TY  - JOUR
AB  - Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet-loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.
AU  - Governa, V.*
AU  - de Oliveira, K.G.*
AU  - Bång-Rudenstam, A.*
AU  - Offer, S.
AU  - Cerezo-Magaña, M.*
AU  - Li, J.*
AU  - Beyer, S.*
AU  - Johansson, M.C.*
AU  - Månsson, A.S.*
AU  - Edvardsson, C.*
AU  - Durmo, F.*
AU  - Gustafsson, E.*
AU  - Boukredine, A.*
AU  - Jeannot, P.*
AU  - Schmidt, K.*
AU  - Gezelius, E.*
AU  - Menard, J.A.*
AU  - Garza, R.*
AU  - Jakobsson, J.*
AU  - de Neergaard, T.*
AU  - Sundgren, P.C.*
AU  - Tiihonen, A.M.*
AU  - Haapasalo, H.*
AU  - Rautajoki, K.J.*
AU  - Nordenfelt, P.*
AU  - Darabi, A.*
AU  - Forsberg-Nilsson, K.*
AU  - Pietras, A.*
AU  - Talbot, H.*
AU  - Bengzon, J.*
AU  - Belting, M.*
C1  - 72195
C2  - 56461
TI  - Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.
JO  - Sci. Transl. Med.
VL  - 16
IS  - 771
PY  - 2024
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.
AU  - Ebstein, F.*
AU  - Küry, S.*
AU  - Most, V.*
AU  - Rosenfelt, C.*
AU  - Scott-Boyer, M.P.*
AU  - van Woerden, G.M.*
AU  - Besnard, T.*
AU  - Papendorf, J.J.*
AU  - Studencka-Turski, M.*
AU  - Wang, T.*
AU  - Hsieh, T.C.*
AU  - Golnik, R.*
AU  - Baldridge, D.*
AU  - Forster, C.*
AU  - de Konink, C.*
AU  - Teurlings, S.M.W.*
AU  - Vignard, V.*
AU  - van Jaarsveld, R.H.*
AU  - Ades, L.*
AU  - Cogné, B.*
AU  - Mignot, C.*
AU  - Deb, W.*
AU  - Jongmans, M.C.J.*
AU  - Cole, F.S.*
AU  - van den Boogaard, M.H.*
AU  - Wambach, J.A.*
AU  - Wegner, D.J.*
AU  - Yang, S.*
AU  - Hannig, V.*
AU  - Brault, J.A.*
AU  - Zadeh, N.*
AU  - Bennetts, B.*
AU  - Keren, B.*
AU  - Gélineau, A.C.*
AU  - Powis, Z.*
AU  - Towne, M.*
AU  - Bachman, K.*
AU  - Seeley, A.*
AU  - Beck, A.E.*
AU  - Morrison, J.*
AU  - Westman, R.*
AU  - Averill, K.*
AU  - Brunet, T.
AU  - Haasters, J.*
AU  - Carter, M.T.*
AU  - Osmond, M.*
AU  - Wheeler, P.G.*
AU  - Forzano, F.*
AU  - Mohammed, S.*
AU  - Trakadis, Y.*
AU  - Accogli, A.*
AU  - Harrison, R.*
AU  - Guo, Y.*
AU  - Hakonarson, H.*
AU  - Rondeau, S.*
AU  - Baujat, G.*
AU  - Barcia, G.*
AU  - Feichtinger, R.G.*
AU  - Mayr, J.A.*
AU  - Preisel, M.*
AU  - Laumonnier, F.*
AU  - Kallinich, T.*
AU  - Knaus, A.*
AU  - Isidor, B.*
AU  - Krawitz, P.*
AU  - Völker, U.*
AU  - Hammer, E.*
AU  - Droit, A.*
AU  - Eichler, E.E.*
AU  - Elgersma, Y.*
AU  - Hildebrand, P.W.*
AU  - Bolduc, F.*
AU  - Kruger, E.*
AU  - Bézieau, S.*
C1  - 67866
C2  - 54344
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.
JO  - Sci. Transl. Med.
VL  - 15
IS  - 698
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.
AU  - Lang, N.J.
AU  - Schniering, J.
AU  - Porras-Gonzalez, D.L.
AU  - Yang, L.
AU  - De Sadeleer, L.J.
AU  - Jentzsch, R.C.
AU  - Shitov, V.A.
AU  - Zhou, S.
AU  - Ansari, M.
AU  - Agami, A.
