[Research Articles] Percutaneous liquid ablation agent for tumor treatment and drug delivery
Percutaneous locoregional therapies (LRTs), such as thermal ablation, are performed to limit the progression of hepatocellular carcinoma (HCC) and offer a bridge for patients waiting for liver transplantation. However, physiological challenges related to tumor location, size, and existence of multiple lesions as well as safety concerns related to potential thermal injury to adjacent tissues may preclude the use of thermal ablation or lead to its failure. Here, we showed a successful injection of an ionic liquid into tissue under image guidance, ablation of tumors in response to the injected ionic liquid, and persistence (2...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Albadawi, H., Zhang, Z., Altun, I., Hu, J., Jamal, L., Ibsen, K. N., Tanner, E. E. L., Mitragotri, S., Oklu, R. Tags: Research Articles Source Type: research
[Research Articles] Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses
Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell ...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Chan, Y. K., Wang, S. K., Chu, C. J., Copland, D. A., Letizia, A. J., Costa Verdera, H., Chiang, J. J., Sethi, M., Wang, M. K., Neidermyer, W. J., Chan, Y., Lim, E. T., Graveline, A. R., Sanchez, M., Boyd, R. F., Vihtelic, T. S., Inciong, R. G. C. O., Sla Tags: Research Articles Source Type: research
[Reviews] Cell type-specific microRNA therapies for myocardial infarction
Current interventions fail to recover injured myocardium after infarction and prompt the need for development of cardioprotective strategies. Of increasing interest is the therapeutic use of microRNAs to control gene expression through specific targeting of mRNAs. In this Review, we discuss current microRNA-based therapeutic strategies, describing the outcomes and limitations of key microRNAs with a focus on target cell types and molecular pathways. Last, we offer a perspective on the outlook of microRNA therapies for myocardial infarction, highlighting the outstanding challenges and emerging strategies. (Source: Science T...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Liu, B., Wang, B., Zhang, X., Lock, R., Nash, T., Vunjak-Novakovic, G. Tags: Reviews Source Type: research
[Research Articles] Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies
Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). To hasten treatment development, we established induced pluripotent stem cell (iPSC) lines from patients with CS representing a mutational spectrum, as well as biologically related and isogenic control lines. We demonstrated that pathogenic mutations lead to loss of protein function by a variety of mechanisms: The majority of mutations caused loss of mRNA due to nonsense-mediated mRNA decay; how...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Lizarraga, S. B., Ma, L., Maguire, A. M., van Dyck, L. I., Wu, Q., Ouyang, Q., Kavanaugh, B. C., Nagda, D., Livi, L. L., Pescosolido, M. F., Schmidt, M., Alabi, S., Cowen, M. H., Brito-Vargas, P., Hoffman-Kim, D., Gamsiz Uzun, E. D., Schlessinger, A., Jon Tags: Research Articles Source Type: research
[Research Articles] Smartwatch inertial sensors continuously monitor real-world motor fluctuations in Parkinsons disease
Longitudinal, remote monitoring of motor symptoms in Parkinson’s disease (PD) could enable more precise treatment decisions. We developed the Motor fluctuations Monitor for Parkinson’s Disease (MM4PD), an ambulatory monitoring system that used smartwatch inertial sensors to continuously track fluctuations in resting tremor and dyskinesia. We designed and validated MM4PD in 343 participants with PD, including a longitudinal study of up to 6 months in a 225-subject cohort. MM4PD measurements correlated to clinical evaluations of tremor severity ( = 0.80) and mapped to expert ratings of dyskinesia presence (P <...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Powers, R., Etezadi-Amoli, M., Arnold, E. M., Kianian, S., Mance, I., Gibiansky, M., Trietsch, D., Alvarado, A. S., Kretlow, J. D., Herrington, T. M., Brillman, S., Huang, N., Lin, P. T., Pham, H. A., Ullal, A. V. Tags: Research Articles Source Type: research
[Research Articles] Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis
Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[18F]fl...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Xie, Y. L., de Jager, V. R., Chen, R. Y., Dodd, L. E., Paripati, P., Via, L. E., Follmann, D., Wang, J., Lumbard, K., Lahouar, S., Malherbe, S. T., Andrews, J., Yu, X., Goldfeder, L. C., Cai, Y., Arora, K., Loxton, A. G., Vanker, N., Duvenhage, M., Winter Tags: Research Articles Source Type: research
[Research Articles] Cardiac ryanodine receptor calcium release deficiency syndrome
Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and ...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Sun, B., Yao, J., Ni, M., Wei, J., Zhong, X., Guo, W., Zhang, L., Wang, R., Belke, D., Chen, Y.-X., Lieve, K. V. V., Broendberg, A. K., Roston, T. M., Blankoff, I., Kammeraad, J. A., von Alvensleben, J. C., Lazarte, J., Vallmitjana, A., Bohne, L. J., Rose Tags: Research Articles Source Type: research
