[Research Articles] Mechanism and reversal of drug-induced nephrotoxicity on a chip
The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Cohen, A., Ioannidis, K., Ehrlich, A., Regenbaum, S., Cohen, M., Ayyash, M., Tikva, S. S., Nahmias, Y. Tags: Research Articles Source Type: research

[Research Articles] Load-induced regulation of tendon homeostasis by SPARC, a genetic predisposition factor for tendon and ligament injuries
Tendons and tendon interfaces have a very limited regenerative capacity, rendering their injuries clinically challenging to resolve. Tendons sense muscle-mediated load; however, our knowledge on how loading affects tendon structure and functional adaption remains fragmentary. Here, we provide evidence that the matricellular protein secreted protein acidic and rich in cysteine (SPARC) is critically involved in the mechanobiology of tendons and is required for tissue maturation, homeostasis, and enthesis development. We show that tendon loading at the early postnatal stage leads to tissue hypotrophy and impaired maturation o...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Wang, T., Wagner, A., Gehwolf, R., Yan, W., Passini, F. S., Thien, C., Weissenbacher, N., Lin, Z., Lehner, C., Teng, H., Wittner, C., Zheng, Q., Dai, J., Ni, M., Wang, A., Papadimitriou, J., Leys, T., Tuan, R. S., Senck, S., Snedeker, J. G., Tempfer, H., Tags: Research Articles Source Type: research

[Research Articles] Transitional B cell cytokines predict renal allograft outcomes
Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical reje...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Cherukuri, A., Salama, A. D., Mehta, R., Mohib, K., Zheng, L., Magee, C., Harber, M., Stauss, H., Baker, R. J., Tevar, A., Landsittel, D., Lakkis, F. G., Hariharan, S., Rothstein, D. M. Tags: Research Articles Source Type: research

[Research Articles] Functional reconstruction of human AML reveals stem cell origin and vulnerability of treatment-resistant MLL-rearranged leukemia
This study not only functionally established two distinctive origins of human LSCs for MLL-AML and their role in mediating chemoresistance but also identified a potential therapeutic avenue for stem cell–associated treatment resistance by repurposing a well-tolerated antidiarrhea drug already used in the clinic. (Source: Science Translational Medicine)
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Zeisig, B. B., Fung, T. K., Zarowiecki, M., Tsai, C. T., Luo, H., Stanojevic, B., Lynn, C., Leung, A. Y. H., Zuna, J., Zaliova, M., Bornhauser, M., von Bonin, M., Lenhard, B., Huang, S., Mufti, G. J., So, C. W. E. Tags: Research Articles Source Type: research

[Research Articles] Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy
Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of Pdgf-c in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation o...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Lu, W., Xie, Y., Huang, B., Ma, T., Wang, H., Deng, B., Zou, S., Wang, W., Tang, Q., Yang, Z., Li, X., Wang, L., Fang, L. Tags: Research Articles Source Type: research

[Research Articles] Radiotherapy and immunotherapy converge on elimination of tumor-promoting erythroid progenitor cells through adaptive immunity
Tumor-induced CD45–Ter119+CD71+ erythroid progenitor cells, termed "Ter cells," promote tumor progression by secreting artemin (ARTN), a neurotrophic peptide that activates REarranged during Transfection (RET) signaling. We demonstrate that both local tumor ionizing radiation (IR) and anti–programmed death ligand 1 (PD-L1) treatment decreased tumor-induced Ter cell abundance in the mouse spleen and ARTN secretion outside the irradiation field in an interferon- and CD8+ T cell–dependent manner. Recombinant erythropoietin promoted resistance to radiotherapy or anti–PD-L1 therapies by restori...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Hou, Y., Liang, H. L., Yu, X., Liu, Z., Cao, X., Rao, E., Huang, X., Wang, L., Li, L., Bugno, J., Fu, Y., Chmura, S. J., Wu, W., Luo, S. Z., Zheng, W., Arina, A., Jutzy, J., McCall, A. R., Vokes, E. E., Pitroda, S. P., Fu, Y.-X., Weichselbaum, R. R. Tags: Research Articles Source Type: research