AU  - Mayr, C.
AU  - Hooshiar Kashani, B.
AU  - Chen, Y.
AU  - Heumos, L.
AU  - Pestoni, J.
AU  - Molnar, E.S.
AU  - Geeraerts, E.*
AU  - Anquetil, V.*
AU  - Saniere, L.*
AU  - Wögrath, M.
AU  - Gerckens, M.
AU  - Lehmann, M.
AU  - Yildirim, A.Ö.
AU  - Hatz, R.A.*
AU  - Kneidinger, N.
AU  - Behr, J.
AU  - Wuyts, W.A.*
AU  - Stoleriu, M.-G.
AU  - Luecken, M.
AU  - Theis, F.J.
AU  - Burgstaller, G.
AU  - Schiller, H.
C1  - 68945
C2  - 53784
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
SP  - 19
TI  - Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis.
JO  - Sci. Transl. Med.
VL  - 15
IS  - 725
PB  - Amer Assoc Advancement Science
PY  - 2023
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to "reduce food and avoid drinking to fullness" and begin "running during the night." Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.
AU  - Tschöp, M.H.
AU  - Friedman, J.M.*
C1  - 68912
C2  - 53764
TI  - Seeking satiety: From signals to solutions.
JO  - Sci. Transl. Med.
VL  - 15
IS  - 723
PY  - 2023
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Psoriasis is a widespread inflammatory skin disease affecting about 2% of the general population. Recently, treatments that specifically target key proinflammatory cytokines driving the disease have been developed to complement conventional therapies with unspecific antiproliferative or anti-inflammatory effects. Efficient monitoring of treatment efficacy in the context of precision medicine and the assessment of new therapeutics require accurate noninvasive readouts of disease progression. However, characterization of psoriasis treatment remains subjective based on visual and palpatory clinical assessment of features observed on the skin surface. We hypothesized that optoacoustic (photoacoustic) mesoscopy could offer label-free assessment of inflammation biomarkers, extracted from three-dimensional (3D) high-resolution images of the human skin, not attainable by other noninvasive methods. We developed a second-generation ultra-broadband optoacoustic mesoscopy system, featuring sub-10-μm resolution and advanced motion correction technology, and performed 80 longitudinal measurements of 20 psoriatic skin plaques in humans under conventional inpatient treatment or receiving biologics with concomitant topical corticosteroid treatment. Optoacoustic image analysis revealed inflammatory and morphological skin features that indicated treatment efficacy with sensitivity, accuracy, and precision that was not possible using clinical metrics. We identify 3D imaging biomarkers that reveal responses to treatment and offer the potential to facilitate disease and treatment characterization. Our findings suggest that optoacoustic mesoscopy may offer a method of choice for yielding both qualitative and quantitative evaluations of skin treatments that are inaccessible by other methods, potentially enabling optimized therapies and precision medicine in dermatology.
AU  - Hindelang, B.
AU  - Nau, T.
AU  - Englert, L.
AU  - Berezhnoi, A.
AU  - Lauffer, F.*
AU  - Darsow, U.*
AU  - Biedermann, T.*
AU  - Eyerich, K.*
AU  - Aguirre Bueno, J.
AU  - Ntziachristos, V.
C1  - 65010
C2  - 52132
TI  - Enabling precision monitoring of psoriasis treatment by optoacoustic mesoscopy.
JO  - Sci. Transl. Med.
VL  - 14
IS  - 644
PY  - 2022
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.
AU  - Xhonneux, L.P.*
AU  - Knight, O.*
AU  - Lernmark, Å.*
AU  - Bonifacio, E.*
AU  - Hagopian, W.A.*
AU  - Rewers, M.J.*
AU  - She, J.X.*
AU  - Toppari, J.*
AU  - Parikh, H.*
AU  - Smith, K.G.C.*
AU  - Ziegler, A.-G.
AU  - Akolkar, B.*
AU  - Krischer, J.P.*
AU  - McKinney, E.F.*
C1  - 61753
C2  - 50446
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression.
JO  - Sci. Transl. Med.
VL  - 13
IS  - 587
PB  - Amer Assoc Advancement Science
PY  - 2021
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondria! dysfunction. Targeting defective exon skipping with genetically engineered U1 -snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondria! dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.
