[Research Articles] An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo
Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increa...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Cao, D.-Y., Giani, J. F., Veiras, L. C., Bernstein, E. A., Okwan-Duodu, D., Ahmed, F., Bresee, C., Tourtellotte, W. G., Karumanchi, S. A., Bernstein, K. E., Khan, Z. Tags: Research Articles Source Type: research
[Research Articles] Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS
Alterations in the components [nucleoporins (Nups)] and function of the nuclear pore complex (NPC) have been implicated as contributors to the pathogenesis of genetic forms of neurodegeneration including C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). We hypothesized that Nup alterations and the consequential loss of NPC function may lie upstream of TDP-43 dysfunction and mislocalization widely observed in ALS, FTD, and related neurodegenerative diseases. Here, we provide evidence that CHMP7, a critical mediator of NPC quality control, is increased in nuclei of C9orf72 and sporadic ALS induced plur...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Coyne, A. N., Baskerville, V., Zaepfel, B. L., Dickson, D. W., Rigo, F., Bennett, F., Lusk, C. P., Rothstein, J. D. Tags: Research Articles Source Type: research
[Research Articles] Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion
Clinical outcomes from granulocyte transfusion (GTX) are disadvantaged by the short shelf life and compromised function of donor neutrophils. Spontaneous neutrophil death is heterogeneous and mediated by multiple pathways. Leveraging mechanistic knowledge and pharmacological screening, we identified a combined treatment, caspases–lysosomal membrane permeabilization–oxidant–necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which altered neutrophil fate by simultaneously targeting multiple cell death pathways. CLON-G prolonged human and mouse neutrophil half-life in vitro from less...
Source: Science Translational Medicine - July 28, 2021 Category: Biomedical Science Authors: Fan, Y., Teng, Y., Loison, F., Pang, A., Kasorn, A., Shao, X., Zhang, C., Ren, Q., Yu, H., Zheng, Y., Cancelas, J. A., Manis, J., Chai, L., Park, S.-Y., Zhao, L., Xu, Y., Feng, S., Silberstein, L. E., Ma, F., Luo, H. R. Tags: Research Articles Source Type: research
[Research Articles] The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance
The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low prop...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Murithi, J. M., Pascal, C., Bath, J., Boulenc, X., Gnädig, N. F., Pasaje, C. F. A., Rubiano, K., Yeo, T., Mok, S., Klieber, S., Desert, P., Jimenez-Diaz, M. B., Marfurt, J., Rouillier, M., Cherkaoui-Rbati, M. H., Gobeau, N., Wittlin, S., Uhlemann, Tags: Research Articles Source Type: research
[Research Articles] A resident stromal cell population actively restrains innate immune response in the propagation phase of colitis pathogenesis in mice
Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin+ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, an...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Gao, L., Yu, Q., Zhang, H., Wang, Z., Zhang, T., Xiang, J., Yu, S., Zhang, S., Wu, H., Xu, Y., Wang, Z., Shen, L., Shu, G., Chen, Y.-G., Liu, H., Shen, L., Li, B. Tags: Research Articles Source Type: research
[Research Articles] Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration
In conclusion, we found that EPO promotes the formation of AAA in both Apoe–/– and WT mice by enhancing angiogenesis, inflammation, collagen degradation, and apoptosis of SMCs and that EPO/EPOR signaling is essential for AngII-induced AAA. The association between EPO and AAA in humans warrants further study. (Source: Science Translational Medicine)
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Zhang, M., Sui, W., Cheng, C., Xue, F., Tian, Z., Cheng, J., Zhang, J., Zhang, T., Zhang, J., Wang, W., Xiong, W., Hao, P., Ma, J., Xu, X., Wang, S., Sun, S., Zhang, M., Zhang, Y., Zhang, C. Tags: Research Articles Source Type: research
[Research Articles] Toward predicting CYP2D6-mediated variable drug response from CYP2D6 gene sequencing data
Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read ampli...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: van der Lee, M., Allard, W. G., Vossen, R. H. A. M., Baak-Pablo, R. F., Menafra, R., Deiman, B. A. L. M., Deenen, M. J., Neven, P., Johansson, I., Gastaldello, S., Ingelman-Sundberg, M., Guchelaar, H.-J., Swen, J. J., Anvar, S. Y. Tags: Research Articles Source Type: research
[Research Articles] Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype
The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)–derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables u...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Bliley, J. M., Vermeer, M. C. S. C., Duffy, R. M., Batalov, I., Kramer, D., Tashman, J. W., Shiwarski, D. J., Lee, A., Teplenin, A. S., Volkers, L., Coffin, B., Hoes, M. F., Kalmykov, A., Palchesko, R. N., Sun, Y., Jongbloed, J. D. H., Bomer, N., de Boer, Tags: Research Articles Source Type: research
[Research Articles] A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice
Metastatic estrogen receptor α (ERα)–positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperiton...