[Research Articles] A heterozygous germline CD100 mutation in a family with primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease without clear etiology or effective treatment. Genetic factors contribute to PSC pathogenesis, but so far, no causative mutation has been found. We performed whole-exome sequencing in a family with autosomal dominant inheritance of PSC and identified a heterozygous germline missense mutation in SEMA4D, encoding a K849T variant of CD100. The mutation was located in an evolutionarily conserved, unstructured cytosolic region of CD100 affecting downstream signaling. It was found to alter the function of CD100-expressing cells with a bias toward the T ...
Source: Science Translational Medicine - February 24, 2021 Category: Biomedical Science Authors: Jiang, X., Bergquist, A., Löscher, B.-S., Venkatesh, G., Mold, J. E., Holm, K., Laerdahl, J. K., Skanland, S. S., Maleki, K. T., Cornillet, M., Tasken, K., Franke, A., Karlsen, T. H., Björkström, N. K., Melum, E. Tags: Research Articles Source Type: research

[Research Articles] Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses
Although immune checkpoint inhibitors (ICIs), such as anti–programmed cell death protein–1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients w...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Lo, J. A., Kawakubo, M., Juneja, V. R., Su, M. Y., Erlich, T. H., LaFleur, M. W., Kemeny, L. V., Rashid, M., Malehmir, M., Rabi, S. A., Raghavan, R., Allouche, J., Kasumova, G., Frederick, D. T., Pauken, K. E., Weng, Q. Y., Pereira da Silva, M., Xu, Y., v Tags: Research Articles Source Type: research

[Research Articles] APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function
The 4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treat...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Xiong, M., Jiang, H., Serrano, J. R., Gonzales, E. R., Wang, C., Gratuze, M., Hoyle, R., Bien-Ly, N., Silverman, A. P., Sullivan, P. M., Watts, R. J., Ulrich, J. D., Zipfel, G. J., Holtzman, D. M. Tags: Research Articles Source Type: research

[Research Articles] Platelets release mitochondrial antigens in systemic lupus erythematosus
The accumulation of DNA and nuclear components in blood and their recognition by autoantibodies play a central role in the pathophysiology of systemic lupus erythematosus (SLE). Despite the efforts, the sources of circulating autoantigens in SLE are still unclear. Here, we show that in SLE, platelets release mitochondrial DNA, the majority of which is associated with the extracellular mitochondrial organelle. Mitochondrial release in patients with SLE correlates with platelet degranulation. This process requires the stimulation of platelet FcRIIA, a receptor for immune complexes. Because mice lack FcRIIA and murine platele...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Melki, I., Allaeys, I., Tessandier, N., Levesque, T., Cloutier, N., Laroche, A., Vernoux, N., Becker, Y., Benk-Fortin, H., Zufferey, A., Rollet-Labelle, E., Pouliot, M., Poirier, G., Patey, N., Belleannee, C., Soulet, D., McKenzie, S. E., Brisson, A., Tre Tags: Research Articles Source Type: research

[Research Articles] Elastin-like recombinamers-based hydrogel modulates post-ischemic remodeling in a non-transmural myocardial infarction in sheep
Ischemic heart disease is a leading cause of mortality due to irreversible damage to cardiac muscle. Inspired by the post-ischemic microenvironment, we devised an extracellular matrix (ECM)–mimicking hydrogel using catalyst-free click chemistry covalent bonding between two elastin-like recombinamers (ELRs). The resulting customized hydrogel included functional domains for cell adhesion and protease cleavage sites, sensitive to cleavage by matrix metalloproteases overexpressed after myocardial infarction (MI). The scaffold permitted stromal cell invasion and endothelial cell sprouting in vitro. The incidence of non-tr...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Contessotto, P., Orbanic, D., Da Costa, M., Jin, C., Owens, P., Chantepie, S., Chinello, C., Newell, J., Magni, F., Papy-Garcia, D., Karlsson, N. G., Kilcoyne, M., Dockery, P., Rodriguez-Cabello, J. C., Pandit, A. Tags: Research Articles Source Type: research

