[Research Articles] Faciogenital Dysplasia 5 supports cancer stem cell traits in basal-like breast cancer by enhancing EGFR stability
Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which have the worst prognosis and distant metastasis-free survival among breast cancer subtypes. Now, no targeted therapies are available for patients with BLBC due to the lack of reliable and effective molecular targets. Here, we performed the BLBC tissue microarray–based immunohistochemical analysis and showed that Faciogenital Dysplasia 5 (FGD5) abundance is associated with poor prognosis in BLBCs. FGD5 deletion decreased the proliferation, invasion, and tumorsphere formation capacity of BLBC cells. Furthermore, genetic inhibition ...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Li, K., Zhang, T.-t., Zhao, C.-x., Wang, F., Cui, B., Yang, Z.-n., Lv, X.-x., Yeerjiang, Z., Yuan, Y.-f., Yu, J.-m., Wang, Z.-h., Zhang, X.-w., Yu, J.-j., Liu, S.-s., Shang, S., Huang, B., Hua, F., Hu, Z.-w. Tags: Research Articles Source Type: research
[Perspectives] Reproducibility in machine learning for health research: Still a ways to go
Machine learning for health must be reproducible to ensure reliable clinical use. We evaluated 511 scientific papers across several machine learning subfields and found that machine learning for health compared poorly to other areas regarding reproducibility metrics, such as dataset and code accessibility. We propose recommendations to address this problem. (Source: Science Translational Medicine)
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: McDermott, M. B. A., Wang, S., Marinsek, N., Ranganath, R., Foschini, L., Ghassemi, M. Tags: Perspectives Source Type: research
[Research Articles] SVEP1 is a human coronary artery disease locus that promotes atherosclerosis
A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proli...
Source: Science Translational Medicine - March 24, 2021 Category: Biomedical Science Authors: Jung, I.-H., Elenbaas, J. S., Alisio, A., Santana, K., Young, E. P., Kang, C. J., Kachroo, P., Lavine, K. J., Razani, B., Mecham, R. P., Stitziel, N. O. Tags: Research Articles Source Type: research
[Research Articles] Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs
There is a need for replacement heart valves that can grow with children. We fabricated tubes of fibroblast-derived collagenous matrix that have been shown to regenerate and grow as a pulmonary artery replacement in lambs and implemented a design for a valved conduit consisting of three tubes sewn together. Seven lambs were implanted with tri-tube valved conduits in sequential cohorts and compared to bioprosthetic conduits. Valves implanted into the pulmonary artery of two lambs of the first cohort of four animals functioned with mild regurgitation and systolic pressure drops <10 mmHg up to 52 weeks after implantation, ...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Syedain, Z. H., Haynie, B., Johnson, S. L., Lahti, M., Berry, J., Carney, J. P., Li, J., Hill, R. C., Hansen, K. C., Thrivikraman, G., Bianco, R., Tranquillo, R. T. Tags: Research Articles Source Type: research
[Research Articles] GDE2-RECK controls ADAM10 {alpha}-secretase-mediated cleavage of amyloid precursor protein
A disintegrin and metalloprotease 10 (ADAM10) is the α-secretase for amyloid precursor protein (APP). ADAM10 cleaves APP to generate neuroprotective soluble APPα (sAPPα), which precludes the generation of Aβ, a defining feature of Alzheimer’s disease (AD) pathophysiology. Reduced ADAM10 activity is implicated in AD, but the mechanisms mediating ADAM10 modulation are unclear. We find that the plasma membrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2) stimulates ADAM10 APP cleavage by shedding and inactivating reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glyco...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Nakamura, M., Li, Y., Choi, B.-R., Matas-Rico, E., Troncoso, J., Takahashi, C., Sockanathan, S. Tags: Research Articles Source Type: research
[Perspectives] Advanced bandages for diabetic wound healing
Current treatment options for foot ulcers, a serious and prevalent complication of diabetes, remain nonspecific. In this Perspective, we present recent advances in understanding the pathophysiology of diabetic wound healing and the emergence of previously unidentified targets. We discuss wound dressings tailored to the diabetic wound environment currently under development. (Source: Science Translational Medicine)
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Matoori, S., Veves, A., Mooney, D. J. Tags: Perspectives Source Type: research
[Research Articles] Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates
Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fc receptors (FcRs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of FcR effector function benefits by dominant neutralization and using a ...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Hangartner, L., Beauparlant, D., Rakasz, E., Nedellec, R., Hoze, N., McKenney, K., Martins, M. A., Seabright, G. E., Allen, J. D., Weiler, A. M., Friedrich, T. C., Regoes, R. R., Crispin, M., Burton, D. R. Tags: Research Articles Source Type: research
[Research Articles] Citrullinated vimentin mediates development and progression of lung fibrosis
The mechanisms by which environmental exposures contribute to the pathogenesis of lung fibrosis are unclear. Here, we demonstrate an increase in cadmium (Cd) and carbon black (CB), common components of cigarette smoke (CS) and environmental particulate matter (PM), in lung tissue from subjects with idiopathic pulmonary fibrosis (IPF). Cd concentrations were directly proportional to citrullinated vimentin (Cit-Vim) amounts in lung tissue of subjects with IPF. Cit-Vim amounts were higher in subjects with IPF, especially smokers, which correlated with lung function and were associated with disease manifestations. Cd/CB induce...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Li, F. J., Surolia, R., Li, H., Wang, Z., Liu, G., Kulkarni, T., Massicano, A. V. F., Mobley, J. A., Mondal, S., de Andrade, J. A., Coonrod, S. A., Thompson, P. R., Wille, K., Lapi, S. E., Athar, M., Thannickal, V. J., Carter, A. B., Antony, V. B. Tags: Research Articles Source Type: research
