lung transplantation recipients. Pazopanib inhibits mitogen-activated protein kinase kinase kinase 2 (MAP3K2)– and MAP3K3-mediated phosphorylation of NADPH oxidase 2 subunit p47phox at Ser208 to increase reactive oxygen species (ROS) formation in myeloid cells. Genetic inactivation of MAP3K2 and MAP3K3 in myeloid cells or hematopoietic mutation of p47phox Ser208 to alanine attenuated ALI manifestation...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Yuan, Q., Basit, A., Liang, W., Qu, R., Luan, Y., Ren, C., Li, A., Xu, X., Liu, X., Yang, C., Kuo, A., Pierce, R., Zhang, L., Turk, B., Hu, X., Li, F., Cui, W., Li, R., Huang, D., Mo, L., Sessa, W. C., Lee, P. J., Kluger, Y., Su, B., Tang, W., He, J., Wu, Tags: Research Articles Source Type: research
[Research Articles] Sustained fetal hemoglobin induction in vivo is achieved by BCL11A interference and coexpressed truncated erythropoietin receptor
Hematopoietic stem cell gene therapy for hemoglobin disorders, including sickle cell disease, requires high-efficiency lentiviral gene transfer and robust therapeutic globin expression in erythroid cells. Erythropoietin is a key cytokine for erythroid proliferation and differentiation (erythropoiesis), and truncated human erythropoietin receptors (thEpoR) have been reported in familial polycythemia. We reasoned that coexpression of thEpoR could enhance the phenotypic effect of a therapeutic vector in erythroid cells in xenograft mouse and autologous nonhuman primate transplantation models. We generated thEpoR by deleting 4...
Source: Science Translational Medicine - April 28, 2021 Category: Biomedical Science Authors: Uchida, N., Ferrara, F., Drysdale, C. M., Yapundich, M., Gamer, J., Nassehi, T., DiNicola, J., Shibata, Y., Wielgosz, M., Kim, Y.-S., Bauler, M., Throm, R. E., Haro-Mora, J. J., Demirci, S., Bonifacino, A. C., Krouse, A. E., Linde, N. S., Donahue, R. E., Tags: Research Articles Source Type: research