AU  - Boussaad, I.*
AU  - Obermaier, C.D.*
AU  - Hanss, Z.*
AU  - Bobbili, D.R.*
AU  - Bolognin, S.*
AU  - Glaab, E.*
AU  - Wołyńska, K.*
AU  - Weisschuh, N.*
AU  - De Conti, L.*
AU  - May, C.*
AU  - Giesert, F.
AU  - Grossmann, D.*
AU  - Lambert, A.*
AU  - Kirchen, S.*
AU  - Biryukov, M.*
AU  - Burbulla, L.F.*
AU  - Massart, F.*
AU  - Bohler, J.*
AU  - Cruciani, G.*
AU  - Schmid, B.*
AU  - Kurz-Drexler, A.
AU  - May, P.*
AU  - Duga, S.*
AU  - Klein, C.*
AU  - Schwamborn, J.C.*
AU  - Marcus, K.*
AU  - Woitalla, D.*
AU  - Vogt Weisenhorn, D.M.
AU  - Wurst, W.
AU  - Baralle, M.*
AU  - Krainc, D.*
AU  - Gasser, T.*
AU  - Wissinger, B.*
AU  - Krüger, R.*
C1  - 60067
C2  - 49218
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
JO  - Sci. Transl. Med.
VL  - 12
IS  - 560
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E-2 (PGE(2)) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE(2)-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1 alpha (HIF-1 alpha), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.
AU  - de los Reyes Jimenez, M.
AU  - Lechner, A.
AU  - Alessandrini, F.
AU  - Bohnacker, S.
AU  - Schindela, S.
AU  - Trompette, A.*
AU  - Haimerl, P.
AU  - Thomas, D.*
AU  - Henkel, F.
AU  - Mourao, A.
AU  - Geerlof, A.
AU  - da Costa, C.P.*
AU  - Chaker, A.
AU  - Brüne, B.*
AU  - Nüsing, R.*
AU  - Jakobsson, P.J.*
AU  - Nockher, W.A.*
AU  - Feige, M.J.*
AU  - Haslbeck, M.*
AU  - Ohnmacht, C.
AU  - Marsland, B.J.*
AU  - Voehringer, D.*
AU  - Harris, N.L.*
AU  - Schmidt-Weber, C.B.
AU  - Esser-von Bieren, J.
C1  - 58930
C2  - 48563
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products.
JO  - Sci. Transl. Med.
VL  - 12
IS  - 540
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Although infection with the human enteropathogen Giardia lamblia causes self-limited diarrhea in adults, infant populations in endemic areas experience persistent pathogen carriage in the absence of diarrhea. The persistence of this protozoan parasite in infants has been associated with reduced weight gain and linear growth (height-for-age). The mechanisms that support persistent infection and determine the different disease outcomes in the infant host are incompletely understood. Using a neonatal mouse model of persistent G. lamblia infection, we demonstrate that G. lamblia induced bile secretion and used the bile constituent phosphatidylcholine as a substrate for parasite growth. In addition, we show that G. lamblia infection altered the enteric microbiota composition, leading to enhanced bile acid deconjugation and increased expression of fibroblast growth factor 15. This resulted in elevated energy expenditure and dysregulated lipid metabolism with reduced adipose tissue, body weight gain, and growth in the infected mice. Our results indicate that this enteropathogen's modulation of bile acid metabolism and lipid metabolism in the neonatal mouse host led to an altered body composition, suggesting how G. lamblia infection could contribute to growth restriction in infants in endemic areas.
AU  - Riba, A.*
AU  - Hassani, K.*
AU  - Walker, A.
AU  - van Best, N.*
AU  - von Zeschwitz, D.*
AU  - Anslinger, T.*
AU  - Sillner, N.
AU  - Rosenhain, S.*
AU  - Eibach, D.*
AU  - Maiga-Ascofaré, O.*
AU  - Rolle-Kampczyk, U.*
AU  - Basic, M.*
AU  - Binz, A.*
AU  - Mocek, S.*
AU  - Sodeik, B.*
AU  - Bauerfeind, R.*
AU  - Mohs, A.*
AU  - Trautwein, C.*
AU  - Kiessling, F.*
AU  - May, J.*
AU  - Klingenspor, M.*
AU  - Gremse, F.*
AU  - Schmitt-Kopplin, P.
AU  - Bleich, A.*
AU  - Torow, N.*
AU  - von Bergen, M.*
AU  - Hornef, M.W.*
C1  - 60375
C2  - 49320
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Disturbed gut microbiota and bile homeostasis in Giardia-infected mice contributes to metabolic dysregulation and growth impairment.
