[Research Articles] Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models
Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor’s sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Lin, Y.-X., Wang, Y., Ding, J., Jiang, A., Wang, J., Yu, M., Blake, S., Liu, S., Bieberich, C. J., Farokhzad, O. C., Mei, L., Wang, H., Shi, J. Tags: Research Articles Source Type: research
[Research Resource] A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders. (Source: Science Translational Medicine)
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Zimmer, C. L., von Seth, E., Buggert, M., Strauss, O., Hertwig, L., Nguyen, S., Wong, A. Y. W., Zotter, C., Berglin, L., Michaëlsson, J., Hansson, M. R., Arnelo, U., Sparrelid, E., Ellis, E. C. S., Söderholm, J. D., Keita, A. V., Holm, K., Tags: Research Resource Source Type: research
[Research Articles] The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy
Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1–infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound w...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: SenGupta, D., Brinson, C., DeJesus, E., Mills, A., Shalit, P., Guo, S., Cai, Y., Wallin, J. J., Zhang, L., Humeniuk, R., Begley, R., Geleziunas, R., Mellors, J., Wrin, T., Jones, N., Milush, J., Ferre, A. L., Shacklett, B. L., Laird, G. M., Moldt, B., Ven Tags: Research Articles Source Type: research
[Research Articles] Functional human IgA targets a conserved site on malaria sporozoites
This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies. (Source: Science Translational Medicine)
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Tan, J., Cho, H., Pholcharee, T., Pereira, L. S., Doumbo, S., Doumtabe, D., Flynn, B. J., Schön, A., Kanatani, S., Aylor, S. O., Oyen, D., Vistein, R., Wang, L., Dillon, M., Skinner, J., Peterson, M., Li, S., Idris, A. H., Molina-Cruz, A., Zhao, M Tags: Research Articles Source Type: research
[Research Articles] A self-amplifying loop of YAP and SHH drives formation and expansion of heterotopic ossification
Heterotopic ossification (HO) occurs as a common complication after injury or in genetic disorders. The mechanisms underlying HO remain incompletely understood, and there are no approved prophylactic or secondary treatments available. Here, we identify a self-amplifying, self-propagating loop of Yes-associated protein (YAP)–Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. In mouse models of progressive osseous heteroplasia (POH), a disease caused by null mutations in GNAS, we found that Gnas–/– mesenchymal cells secreted SHH, which induced osteoblast differentiation of th...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Cong, Q., Liu, Y., Zhou, T., Zhou, Y., Xu, R., Cheng, C., Chung, H. S., Yan, M., Zhou, H., Liao, Z., Gao, B., Bocobo, G. A., Covington, T. A., Song, H. J., Su, P., Yu, P. B., Yang, Y. Tags: Research Articles Source Type: research
[Research Articles] Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis
Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor B (NF-B) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression ex...
Source: Science Translational Medicine - June 23, 2021 Category: Biomedical Science Authors: Yu, J., Zhu, C., Wang, X., Kim, K., Bartolome, A., Dongiovanni, P., Yates, K. P., Valenti, L., Carrer, M., Sadowski, T., Qiang, L., Tabas, I., Lavine, J. E., Pajvani, U. B. Tags: Research Articles Source Type: research
[Research Articles] Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro
Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Reyes, M., Filbin, M. R., Bhattacharyya, R. P., Sonny, A., Mehta, A., Billman, K., Kays, K. R., Pinilla-Vera, M., Benson, M. E., Cosimi, L. A., Hung, D. T., Levy, B. D., Villani, A.-C., Sade-Feldman, M., Baron, R. M., Goldberg, M. B., Blainey, P. C., Haco Tags: Research Articles Source Type: research
[Research Articles] A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections
More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting t...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Gege, C., Bravo, F. J., Uhlig, N., Hagmaier, T., Schmachtenberg, R., Elis, J., Burger-Kentischer, A., Finkelmeier, D., Hamprecht, K., Grunwald, T., Bernstein, D. I., Kleymann, G. Tags: Research Articles Source Type: research
[Research Articles] A randomized controlled trial to isolate the effects of fasting and energy restriction on weight loss and metabolic health in lean adults