[Research Articles] Using deep learning for dermatologist-level detection of suspicious pigmented skin lesions from wide-field images
A reported 96,480 people were diagnosed with melanoma in the United States in 2019, leading to 7230 reported deaths. Early-stage identification of suspicious pigmented lesions (SPLs) in primary care settings can lead to improved melanoma prognosis and a possible 20-fold reduction in treatment cost. Despite this clinical and economic value, efficient tools for SPL detection are mostly absent. To bridge this gap, we developed an SPL analysis system for wide-field images using deep convolutional neural networks (DCNNs) and applied it to a 38,283 dermatological dataset collected from 133 patients and publicly available images....
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Soenksen, L. R., Kassis, T., Conover, S. T., Marti-Fuster, B., Birkenfeld, J. S., Tucker-Schwartz, J., Naseem, A., Stavert, R. R., Kim, C. C., Senna, M. M., Aviles-Izquierdo, J., Collins, J. J., Barzilay, R., Gray, M. L. Tags: Research Articles Source Type: research

[Research Articles] Analysis of recurrently protected genomic regions in cell-free DNA found in urine
Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented. Whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we characterized fragmentation patterns in urine cfDNA using whole-genome sequencing. Size distribution of urine cfDNA fragments showed multiple strong peaks between 40 and 120 base pairs (bp) with a modal size of 81- and sharp 10-bp periodicity, suggesting transient protection from complete degradation. These properties were robust to preanalytical perturbations, such as at-home collection and delay...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Markus, H., Zhao, J., Contente-Cuomo, T., Stephens, M. D., Raupach, E., Odenheimer-Bergman, A., Connor, S., McDonald, B. R., Moore, B., Hutchins, E., McGilvrey, M., de la Maza, M. C., Van Keuren-Jensen, K., Pirrotte, P., Goel, A., Becerra, C., Von Hoff, D Tags: Research Articles Source Type: research

[Research Articles] Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2mut/mut hearts, which induced calpain-1 (CAPN1) activat...
Source: Science Translational Medicine - February 17, 2021 Category: Biomedical Science Authors: Chelko, S. P., Keceli, G., Carpi, A., Doti, N., Agrimi, J., Asimaki, A., Beti, C. B., Miyamoto, M., Amat-Codina, N., Bedja, D., Wei, A.-C., Murray, B., Tichnell, C., Kwon, C., Calkins, H., James, C. A., ORourke, B., Halushka, M. K., Melloni, E., Saffitz, Tags: Research Articles Source Type: research

[Errata] Erratum for the Research Article: "Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum" by J. Schalkwijk, E. L. Allman, P. A. M. Jansen, L. E. de Vries, J. M. J. Verhoef, S. Jackowski, P. N. M. Botman, C. A. Beuckens-Schortinghuis, K. M. J. Koolen, J. M. Bolscher, M. W. Vos, K. Miller, S. A. Reeves, H. Pett, G. Trevitt, S. Wittlin, C. Scheurer, S. Sax, C. Fischli, I. Angulo-Barturen, M. B. Jimenez-Diaz, G. Josling, T. W. A. Kooij, R. Bonnert, B. Campo, R. H. Blaauw, F. P. J. T. Rutjes, R. W. Sauerwein, M. Llinas, P. H. H. Hermkens, K. J. Dechering
(Source: Science Translational Medicine)
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Tags: Errata Source Type: research

[Research Articles] Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis
Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein–coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein–coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhi...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Carlson, E. L., Karuppagounder, V., Pinamont, W. J., Yoshioka, N. K., Ahmad, A., Schott, E. M., Le Bleu, H. K., Zuscik, M. J., Elbarbary, R. A., Kamal, F. Tags: Research Articles Source Type: research

[Research Articles] Nicotinamide for the treatment of heart failure with preserved ejection fraction
Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbid...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Abdellatif, M., Trummer-Herbst, V., Koser, F., Durand, S., Adao, R., Vasques-Novoa, F., Freundt, J. K., Voglhuber, J., Pricolo, M.-R., Kasa, M., Türk, C., Aprahamian, F., Herrero-Galan, E., Hofer, S. J., Pendl, T., Rech, L., Kargl, J., Anto-Michel Tags: Research Articles Source Type: research

