[Research Articles] Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup
Adult "T cell" acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is associated with poor outcomes, requiring additional therapeutic options. The DNA methylation landscapes of adult T-ALL remain undercharacterized. Here, we systematically analyzed the DNA methylation profiles of normal thymic-sorted T cell subpopulations and 143 primary adult T-ALLs as part of the French GRAALL 2003–2005 trial. Our results indicated that T-ALL is epigenetically heterogeneous consisting of five subtypes (C1-C5), which were either associated with co-occurring DNA methyltransferase 3 alpha (DNMT3A)/isoci...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Touzart, A., Mayakonda, A., Smith, C., Hey, J., Toth, R., Cieslak, A., Andrieu, G. P., Tran Quang, C., Latiri, M., Ghysdael, J., Spicuglia, S., Dombret, H., Ifrah, N., Macintyre, E., Lutsik, P., Boissel, N., Plass, C., Asnafi, V. Tags: Research Articles Source Type: research
[Research Articles] Viral genomes reveal patterns of the SARS-CoV-2 outbreak in Washington State
The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gravely affected societies around the world. Outbreaks in different parts of the globe have been shaped by repeated introductions of new viral lineages and subsequent local transmission of those lineages. Here, we sequenced 3940 SARS-CoV-2 viral genomes from Washington State (USA) to characterize how the spread of SARS-CoV-2 in Washington State in early 2020 was shaped by differences in timing of mitigation strategies across counties and by repeated introductions of viral lineages into the state. In addition, we show that the increase in f...
Source: Science Translational Medicine - May 26, 2021 Category: Biomedical Science Authors: Müller, N. F., Wagner, C., Frazar, C. D., Roychoudhury, P., Lee, J., Moncla, L. H., Pelle, B., Richardson, M., Ryke, E., Xie, H., Shrestha, L., Addetia, A., Rachleff, V. M., Lieberman, N. A. P., Huang, M.-L., Gautom, R., Melly, G., Hiatt, B., Dyke Tags: Research Articles Source Type: research
[Research Articles] cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes
Loss of major histocompatibility complex (MHC) class I and interferon- (IFN-) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor B (NF-B) signaling. Induction of noncanonical NF-B signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-B signaling induces T cell–dependent immune respon...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Roehle, K., Qiang, L., Ventre, K. S., Heid, D., Ali, L. R., Lenehan, P., Heckler, M., Crowley, S. J., Stump, C. T., Ro, G., Godicelj, A., Bhuiyan, A. M., Yang, A., Quiles del Rey, M., Biary, T., Luoma, A. M., Bruck, P. T., Tegethoff, J. F., Nopper, S. L., Tags: Research Articles Source Type: research
[Research Articles] ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity
Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a m...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Shum, M., Shintre, C. A., Althoff, T., Gutierrez, V., Segawa, M., Saxberg, A. D., Martinez, M., Adamson, R., Young, M. R., Faust, B., Gharakhanian, R., Su, S., Chella Krishnan, K., Mahdaviani, K., Veliova, M., Wolf, D. M., Ngo, J., Nocito, L., Stiles, L., Tags: Research Articles Source Type: research
[Research Articles] A method to delineate de novo missense variants across pathways prioritizes genes linked to autism
Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Koire, A., Katsonis, P., Kim, Y. W., Buchovecky, C., Wilson, S. J., Lichtarge, O. Tags: Research Articles Source Type: research
[Research Articles] Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism
Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-d...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Ng, J., Barral, S., De La Fuente Barrigon, C., Lignani, G., Erdem, F. A., Wallings, R., Privolizzi, R., Rossignoli, G., Alrashidi, H., Heasman, S., Meyer, E., Ngoh, A., Pope, S., Karda, R., Perocheau, D., Baruteau, J., Suff, N., Antinao Diaz, J., Schorge, Tags: Research Articles Source Type: research
[Research Articles] Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer
We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells ar...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Garris, C. S., Wong, J. L., Ravetch, J. V., Knorr, D. A. Tags: Research Articles Source Type: research
[Research Articles] Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays
Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Kraus, R. L., Zhao, F., Pall, P. S., Zhou, D., Vardigan, J. D., Danziger, A., Li, Y., Daley, C., Ballard, J. E., Clements, M. K., Klein, R. M., Holahan, M. A., Greshock, T. J., Kim, R. M., Layton, M. E., Burgey, C. S., Serra, J., Henze, D. A., Houghton, A Tags: Research Articles Source Type: research
[Research Articles] Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair
The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kid...
