[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 restoring Ter cel...
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 suppresses a...
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