Source: Science Translational Medicine - July 21, 2021 Category: Biomedical Science Authors: Boudreau, M. W., Duraki, D., Wang, L., Mao, C., Kim, J. E., Henn, M. A., Tang, B., Fanning, S. W., Kiefer, J., Tarasow, T. M., Bruckheimer, E. M., Moreno, R., Mousses, S., Greene, G. L., Roy, E. J., Park, B. H., Fan, T. M., Nelson, E. R., Hergenrother, P. Tags: Research Articles Source Type: research
[Reports] Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19
Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without over...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Prudencio, M., Erben, Y., Marquez, C. P., Jansen-West, K. R., Franco-Mesa, C., Heckman, M. G., White, L. J., Dunmore, J. A., Cook, C. N., Lilley, M. T., Song, Y., Harlow, C. F., Oskarsson, B., Nicholson, K. A., Wszolek, Z. K., Hickson, L. J., OHoro, J. C. Tags: Reports Source Type: research
[Research Articles] Ebola vaccine-induced protection in nonhuman primates correlates with antibody specificity and Fc-mediated effects
Although substantial progress has been made with Ebola virus (EBOV) vaccine measures, the immune correlates of vaccine-mediated protection remain uncertain. Here, five mucosal vaccine vectors based on human and avian paramyxoviruses provided nonhuman primates with varying degrees of protection, despite expressing the same EBOV glycoprotein (GP) immunogen. Each vaccine produced antibody responses that differed in Fc-mediated functions and isotype composition, as well as in magnitude and coverage toward GP and its conformational and linear epitopes. Differences in the degree of protection and comprehensive characterization o...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Meyer, M., Gunn, B. M., Malherbe, D. C., Gangavarapu, K., Yoshida, A., Pietzsch, C., Kuzmina, N. A., Saphire, E. O., Collins, P. L., Crowe, J. E., Zhu, J. J., Suchard, M. A., Brining, D. L., Mire, C. E., Cross, R. W., Geisbert, J. B., Samal, S. K., Anders Tags: Research Articles Source Type: research
[Research Articles] Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models
Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) inc...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Wu, L., Vasilijic, S., Sun, Y., Chen, J., Landegger, L. D., Zhang, Y., Zhou, W., Ren, J., Early, S., Yin, Z., Ho, W. W., Zhang, N., Gao, X., Lee, G. Y., Datta, M., Sagers, J. E., Brown, A., Muzikansky, A., Stemmer-Rachamimov, A., Zhang, L., Plotkin, S. R. Tags: Research Articles Source Type: research
[Research Articles] Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer
Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxaci...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Chrysostomou, S., Roy, R., Prischi, F., Thamlikitkul, L., Chapman, K. L., Mufti, U., Peach, R., Ding, L., Hancock, D., Moore, C., Molina-Arcas, M., Mauri, F., Pinato, D. J., Abrahams, J. M., Ottaviani, S., Castellano, L., Giamas, G., Pascoe, J., Moonamale Tags: Research Articles Source Type: research
[Research Articles] Key epidemiological drivers and impact of interventions in the 2020 SARS-CoV-2 epidemic in England
We fitted a model of SARS-CoV-2 transmission in care homes and the community to regional surveillance data for England. Compared with other approaches, our model provides a synthesis of multiple surveillance data streams into a single coherent modeling framework, allowing transmission and severity to be disentangled from features of the surveillance system. Of the control measures implemented, only national lockdown brought the reproduction number (Rteff) below 1 consistently; if introduced 1 week earlier, it could have reduced deaths in the first wave from an estimated 48,600 to 25,600 [95% credible interval (CrI): 15,900...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Knock, E. S., Whittles, L. K., Lees, J. A., Perez-Guzman, P. N., Verity, R., FitzJohn, R. G., Gaythorpe, K. A. M., Imai, N., Hinsley, W., Okell, L. C., Rosello, A., Kantas, N., Walters, C. E., Bhatia, S., Watson, O. J., Whittaker, C., Cattarino, L., Boony Tags: Research Articles Source Type: research
[Research Articles] Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade
Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 ...
Source: Science Translational Medicine - July 14, 2021 Category: Biomedical Science Authors: Patel, R. B., Hernandez, R., Carlson, P., Grudzinski, J., Bates, A. M., Jagodinsky, J. C., Erbe, A., Marsh, I. R., Arthur, I., Aluicio-Sarduy, E., Sriramaneni, R. N., Jin, W. J., Massey, C., Rakhmilevich, A. L., Vail, D., Engle, J. W., Le, T., Kim, K., Be Tags: Research Articles Source Type: research