JO  - Sci. Transl. Med.
VL  - 12
IS  - 565
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus. Mutational studies and biophysical measurements demonstrate that Mex3a binds to the central U- and G-rich regions of miR-126-5p with nanomolar affinity via its two K homology domains. In the nucleus, miR-126-5p dissociates from Ago2 and binds to caspase-3 in an aptamer-like fashion with its seed sequence, preventing dimerization of the caspase and inhibiting its activity to limit apoptosis. The antiapoptotic effect of miR-126-5p outside of the RNA-induced silencing complex is important for endothelial integrity under conditions of high shear stress promoting autophagy: ablation of Mex3a or ATG5 in vivo attenuates nuclear import of miR-126-5p, aggravates endothelial apoptosis, and exacerbates atherosclerosis. In human plaques, we found reduced nuclear miR-126-5p and active caspase-3 in areas of disturbed flow. The direct inhibition of caspase-3 by nuclear miR-126-5p reveals a noncanonical mechanism by which miRNAs can modulate protein function.
AU  - Santovito, D.*
AU  - Egea, V.*
AU  - Bidzhekov, K.*
AU  - Natarelli, L.*
AU  - Mourao, A.
AU  - Blanchet, X.*
AU  - Wichapong, K.*
AU  - Aslani, M.*
AU  - Brunßen, C.*
AU  - Horckmans, M.*
AU  - Hristov, M.*
AU  - Geerlof, A.
AU  - Lutgens, E.*
AU  - Daemen, M.J.A.P.*
AU  - Hackeng, T.*
AU  - Ries, C.*
AU  - Chavakis, T.*
AU  - Morawietz, H.*
AU  - Naumann, R.*
AU  - von Hundelshausen, P.*
AU  - Steffens, S.*
AU  - Duchêne, J.*
AU  - Megens, R.T.A.*
AU  - Sattler, M.
AU  - Weber, C.*
C1  - 59294
C2  - 48736
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis.
JO  - Sci. Transl. Med.
VL  - 12
IS  - 546
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified an ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve in rodents. beta-amyloid (A beta) was cleared from the retina and vitreous via a pathway dependent on glial water channel aquaporin-4 (AQP4) and driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal A beta was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced efflux, whereas atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, A. leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The results suggest that, in rodents, the removal of fluid and metabolites from the intraocular space occurs through a glymphatic pathway that might be impaired in glaucoma.
AU  - Wang, X.*
AU  - Lou, N.*
AU  - Eberhardt, A.*
AU  - Yang, Y.*
AU  - Kusk, P.*
AU  - Xu, Q.*
AU  - Förstera, B.
AU  - Peng, S.*
AU  - Shi, M.*
AU  - Ladrón-de-Guevara, A.*
AU  - Delle, C.*
AU  - Sigurdsson, B.*
AU  - Xavier, A.L.R.*
AU  - Ertürk, A.
AU  - Libby, R.T.*
AU  - Chen, L.*
AU  - Thrane, A.S.*
AU  - Nedergaard, M.*
C1  - 58715
C2  - 48292
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - An ocular glymphatic clearance system removes beta-amyloid from the rodent eye.
JO  - Sci. Transl. Med.
VL  - 12
IS  - 536
PB  - Amer Assoc Advancement Science
PY  - 2020
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (T(H)17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes T(H)2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-gamma (IFN-gamma) production in memory T cells. It diverted alternative T cell fates into the T(H)2 cell phenotype and also induced de novo T(H)2 cell polarization from naive T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated T(H)2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce T(H)2 cell responses, the orchestrators of atopic diseases.
AU  - Matthias, J.*
AU  - Maul, J.*
AU  - Noster, R.*
AU  - Meinl, H.*
AU  - Chao, Y.Y.*
AU  - Gerstenberg, H.*
AU  - Jeschke, F.*
AU  - Gasparoni, G.*
AU  - Welle, A.*
AU  - Walter, J.*
AU  - Nordström, K.*
AU  - Eberhardt, K.*
AU  - Renisch, D.*
AU  - Donakonda, S.*
AU  - Knolle, P.*
AU  - Soll, D.*
AU  - Grabbe, S.*
AU  - Garzorz-Stark, N.
AU  - Eyerich, K.
AU  - Biedermann, T.
AU  - Baumjohann, D.*
AU  - Zielinski, C.E.*
C1  - 55565
C2  - 46240
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Sodium chloride is an ionic checkpoint for human TH2 cells and shapes the atopic skin microenvironment.
