[Reviews] Druggable cancer phosphatases
We describe the modes of action for currently available small molecules that target phosphatases, their use in drug combinations, and advances in clinical development toward future cancer therapies. (Source: Science Translational Medicine)
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Vainonen, J. P., Momeny, M., Westermarck, J. Tags: Reviews Source Type: research
[Research Articles] SerpinB13 antibodies promote {beta} cell development and resistance to type 1 diabetes
Pancreatic endocrine cell development is dependent on the rescue of the neurogenin3 (Ngn3) transcription factor from repression by Notch. The signals that prevent Notch signaling, thereby allowing the formation of pancreatic endocrine cells, remain unclear. We show that inhibiting serpinB13, a cathepsin L (CatL) protease inhibitor expressed in the pancreatic epithelium, caused in vitro and in vivo cleavage of the extracellular domain of Notch1. This was followed by a twofold increase in the Ngn3+ progenitor cell population and enhanced conversion of these cells to express insulin. Conversely, both recombinant serpinB13 pro...
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Kryvalap, Y., Jiang, M. L., Kryvalap, N., Hendrickson, C., Czyzyk, J. Tags: Research Articles Source Type: research
[Research Articles] Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke
Neuroprotection for acute ischemic stroke is achievable with the eicosapeptide nerinetide, an inhibitor of the protein-protein interactions of the synaptic scaffolding protein PSD-95. However, nerinetide is subject to proteolytic cleavage if administered after alteplase, a standard-of-care thrombolytic agent that nullifies nerinetide’s beneficial effects. Here, we showed, on the basis of pharmacokinetic data consistent between rats, primates, and humans, that in a rat model of embolic middle cerebral artery occlusion (eMCAO), nerinetide maintained its effectiveness when administered before alteplase. Because of its s...
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Mayor-Nunez, D., Ji, Z., Sun, X., Teves, L., Garman, J. D., Tymianski, M. Tags: Research Articles Source Type: research
[Research Articles] Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, and despite advances in genetic and pharmacological disease-modifying treatments, its management remains a major challenge. Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive. Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction. Mitophagy markers were reduced in skeletal muscle and in muscle stem cells (MuSCs) of a mouse model of DMD. Administration of the mitophagy activa...
Source: Science Translational Medicine - April 7, 2021 Category: Biomedical Science Authors: Luan, P., DAmico, D., Andreux, P. A., Laurila, P.-P., Wohlwend, M., Li, H., Imamura de Lima, T., Place, N., Rinsch, C., Zanou, N., Auwerx, J. Tags: Research Articles Source Type: research
[Research Articles] Soft, skin-interfaced sweat stickers for cystic fibrosis diagnosis and management
The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") des...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Ray, T. R., Ivanovic, M., Curtis, P. M., Franklin, D., Guventurk, K., Jeang, W. J., Chafetz, J., Gaertner, H., Young, G., Rebollo, S., Model, J. B., Lee, S. P., Ciraldo, J., Reeder, J. T., Hourlier-Fargette, A., Bandodkar, A. J., Choi, J., Aranyosi, A. J. Tags: Research Articles Source Type: research
[Research Articles] Dysfunction of the proteoglycan Tsukushi causes hydrocephalus through altered neurogenesis in the subventricular zone in mice
The lateral ventricle (LV) is flanked by the subventricular zone (SVZ), a neural stem cell (NSC) niche rich in extrinsic growth factors regulating NSC maintenance, proliferation, and neuronal differentiation. Dysregulation of the SVZ niche causes LV expansion, a condition known as hydrocephalus; however, the underlying pathological mechanisms are unclear. We show that deficiency of the proteoglycan Tsukushi (TSK) in ependymal cells at the LV surface and in the cerebrospinal fluid results in hydrocephalus with neurodevelopmental disorder-like symptoms in mice. These symptoms are accompanied by altered differentiation and su...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Ito, N., Riyadh, M. A., Ahmad, S. A. I., Hattori, S., Kanemura, Y., Kiyonari, H., Abe, T., Furuta, Y., Shinmyo, Y., Kaneko, N., Hirota, Y., Lupo, G., Hatakeyama, J., Abdulhaleem M, F. A., Anam, M. B., Yamaguchi, M., Takeo, T., Takebayashi, H., Takebayashi Tags: Research Articles Source Type: research
[Research Articles] Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection
Pegylated interferon-α (PEG–IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG–IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG–IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG–IFN-α injection experienced grea...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Nishio, A., Bolte, F. J., Takeda, K., Park, N., Yu, Z.-X., Park, H., Valdez, K., Ghany, M. G., Rehermann, B. Tags: Research Articles Source Type: research
[Research Articles] Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy
The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T c...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Liu, X., Hartman, C. L., Li, L., Albert, C. J., Si, F., Gao, A., Huang, L., Zhao, Y., Lin, W., Hsueh, E. C., Shen, L., Shao, Q., Hoft, D. F., Ford, D. A., Peng, G. Tags: Research Articles Source Type: research
[Research Resources] Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression
Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Xhonneux, L.-P., Knight, O., Lernmark, A., Bonifacio, E., Hagopian, W. A., Rewers, M. J., She, J.-X., Toppari, J., Parikh, H., Smith, K. G. C., Ziegler, A.-G., Akolkar, B., Krischer, J. P., McKinney, E. F. Tags: Research Resources Source Type: research
[Research Articles] Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor
The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 cancer types. The sensitivity to VCP inhibition of human AML cell lines...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Roux, B., Vaganay, C., Vargas, J. D., Alexe, G., Benaksas, C., Pardieu, B., Fenouille, N., Ellegast, J. M., Malolepsza, E., Ling, F., Sodaro, G., Ross, L., Pikman, Y., Conway, A. S., Tang, Y., Wu, T., Anderson, D. J., Le Moigne, R., Zhou, H.-J., Luciano, Tags: Research Articles Source Type: research
[Research Articles] Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health
Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk ...