[Research Articles] Structure-switching aptamer sensors for the specific detection of piperaquine and mefloquine
Tracking antimalarial drug use and efficacy is essential for monitoring the current spread of antimalarial drug resistance. However, available methods for determining tablet quality and patient drug use are often inaccessible, requiring well-equipped laboratories capable of performing liquid chromatography–mass spectrometry (LC-MS). Here, we report the development of aptamer-based fluorescent sensors for the rapid, specific detection of the antimalarial compounds piperaquine and mefloquine—two slow-clearing partner drugs in current first-line artemisinin-based combination therapies (ACTs). Highly selective DNA ...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Coonahan, E. S., Yang, K.-A., Pecic, S., De Vos, M., Wellems, T. E., Fay, M. P., Andersen, J. F., Tarning, J., Long, C. A. Tags: Research Articles Source Type: research
[Research Articles] RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity
Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression wa...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Peltier, D., Radosevich, M., Ravikumar, V., Pitchiaya, S., Decoville, T., Wood, S. C., Hou, G., Zajac, C., Oravecz-Wilson, K., Sokol, D., Henig, I., Wu, J., Kim, S., Taylor, A., Fujiwara, H., Sun, Y., Rao, A., Chinnaiyan, A. M., Goldstein, D. R., Reddy, P Tags: Research Articles Source Type: research
[Research Articles] Graft-derived extracellular vesicles transported across subcapsular sinus macrophages elicit B cell alloimmunity after transplantation
Despite the role of donor-specific antibodies (DSAs) in recognizing major histocompatibility complex (MHC) antigens and mediating transplant rejection, how and where recipient B cells in lymphoid tissues encounter donor MHC antigens remains unclear. Contrary to the dogma, we demonstrated here that migration of donor leukocytes out of skin or heart allografts is not necessary for B or T cell allosensitization in mice. We found that mouse skin and cardiac allografts and human skin grafts release cell-free donor MHC antigens via extracellular vesicles (EVs) that are captured by subcapsular sinus (SCS) macrophages in lymph nod...
Source: Science Translational Medicine - March 17, 2021 Category: Biomedical Science Authors: Zeng, F., Chen, Z., Chen, R., Shufesky, W. J., Bandyopadhyay, M., Camirand, G., Oberbarnscheidt, M. H., Sullivan, M. L. G., Baty, C. J., Yang, M.-q., Calderon, M., Stolz, D. B., Erdos, G., Pelanda, R., Brennan, T. V., Catz, S. D., Watkins, S. C., Larregin Tags: Research Articles Source Type: research
[Research Articles] Modular immune-homeostatic microparticles promote immune tolerance in mouse autoimmune models
In this study, we developed immune-homeostatic microparticles (IHMs) that treat multiple mouse models of autoimmunity via induction of apoptosis in activated T cells and reestablishment of regulatory T cells. Specifically, in an experimental model of colitis, IHMs rapidly released monocyte chemotactic protein–1 after intravenous administration, which recruited activated T cells and then induced their apoptosis by conjugated Fas ligand on the IHM surface. This triggered professional macrophages to ingest apoptotic T cells and produce high quantities of transforming growth factor–β, which drove regulatory T ...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Chen, X., Yang, X., Yuan, P., Jin, R., Bao, L., Qiu, X., Liu, S., Liu, T., Gooding, J. J., Chen, W., Liu, G., Bai, Y., Liu, S., Jin, Y. Tags: Research Articles Source Type: research
[Research Articles] Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice
Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Moreno, A. M., Aleman, F., Catroli, G. F., Hunt, M., Hu, M., Dailamy, A., Pla, A., Woller, S. A., Palmer, N., Parekh, U., McDonald, D., Roberts, A. J., Goodwill, V., Dryden, I., Hevner, R. F., Delay, L., Goncalves dos Santos, G., Yaksh, T. L., Mali, P. Tags: Research Articles Source Type: research
[Perspectives] Academic careers and the COVID-19 pandemic: Reversing the tide
The COVID-19 pandemic halted research operations at academic medical centers. This shutdown has adversely affected research infrastructure, the current research workforce, and the research pipeline. We discuss the impact of the pandemic on overall research operations, examine its disproportionate effect on underrepresented minority researchers, and provide concrete strategies to reverse these losses. (Source: Science Translational Medicine)
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Carr, R. M., Lane-Fall, M. B., South, E., Brady, D., Momplaisir, F., Guerra, C. E., Montoya-Williams, D., Dalembert, G., Lavizzo-Mourey, R., Hamilton, R. Tags: Perspectives Source Type: research
[Research Articles] A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma
Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference–based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we cond...
Source: Science Translational Medicine - March 10, 2021 Category: Biomedical Science Authors: Kumthekar, P., Ko, C. H., Paunesku, T., Dixit, K., Sonabend, A. M., Bloch, O., Tate, M., Schwartz, M., Zuckerman, L., Lezon, R., Lukas, R. V., Jovanovic, B., McCortney, K., Colman, H., Chen, S., Lai, B., Antipova, O., Deng, J., Li, L., Tommasini-Ghelfi, S Tags: Research Articles Source Type: research