[Errata] Erratum for the Research Article: "Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth" by H. C. Zierden, J. I. Ortiz, K. DeLong, J. Yu, G. Li, P. Dimitrion, S. Bensouda, V. Laney, A. Bailey, N. M. Anders, M. Scardina, M. Mahendroo, S. Mesiano, I. Burd, G. Wagner, J. Hanes, L. M. Ensign
(Source: Science Translational Medicine)
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Tags: Errata Source Type: research
[Research Articles] Eosinophils attenuate hepatic ischemia-reperfusion injury in mice through ST2-dependent IL-13 production
Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow–derived eosinophils normalized liver injury of eosinophil-deficient mice and reduce...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Wang, Y., Yang, Y., Wang, M., Wang, S., Jeong, J.-M., Xu, L., Wen, Y., Emontzpohl, C., Atkins, C. L., Duong, K., Moreno, N. F., Yuan, X., Hall, D. R., Dar, W., Feng, D., Gao, B., Xu, Y., Czigany, Z., Colgan, S. P., Bynon, J. S., Akira, S., Brown, J. M., E Tags: Research Articles Source Type: research
[Research Articles] Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate
Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Kong, F.-E., Li, G.-M., Tang, Y.-Q., Xi, S.-Y., Loong, J. H. C., Li, M.-M., Li, H.-L., Cheng, W., Zhu, W.-J., Mo, J.-Q., Gong, Y.-F., Tang, H., Zhao, Y., Zhang, Y., Ma, S., Guan, X.-Y., Ma, N.-F., Xie, M.-B., Liu, M. Tags: Research Articles Source Type: research
[Research Articles] Morphine acts on spinal dynorphin neurons to cause itch through disinhibition
Morphine-induced itch is a very common and debilitating side effect that occurs in laboring women who receive epidural analgesia and in patients who receive spinal morphine for relief of perioperative pain. Although antihistamines are still widely prescribed for the treatment of morphine-induced itch, their use is controversial because the cellular basis for morphine-induced itch remains unclear. Here, we used animal models and show that neuraxial morphine causes itch through neurons and not mast cells. In particular, we found that spinal dynorphin (Pdyn) neurons are both necessary and sufficient for morphine-induced itch ...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Nguyen, E., Lim, G., Ding, H., Hachisuka, J., Ko, M.-C., Ross, S. E. Tags: Research Articles Source Type: research
[Research Articles] NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models
Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily fo...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Moquin, S. A., Simon, O., Karuna, R., Lakshminarayana, S. B., Yokokawa, F., Wang, F., Saravanan, C., Zhang, J., Day, C. W., Chan, K., Wang, Q.-Y., Lu, S., Dong, H., Wan, K. F., Lim, S. P., Liu, W., Seh, C. C., Chen, Y.-L., Xu, H., Barkan, D. T., Kounde, C Tags: Research Articles Source Type: research
[Reviews] Development and deployment of COVID-19 vaccines for those most vulnerable
Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for...
Source: Science Translational Medicine - February 3, 2021 Category: Biomedical Science Authors: Koff, W. C., Schenkelberg, T., Williams, T., Baric, R. S., McDermott, A., Cameron, C. M., Cameron, M. J., Friemann, M. B., Neumann, G., Kawaoka, Y., Kelvin, A. A., Ross, T. M., Schultz-Cherry, S., Mastro, T. D., Priddy, F. H., Moore, K. A., Ostrowsky, J. Tags: Reviews Source Type: research
[Research Articles] Extracellular vesicles deposit PCNA to rejuvenate aged bone marrow-derived mesenchymal stem cells and slow age-related degeneration
Stem cell senescence increases alongside the progressive functional declines that characterize aging. The effects of extracellular vesicles (EVs) are now attracting intense interest in the context of aging and age-related diseases. Here, we demonstrate that neonatal umbilical cord (UC) is a source of EVs derived from mesenchymal stem cells (MSC-EVs). These UC-produced MSC-EVs (UC-EVs) contain abundant anti-aging signals and rejuvenate senescing adult bone marrow–derived MSCs (AB-MSCs). UC-EV–rejuvenated AB-MSCs exhibited alleviated aging phenotypes and increased self-renewal capacity and telomere length. Mechan...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Lei, Q., Gao, F., Liu, T., Ren, W., Chen, L., Cao, Y., Chen, W., Guo, S., Zhang, Q., Chen, W., Wang, H., Chen, Z., Li, Q., Hu, Y., Guo, A.-Y. Tags: Research Articles Source Type: research
[Research Articles] Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys
Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be hig...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Speranza, E., Williamson, B. N., Feldmann, F., Sturdevant, G. L., Perez- Perez, L., Meade-White, K., Smith, B. J., Lovaglio, J., Martens, C., Munster, V. J., Okumura, A., Shaia, C., Feldmann, H., Best, S. M., de Wit, E. Tags: Research Articles Source Type: research