Intermittent fasting may impart metabolic benefits independent of energy balance by initiating fasting-mediated mechanisms. This randomized controlled trial examined 24-hour fasting with 150% energy intake on alternate days for 3 weeks in lean, healthy individuals (0:150; n = 12). Control groups involved a matched degree of energy restriction applied continuously without fasting (75% energy intake daily; 75:75; n = 12) or a matched pattern of fasting without net energy restriction (200% energy intake on alternate days; 0:200; n = 12). Primary outcomes were body composition, components of energy balance, and postprandial me...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Templeman, I., Smith, H. A., Chowdhury, E., Chen, Y.-C., Carroll, H., Johnson-Bonson, D., Hengist, A., Smith, R., Creighton, J., Clayton, D., Varley, I., Karagounis, L. G., Wilhelmsen, A., Tsintzas, K., Reeves, S., Walhin, J.-P., Gonzalez, J. T., Thompson Tags: Research Articles Source Type: research
[Research Articles] Macrophage depletion induces edema through release of matrix-degrading proteases and proteoglycan deposition
In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix–remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in t...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Bissinger, S., Hage, C., Wagner, V., Maser, I.-P., Brand, V., Schmittnaegel, M., Jegg, A.-M., Cannarile, M., Watson, C., Klaman, I., Rieder, N., Gonzalez Loyola, A., Petrova, T. V., Cassier, P. A., Gomez-Roca, C., Sibaud, V., De Palma, M., Hoves, S., Ries Tags: Research Articles Source Type: research
[Research Articles] Enhancing proteasomal processing improves survival for a peptide vaccine used to treat glioblastoma
We examined 20 peptides in silico and experimentally, which showed that a tyrosine substitution (Y6-pepVIII) maximizes proteasome cleavage and survival in a subcutaneous tumor model in mice. In an intracranial glioma model, Y6-pepVIII showed a 62 and 31% improvement in median survival compared to control animals and pepVIII-vaccinated mice. Y6-pepVIII vaccination altered tumor-infiltrating lymphocyte subsets and expression of PD-1 on intratumoral T cells. Combination with anti–PD-1 therapy cured 45% of the Y6-pepVIII–vaccinated mice but was ineffective for pepVIII-treated mice. Liquid chromatography–tande...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Fidanza, M., Gupta, P., Sayana, A., Shanker, V., Pahlke, S.-M., Vu, B., Krantz, F., Azameera, A., Wong, N., Anne, N., Xia, Y., Rong, J., Anne, A., Skirboll, S., Lim, M., Wong, A. J. Tags: Research Articles Source Type: research
[Research Articles] Development of {beta}-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease
Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)–mediated HBB gen...
Source: Science Translational Medicine - June 16, 2021 Category: Biomedical Science Authors: Lattanzi, A., Camarena, J., Lahiri, P., Segal, H., Srifa, W., Vakulskas, C. A., Frock, R. L., Kenrick, J., Lee, C., Talbott, N., Skowronski, J., Cromer, M. K., Charlesworth, C. T., Bak, R. O., Mantri, S., Bao, G., DiGiusto, D., Tisdale, J., Wright, J. F., Tags: Research Articles Source Type: research
[Research Articles] Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury
Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)–dependent cell de...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Widjaja, A. A., Dong, J., Adami, E., Viswanathan, S., Ng, B., Pakkiri, L. S., Chothani, S. P., Singh, B. K., Lim, W. W., Zhou, J., Shekeran, S. G., Tan, J., Lim, S. Y., Goh, J., Wang, M., Holgate, R., Hearn, A., Felkin, L. E., Yen, P. M., Dear, J. W., Dru Tags: Research Articles Source Type: research
[Research Articles] An MD2-perturbing peptide has therapeutic effects in rodent and rhesus monkey models of stroke
Studies have failed to translate more than 1000 experimental treatments from bench to bedside, leaving stroke as the second leading cause of death in the world. Thrombolysis within 4.5 hours is the recommended therapy for stroke and cannot be performed until neuroimaging is used to distinguish ischemic stroke from hemorrhagic stroke. Therefore, finding a common and critical therapeutic target for both ischemic and hemorrhagic stroke is appealing. Here, we report that the expression of myeloid differentiation protein 2 (MD2), which is traditionally regarded to be expressed only in microglia in the normal brain, was markedly...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Fang, Z., Wu, D., Deng, J., Yang, Q., Zhang, X., Chen, J., Wang, S., Hu, S., Hou, W., Ning, S., Ding, Y., Fan, Z., Jiang, Z., Kang, J., Liu, Y., Miao, J., Ji, X., Dong, H., Xiong, L. Tags: Research Articles Source Type: research
[Research Articles] A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains
A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy a...
Source: Science Translational Medicine - June 9, 2021 Category: Biomedical Science Authors: Mateo, M., Reynard, S., Journeaux, A., Germain, C., Hortion, J., Carnec, X., Picard, C., Baillet, N., Borges-Cardoso, V., Merabet, O., Vallve, A., Barron, S., Jourjon, O., Lacroix, O., Duthey, A., Dirheimer, M., Jouvion, G., Moreau, P.-H., Fellmann, L., C Tags: Research Articles Source Type: research