[Research Articles] Targeted immunotherapy for HER2-low breast cancer with 17p loss
The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)–low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53. Our analyses revealed that 17p loss leads to global gene expression changes and r...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Li, Y., Sun, Y., Kulke, M., Hechler, T., Van der Jeught, K., Dong, T., He, B., Miller, K. D., Radovich, M., Schneider, B. P., Pahl, A., Zhang, X., Lu, X. Tags: Research Articles Source Type: research

[Research Articles] Loss of TGF{beta} signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types
Among the pleotropic roles of transforming growth factor–β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGFβ broadly controls the DNA damage response and su...
Source: Science Translational Medicine - February 10, 2021 Category: Biomedical Science Authors: Liu, Q., Palomero, L., Moore, J., Guix, I., Espin, R., Aytes, A., Mao, J.-H., Paulovich, A. G., Whiteaker, J. R., Ivey, R. G., Iliakis, G., Luo, D., Chalmers, A. J., Murnane, J., Pujana, M. A., Barcellos-Hoff, M. H. Tags: Research Articles Source Type: research

[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

[Research Articles] Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies
Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced me...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Tlemsani, C., Takahashi, N., Pongor, L., Rajapakse, V. N., Tyagi, M., Wen, X., Fasaye, G.-A., Schmidt, K. T., Desai, P., Kim, C., Rajan, A., Swift, S., Sciuto, L., Vilimas, R., Webb, S., Nichols, S., Figg, W. D., Pommier, Y., Calzone, K., Steinberg, S. M. Tags: Research Articles Source Type: research

[Research Articles] A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity
Although chimeric antigen receptor (CAR)–modified T cells have shown great success in the treatment of B cell malignancies, this approach has limited efficacy in patients with solid tumors. Various modifications in CAR structure have been explored to improve this efficacy, including the incorporation of two costimulatory domains. Because costimulatory signals are transduced together with T cell receptor signals during T cell activation, we engineered a type of CAR-T cells with a costimulatory signal that was activated independently from the tumor antigen to recapitulate physiological stimulation. We screened 12 costi...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Zhang, H., Li, F., Cao, J., Wang, X., Cheng, H., Qi, K., Wang, G., Xu, K., Zheng, J., Fu, Y.-X., Yang, X. Tags: Research Articles Source Type: research

[Research Articles] Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in patients with COVID-19 and healthy individuals
Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were composed of immunoglobulin heavy variable 3-53 (IGHV3-53) or IGHV3-66 and immunoglobulin heavy joining 6 (IGHJ6) genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching a...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Kim, S. I., Noh, J., Kim, S., Choi, Y., Yoo, D. K., Lee, Y., Lee, H., Jung, J., Kang, C. K., Song, K.-H., Choe, P. G., Kim, H. B., Kim, E. S., Kim, N.-J., Seong, M.-W., Park, W. B., Oh, M.-d., Kwon, S., Chung, J. Tags: Research Articles Source Type: research

[Research Articles] Impaired prenatal motor axon development necessitates early therapeutic intervention in severe SMA
Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resul...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Kong, L., Valdivia, D. O., Simon, C. M., Hassinan, C. W., Delestree, N., Ramos, D. M., Park, J. H., Pilato, C. M., Xu, X., Crowder, M., Grzyb, C. C., King, Z. A., Petrillo, M., Swoboda, K. J., Davis, C., Lutz, C. M., Stephan, A. H., Zhao, X., Weetall, M., Tags: Research Articles Source Type: research

[Reviews] Engineering biopharmaceutical formulations to improve diabetes management
Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the manage...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Maikawa, C. L., dAquino, A. I., Lal, R. A., Buckingham, B. A., Appel, E. A. Tags: Reviews Source Type: research

[Editors' Choice] Visualizing antibody production in a human lymph node in a dish
Development of a human lymphoid organoid system enables in vitro modeling of immune responses and antibody formation. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Morris, G. P. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Better together: Alveolar macrophage and memory T cell cosignaling in ex vivo human lungs
Ex vivo lung perfusion enables assessment of the resident adaptive immune system and provides insight into the lung response to pathogen exposure. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Keller, S. P. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Folding DNA to foil the clotting cascade
Origami-inspired DNA aptamer arrays prevent blood clotting in hemodialysis circuits. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Baca, J. T. Tags: Editors ' Choice Source Type: research