Source: Science Translational Medicine - May 19, 2021 Category: Biomedical Science Authors: Mylonas, K. J., OSullivan, E. D., Humphries, D., Baird, D. P., Docherty, M.-H., Neely, S. A., Krimpenfort, P. J., Melk, A., Schmitt, R., Ferreira-Gonzalez, S., Forbes, S. J., Hughes, J., Ferenbach, D. A. Tags: Research Articles Source Type: research
[Technical Comments] Response to comment on "Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI"
The nuclear pregnane X receptor protects against bilateral renal ischemia/reperfusion-induced acute kidney injury in mice. (Source: Science Translational Medicine)
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Yu, X., Zhang, Y., Jia, Z., Zhang, A. Tags: Technical Comments Source Type: research
[Research Articles] An oral antisense oligonucleotide for PCSK9 inhibition
We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to redu...
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Gennemark, P., Walter, K., Clemmensen, N., Rekic, D., Nilsson, C. A. M., Knöchel, J., Hölttä, M., Wernevik, L., Rosengren, B., Kakol-Palm, D., Wang, Y., Yu, R. Z., Geary, R. S., Riney, S. J., Monia, B. P., Isaksson, R., Jansson-Lo& Tags: Research Articles Source Type: research
[Research Articles] CD4+ T cells are essential for the development of destructive thyroiditis induced by anti-PD-1 antibody in thyroglobulin-immunized mice
Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by...
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Yasuda, Y., Iwama, S., Sugiyama, D., Okuji, T., Kobayashi, T., Ito, M., Okada, N., Enomoto, A., Ito, S., Yan, Y., Sugiyama, M., Onoue, T., Tsunekawa, T., Ito, Y., Takagi, H., Hagiwara, D., Goto, M., Suga, H., Banno, R., Takahashi, M., Nishikawa, H., Arima Tags: Research Articles Source Type: research
[Reports] A portable magnetofluidic platform for detecting sexually transmitted infections and antimicrobial susceptibility
This study paves the way for delivering accessible PCR diagnostics for rapidly detecting STIs at the point of care, helping to guide treatment decisions and combat the rise of antimicrobial resistant pathogens. (Source: Science Translational Medicine)
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Trick, A. Y., Melendez, J. H., Chen, F.-E., Chen, L., Onzia, A., Zawedde, A., Nakku-Joloba, E., Kyambadde, P., Mande, E., Matovu, J., Atuheirwe, M., Kwizera, R., Gilliams, E. A., Hsieh, Y.-H., Gaydos, C. A., Manabe, Y. C., Hamill, M. M., Wang, T.-H. Tags: Reports Source Type: research
[Research Articles] Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide
Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice wer...
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Sishc, B. J., Ding, L., Nam, T.-K., Heer, C. D., Rodman, S. N., Schoenfeld, J. D., Fath, M. A., Saha, D., Pulliam, C. F., Langen, B., Beardsley, R. A., Riley, D. P., Keene, J. L., Spitz, D. R., Story, M. D. Tags: Research Articles Source Type: research
[Research Articles] Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimers disease
We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence o...
Source: Science Translational Medicine - May 12, 2021 Category: Biomedical Science Authors: Ayalon, G., Lee, S.-H., Adolfsson, O., Foo-Atkins, C., Atwal, J. K., Blendstrup, M., Booler, H., Bravo, J., Brendza, R., Brunstein, F., Chan, R., Chandra, P., Couch, J. A., Datwani, A., Demeule, B., DiCara, D., Erickson, R., Ernst, J. A., Foreman, O., He, Tags: Research Articles Source Type: research