Source: Science Translational Medicine - March 31, 2021 Category: Biomedical Science Authors: Ribo, S., Sanchez-Infantes, D., Martinez-Guino, L., Garcia-Mantrana, I., Ramon-Krauel, M., Tondo, M., Arning, E., Nofrarias, M., Osorio-Conles, O., Fernandez-Perez, A., Gonzalez-Torres, P., Cebria, J., Gavalda-Navarro, A., Chenoll, E., Isganaitis, E., Vil Tags: Research Articles Source Type: research
[Research Articles] Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia
Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly pr...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Sun, J., Uchiyama, S., Olson, J., Morodomi, Y., Cornax, I., Ando, N., Kohno, Y., Kyaw, M. M. T., Aguilar, B., Haste, N. M., Kanaji, S., Kanaji, T., Rose, W. E., Sakoulas, G., Marth, J. D., Nizet, V. Tags: Research Articles Source Type: research
[Research Articles] Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models
A substantial number of patients with leukemia and lymphoma treated with anti-CD19 or anti-CD22 monoCAR-T cell therapy relapse because of antigen loss or down-regulation. We hypothesized that B cell tumor antigen escape may be overcome by a chimeric antigen receptor (CAR) design that simultaneously targets three B cell leukemia antigens. We engineered trispecific duoCAR-T cells with lentiviral vectors encoding two CAR open reading frames that target CD19, CD20, and CD22. The duoCARs were composed of a CAR with a tandem CD19- and CD20-targeting binder, linked by the P2A self-cleaving peptide to a second CAR targeting CD22. ...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Schneider, D., Xiong, Y., Wu, D., Hu, P., Alabanza, L., Steimle, B., Mahmud, H., Anthony-Gonda, K., Krueger, W., Zhu, Z., Dimitrov, D. S., Orentas, R. J., Dropulic, B. Tags: Research Articles Source Type: research
[Research Articles] Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors
Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR-T cells have shown limited efficacy, which is partially attributed to intrinsic defects in CAR signaling. Here, we construct a double-chain chimeric receptor, termed as synthetic T cell receptor (TCR) and antigen receptor (STAR), which incorporates antigen-recognition domain of antibody and constant regions of TCR that engage endogenous CD3 signaling machinery. Under antigen-free conditions, STAR does not trigger tonic signali...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Liu, Y., Liu, G., Wang, J., Zheng, Z.-y., Jia, L., Rui, W., Huang, D., Zhou, Z.-x., Zhou, L., Wu, X., Lin, S., Zhao, X., Lin, X. Tags: Research Articles Source Type: research
[Research Articles] An intracortical neuroprosthesis immediately alleviates walking deficits and improves recovery of leg control after spinal cord injury
Most rehabilitation interventions after spinal cord injury (SCI) only target the sublesional spinal networks, peripheral nerves, and muscles. However, mammalian locomotion is not a mere act of rhythmic pattern generation. Recovery of cortical control is essential for voluntary movement and modulation of gait. We developed an intracortical neuroprosthetic intervention to SCI, with the goal to condition cortical locomotor control. Neurostimulation delivered in phase coherence with ongoing locomotion immediately alleviated primary SCI deficits, such as leg dragging, in rats with incomplete SCI. Cortical neurostimulation achie...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Bonizzato, M., Martinez, M. Tags: Research Articles Source Type: research