[Research Articles] Toward robust mammography-based models for breast cancer risk
Improved breast cancer risk models enable targeted screening strategies that achieve earlier detection and less screening harm than existing guidelines. To bring deep learning risk models to clinical practice, we need to further refine their accuracy, validate them across diverse populations, and demonstrate their potential to improve clinical workflows. We developed Mirai, a mammography-based deep learning model designed to predict risk at multiple timepoints, leverage potentially missing risk factor information, and produce predictions that are consistent across mammography machines. Mirai was trained on a large dataset ...
Source: Science Translational Medicine - January 27, 2021 Category: Biomedical Science Authors: Yala, A., Mikhael, P. G., Strand, F., Lin, G., Smith, K., Wan, Y.-L., Lamb, L., Hughes, K., Lehman, C., Barzilay, R. Tags: Research Articles Source Type: research

[Research Articles] Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma
Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinic...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Endersby, R., Whitehouse, J., Pribnow, A., Kuchibhotla, M., Hii, H., Carline, B., Gande, S., Stripay, J., Ancliffe, M., Howlett, M., Schoep, T., George, C., Andradas, C., Dyer, P., Schluck, M., Patterson, B., Tacheva-Gigorova, S. K., Cooper, M. N., Robins Tags: Research Articles Source Type: research

[Research Articles] Diet-induced obesity promotes infection by impairment of the innate antimicrobial defense function of dermal adipocyte progenitors
Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor–β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors an...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Zhang, L.-j., Guerrero-Juarez, C. F., Chen, S. X., Zhang, X., Yin, M., Li, F., Wu, S., Chen, J., Li, M., Liu, Y., Jiang, S. I. B., Hata, T., Plikus, M. V., Gallo, R. L. Tags: Research Articles Source Type: research

[Editors' Choice] Unconventional interleukin-1{beta} release suppresses antitumor immunity
Inflammasome-independent release of IL-1β in the tumor microenvironment recruits T cell–suppressive neutrophils that support cancer progression. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Van den Bossche, J. Tags: Editors ' Choice Source Type: research

[Editors' Choice] The benefits of memory growing granular
Brain imaging approaches show that the essential machinery for memory formation continues to develop into late childhood. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Stevens, J. S. Tags: Editors ' Choice Source Type: research

[Editors' Choice] Could COVID-19 eliminate the alarm clock?
Social restriction due to COVID-19 relieves social jet lag. (Source: Science Translational Medicine)
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Hurley, J. M. Tags: Editors ' Choice Source Type: research

[Research Articles] IgA dominates the early neutralizing antibody response to SARS-CoV-2
Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2–specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2–specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly aft...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Sterlin, D., Mathian, A., Miyara, M., Mohr, A., Anna, F., Claër, L., Quentric, P., Fadlallah, J., Devilliers, H., Ghillani, P., Gunn, C., Hockett, R., Mudumba, S., Guihot, A., Luyt, C.-E., Mayaux, J., Beurton, A., Fourati, S., Bruel, T., Schwartz, Tags: Research Articles Source Type: research

[Research Articles] Enhanced SARS-CoV-2 neutralization by dimeric IgA
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), primarily infects cells at mucosal surfaces. Serum neutralizing antibody responses are variable and generally low in individuals that suffer mild forms of COVID-19. Although potent immunoglobulin G (IgG) antibodies can neutralize the virus, less is known about secretory antibodies such as IgA that might affect the initial viral spread and transmissibility from the mucosa. Here, we characterize the IgA response to SARS-CoV-2 in a cohort of 149 convalescent individuals after diagnosis with COVID-19. IgA re...
Source: Science Translational Medicine - January 20, 2021 Category: Biomedical Science Authors: Wang, Z., Lorenzi, J. C. C., Muecksch, F., Finkin, S., Viant, C., Gaebler, C., Cipolla, M., Hoffman, H.-H., Oliveira, T. Y., Oren, D. A., Ramos, V., Nogueira, L., Michailidis, E., Robbiani, D. F., Gazumyan, A., Rice, C. M., Hatziioannou, T., Bieniasz, P. Tags: Research Articles Source Type: research