JO  - Sci. Transl. Med.
VL  - 11
IS  - 480
PB  - Amer Assoc Advancement Science
PY  - 2019
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of. 3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.
AU  - Roth, S.*
AU  - Singh, V.K.*
AU  - Tiedt, S.*
AU  - Schindler, L.*
AU  - Huber, G.
AU  - Geerlof, A.
AU  - Antoine, D.J.*
AU  - Anfray, A.*
AU  - Orset, C.*
AU  - Gauberti, M.*
AU  - Fournier, A.*
AU  - Holdt, L.M.*
AU  - Harris, H.E.*
AU  - Engelhardt, B.*
AU  - Bianchi, M.E.*
AU  - Vivien, D.*
AU  - Haffner, C.*
AU  - Bernhagen, J.*
AU  - Dichgans, M.*
AU  - Liesz, A.*
C1  - 53261
C2  - 44642
CY  - Washington
TI  - Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke.
JO  - Sci. Transl. Med.
VL  - 10
IS  - 432
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)-mediated NFAT5, which interferes with FoxP3+ Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.
AU  - Serr, I.
AU  - Scherm, M.G.
AU  - Zahm, A.M.*
AU  - Schug, J.*
AU  - Flynn, V.K.
AU  - Hippich, M.*
AU  - Kälin, S.*
AU  - Becker, M.
AU  - Achenbach, P.*
AU  - Nikolaev, A.*
AU  - Gerlach, K.*
AU  - Liebsch, N.*
AU  - Loretz, B.*
AU  - Lehr, C.M.*
AU  - Kirchner, B.*
AU  - Spornraft, M.*
AU  - Haase, B.*
AU  - Segars, J.*
AU  - Küper, C.*
AU  - Palmisano, R.*
AU  - Waisman, A.*
AU  - Willis, R.A.*
AU  - Kim, W.U.*
AU  - Weigmann, B.*
AU  - Kaestner, K.H.*
AU  - Ziegler, A.G.*
AU  - Daniel, C.
C1  - 52715
C2  - 44228
CY  - Washington
TI  - A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.
JO  - Sci. Transl. Med.
VL  - 10
IS  - 422
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and are a major cause of postsurgical and infectious morbidity. The primary molecular chain of events leading to the initiation of adhesions has been elusive, chiefly due to the lack of an identifiable cell of origin. Using clonal analysis and lineage tracing, we have identified injured surface mesothelium expressing podoplanin (PDPN) and mesothelin (MSLN) as a primary instigator of peritoneal adhesions after surgery in mice. We demonstrate that an anti-MSLN antibody diminished adhesion formation in a mouse model where adhesions were induced by surgical ligation to form ischemic buttons and subsequent surgical abrasion of the peritoneum. RNA sequencing and bioinformatics analyses of mouse mesothelial cells from injured mesothelium revealed aspects of the pathological mechanism of adhesion development and yielded several potential regulators of this process. Specifically, we show that PDPN+MSLN+ mesothelium responded to hypoxia by early up-regulation of hypoxia-inducible factor 1 alpha (HIF1 alpha) that preceded adhesion development. Inhibition of HIF1. with small molecules ameliorated the injury program in damaged mesothelium and was sufficient to diminish adhesion severity in a mouse model. Analyses of human adhesion tissue suggested that similar surface markers and signaling pathways may contribute to surgical adhesions in human patients.
AU  - Tsai, J.M.*
AU  - Sinha, R.*
AU  - Seita, J.*
AU  - Fernhoff, N.*
AU  - Christ, S.
AU  - Koopmans, T.
AU  - Krampitz, G.W.*
AU  - McKenna, K.M.*
AU  - Xing, L.*
AU  - Sandholzer, M.
AU  - Sales, J.H.
AU  - Shoham, M.*
AU  - McCracken, M.*
AU  - Joubert, L.M.*
AU  - Gordon, S.R.*
AU  - Poux, N.*
AU  - Wernig, G.*
AU  - Norton, J.A.*
AU  - Weissman, I.L.*
AU  - Rinkevich, Y.
C1  - 54854
C2  - 45904
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
TI  - Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers.
JO  - Sci. Transl. Med.
