[Research Articles] Neuromodulation using ultra low frequency current waveform reversibly blocks axonal conduction and chronic pain
Chronic pain remains a leading cause of disability worldwide, and there is still a clinical reliance on opioids despite the medical side effects associated with their use and societal impacts associated with their abuse. An alternative approach is the use of electrical neuromodulation to produce analgesia. Direct current can block action potential propagation but leads to tissue damage if maintained. We have developed a form of ultra low frequency (ULF) biphasic current and studied its effects. In anesthetized rats, this waveform produced a rapidly developing and completely reversible conduction block in >85% of spinal ...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Jones, M. G., Rogers, E. R., Harris, J. P., Sullivan, A., Ackermann, D. M., Russo, M., Lempka, S. F., McMahon, S. B. Tags: Research Articles Source Type: research
[Research Articles] Lithium preserves peritoneal membrane integrity by suppressing mesothelial cell {alpha}B-crystallin
We report that addition of lithium chloride (LiCl) to PDF is a translatable intervention to counteract PDF-induced mesothelial cell death, peritoneal membrane fibrosis, and angiogenesis. LiCl improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most consistently counter-regulated by LiCl. In vitro and in vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like up-regulation of vascular endothelial growth factor (...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Herzog, R., Sacnun, J. M., Gonzalez-Mateo, G., Bartosova, M., Bialas, K., Wagner, A., Unterwurzacher, M., Sobieszek, I. J., Daniel-Fischer, L., Rusai, K., Pascual-Anton, L., Kaczirek, K., Vychytil, A., Schmitt, C. P., Lopez-Cabrera, M., Alper, S. L., Aufr Tags: Research Articles Source Type: research
[Research Articles] Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy
Responsive neurostimulation (RNS) devices, able to detect imminent seizures and to rapidly deliver electrical stimulation to the brain, are effective in reducing seizures in some patients with focal epilepsy. However, therapeutic response to RNS is often slow, is highly variable, and defies prognostication based on clinical factors. A prevailing view holds that RNS efficacy is primarily mediated by acute seizure termination; yet, stimulations greatly outnumber seizures and occur mostly in the interictal state, suggesting chronic modulation of brain networks that generate seizures. Here, using years-long intracranial neural...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Khambhati, A. N., Shafi, A., Rao, V. R., Chang, E. F. Tags: Research Articles Source Type: research
[Research Articles] Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis
Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 x 10–4). S...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Tapmeier, T. T., Rahmioglu, N., Lin, J., De Leo, B., Obendorf, M., Raveendran, M., Fischer, O. M., Bafligil, C., Guo, M., Harris, R. A., Hess-Stumpp, H., Laux-Biehlmann, A., Lowy, E., Lunter, G., Malzahn, J., Martin, N. G., Martinez, F. O., Manek, S., Mes Tags: Research Articles Source Type: research
[Research Articles] LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade
Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survi...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Shen, R., Postow, M. A., Adamow, M., Arora, A., Hannum, M., Maher, C., Wong, P., Curran, M. A., Hollmann, T. J., Jia, L., Al-Ahmadie, H., Keegan, N., Funt, S. A., Iyer, G., Rosenberg, J. E., Bajorin, D. F., Chapman, P. B., Shoushtari, A. N., Betof, A. S., Tags: Research Articles Source Type: research
[Research Articles] Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors
Therapeutic approaches are needed to promote T cell–mediated destruction of poorly immunogenic, "cold" tumors typically associated with minimal response to immune checkpoint blockade (ICB) therapy. Bispecific T cell engager (BiTE) molecules induce redirected lysis of cancer cells by polyclonal T cells and have demonstrated promising clinical activity against solid tumors in some patients. However, little is understood about the key factors that govern clinical responses to these therapies. Using an immunocompetent mouse model expressing a humanized CD3 chain (huCD3e mice) and BiTE molecules directed against mouse CD1...
Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Belmontes, B., Sawant, D. V., Zhong, W., Tan, H., Kaul, A., Aeffner, F., OBrien, S. A., Chun, M., Noubade, R., Eng, J., Ma, H., Muenz, M., Li, P., Alba, B. M., Thomas, M., Cook, K., Wang, X., DeVoss, J., Egen, J. G., Nolan-Stevaux, O. Tags: Research Articles Source Type: research
[Research Articles] Blocking {alpha}4{beta}7 integrin delays viral rebound in SHIVSF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies
Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4β7 or were left untreated as a control. Treatment with bNAbs a...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Frank, I., Cigoli, M., Arif, M. S., Fahlberg, M. D., Maldonado, S., Calenda, G., Pegu, A., Yang, E. S., Rawi, R., Chuang, G.-Y., Geng, H., Liu, C., Zhou, T., Kwong, P. D., Arthos, J., Cicala, C., Grasperge, B. F., Blanchard, J. L., Gettie, A., Fennessey, Tags: Research Articles Source Type: research
[Research Articles] ALT neuroblastoma chemoresistance due to telomere dysfunction-induced ATM activation is reversible with ATM inhibitor AZD0156
Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, P < 0.05; in vivo mouse event-free survival (EFS), P < 0.0001] vs. te...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Koneru, B., Farooqi, A., Nguyen, T. H., Chen, W. H., Hindle, A., Eslinger, C., Makena, M. R., Burrow, T. A., Wilson, J., Smith, A., Pilla Reddy, V., Cadogan, E., Durant, S. T., Reynolds, C. P. Tags: Research Articles Source Type: research
[Research Articles] Protective antibodies elicited by SARS-CoV-2 spike protein vaccination are boosted in the lung after challenge in nonhuman primates
Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHPs). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multifunctional humoral responses that targeted distinct domains of the spike protein and bound to a vari...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Francica, J. R., Flynn, B. J., Foulds, K. E., Noe, A. T., Werner, A. P., Moore, I. N., Gagne, M., Johnston, T. S., Tucker, C., Davis, R. L., Flach, B., OConnell, S., Andrew, S. F., Lamb, E., Flebbe, D. R., Nurmukhambetova, S. T., Donaldson, M. M., Todd, J Tags: Research Articles Source Type: research
[Research Articles] The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia
In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Caffall, Z. F., Wilkes, B. J., Hernandez-Martinez, R., Rittiner, J. E., Fox, J. T., Wan, K. K., Shipman, M. K., Titus, S. A., Zhang, Y.-Q., Patnaik, S., Hall, M. D., Boxer, M. B., Shen, M., Li, Z., Vaillancourt, D. E., Calakos, N. Tags: Research Articles Source Type: research
[Research Articles] Treatment with ROS detoxifying gold quantum clusters alleviates the functional decline in a mouse model of Friedreich ataxia
Friedreich ataxia (FRDA) is caused by the reduced expression of the mitochondrial protein frataxin (FXN) due to an intronic GAA trinucleotide repeat expansion in the FXN gene. Although FRDA has no cure and few treatment options, there is research dedicated to finding an agent that can curb disease progression and address symptoms as neurobehavioral deficits, muscle endurance, and heart contractile dysfunctions. Because oxidative stress and mitochondrial dysfunctions are implicated in FRDA, we demonstrated the systemic delivery of catalysts activity of gold cluster superstructures (Au8-pXs) to improve cell response to mitoc...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: Villa, C., Legato, M., Umbach, A., Riganti, C., Jones, R., Martini, B., Boido, M., Medana, C., Facchinetti, I., Barni, D., Pinto, M., Arguello, T., Belicchi, M., Fagiolari, G., Liaci, C., Moggio, M., Ruffo, R., Moraes, C. T., Monguzzi, A., Merlo, G. R., T Tags: Research Articles Source Type: research
[Research Articles] Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models
ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swa...
Source: Science Translational Medicine - August 18, 2021 Category: Biomedical Science Authors: van Doremalen, N., Purushotham, J. N., Schulz, J. E., Holbrook, M. G., Bushmaker, T., Carmody, A., Port, J. R., Yinda, C. K., Okumura, A., Saturday, G., Amanat, F., Krammer, F., Hanley, P. W., Smith, B. J., Lovaglio, J., Anzick, S. L., Barbian, K., Marten Tags: Research Articles Source Type: research
[Research Articles] Modeling the effect of vaccination on selection for antibiotic resistance in Streptococcus pneumoniae
Vaccines against bacterial pathogens can protect recipients from becoming infected with potentially antibiotic-resistant pathogens. However, by altering the selective balance between antibiotic-sensitive and antibiotic-resistant bacterial strains, vaccines may also suppress—or spread—antibiotic resistance among unvaccinated individuals. Predicting the outcome of vaccination requires knowing what drives selection for drug-resistant bacterial pathogens and what maintains the circulation of both antibiotic-sensitive and antibiotic-resistant strains of bacteria. To address this question, we used mathematical modeli...
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Authors: Davies, N. G., Flasche, S., Jit, M., Atkins, K. E. Tags: Research Articles Source Type: research
[Errata] Erratum for Research Article "Production and transplantation of bioengineered lung into a large-animal model" by J. E. Nichols, S. La Francesca, J. A. Niles, S. P. Vega, L. B. Argueta, L. Frank, D. C. Christiani, R. B. Pyles, B. E. Himes, R. Zhang, S. Li, J. Sakamoto, J. Rhudy, G. Hendricks, F. Begarani, X. Liu, I. Patrikeev, R. Pal, E. Usheva, G. Vargas, A. Miller, L. Woodson, A. Wacher, M. Grimaldo, D. Weaver, R. Mlcak, J. Cortiella
(Source: Science Translational Medicine)
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Tags: Errata Source Type: research
[Errata] Erratum for the Research Article: "Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis" by M. Scherlinger, V. Guillotin, I. Douchet, P. Vacher, A. Boizard-Moracchini, J.-P. Guegan, A. Garreau, N. Merillon, A. Vermorel, E. Ribeiro, I. Machelart, E. Lazaro, L. Couzi, P. Duffau, T. Barnetche, J.-L. Pellegrin, J.-F. Viallard, M. Saleh, T. Schaeverbeke, P. Legembre, M.-E. Truchetet, H. Dumortier, C. Contin-Bordes, V. Sisirak, C. Richez, P. Blanco
(Source: Science Translational Medicine)
Source: Science Translational Medicine - August 11, 2021 Category: Biomedical Science Tags: Errata Source Type: research