VL  - 10
IS  - 469
PB  - Amer Assoc Advancement Science
PY  - 2018
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Autoimmune diabetes is marked by sensitization to β cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in β cell antigen-responsive CD4(+) T cells through pre- and established autoimmune phases. A striking divergence in the gene signature of β cell antigen-responsive naïve CD4(+) T cells from children who developed β cell autoimmunity was found in infancy, well before the appearance of β cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (TH1)/TH17/T follicular helper cell response with expression of CCR6, IL21, TBX21, TNF, RORC, EGR2, TGFB1, and ICOS, in the absence of FOXP3, IL17, and other cytokines. The cells transitioned to an IFNG-TH1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naïve T cell response is a consequence of genetic or environmental priming during unfavorable perinatal exposures and that the signature will guide future efforts to detect and prevent β cell autoimmunity.
AU  - Heninger, A.K.*
AU  - Jergens, S.
AU  - Wilhelm, C.
AU  - Beyerlein, A.
AU  - Ziegler, A.-G.
AU  - Bonifacio, E.
C1  - 50641
C2  - 42539
CY  - Washington
TI  - A divergent population of autoantigen-responsive CD4+ T cells in infants prior to β cell autoimmunity.
JO  - Sci. Transl. Med.
VL  - 9
IS  - 378
PB  - Amer Assoc Advancement Science
PY  - 2017
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
AU  - Scott, R.A.*
AU  - Freitag, D.F.*
AU  - Li, L.*
AU  - Chu, A.Y.*
AU  - Surendran, P.*
AU  - Young, R.*
AU  - Grarup, N.*
AU  - Stancáková, A.*
AU  - Chen, Y.*
AU  - Varga, T.V.*
AU  - Yaghootkar, H.*
AU  - Luan, J.*
AU  - Zhao, J.H.*
AU  - Willems, S.M.*
AU  - Wessel, J.*
AU  - Wang, S.*
AU  - Maruthur, N.M.*
AU  - Michailidou, K.*
AU  - Pirie, A.*
AU  - van der Lee, S.J.*
AU  - Gillson, C.J.*
AU  - Al Olama, A.A.*
AU  - Amouyel, P.*
AU  - Arriola, L.*
AU  - Arveiler, D.*
AU  - Aviles-Olmos, I.*
AU  - Balkau, B.*
AU  - Barricarte, A.*
AU  - Barroso, I.*
AU  - Garcia, S.B.*
AU  - Bis, J.C.*
AU  - Blankenberg, S.*
AU  - Boehnke, M.*
AU  - Boeing, H.*
AU  - Boerwinkle, E.*
AU  - Borecki, I.B.*
AU  - Bork-Jensen, J.*
AU  - Bowden, S.*
AU  - Caldas, C.*
AU  - Caslake, M.*
AU  - Cupples, L.A.*
AU  - Cruchaga, C.*
AU  - Czajkowski, J.*
AU  - den Hoed, M.*
AU  - Dunn, J.A.*
AU  - Earl, H.M.*
AU  - Ehret, G.B.*
AU  - Ferrannini, E.*
AU  - Ferrieres, J.*
AU  - Foltynie, T.*
AU  - Ford, I.*
AU  - Forouhi, N.G.*
AU  - Gianfagna, F.*
AU  - Gonzalez, C.*
AU  - Grioni, S.*
AU  - Hiller, L.*
AU  - Jansson, J.H.*
AU  - Jørgensen, M.E.*
AU  - Jukema, J.W.*
AU  - Kaaks, R.*
AU  - Kee, F.*
AU  - Kerrison, N.D.*
AU  - Key, T.J.*
AU  - Kontto, J.*
AU  - Kote-Jarai, Z.*
AU  - Kraja, A.T.*
AU  - Kuulasmaa, K.*
AU  - Kuusisto, J.*
AU  - Linneberg, A.*
AU  - Liu, C.*
AU  - Marenne, G.*
AU  - Mohlke, K.L.*
AU  - Morris, A.P.*
AU  - Muir, K.*
AU  - Müller-Nurasyid, M.
AU  - Munroe, P.B.*
AU  - Navarro, C.*
AU  - Nielsen, S.F.*
AU  - Nilsson, P.M.*
AU  - Nørdestgaard, B.G.*
AU  - Packard, C.J.*
AU  - Palli, D.*
AU  - Panico, S.*
AU  - Peloso, G.M.*
AU  - Perola, M.*
AU  - Peters, A.
AU  - Poole, C.J.*
AU  - Quirós, J.R.*
AU  - Rolandsson, O.*
AU  - Sacerdote, C.*
AU  - Salomaa, V.*
AU  - Sánchez, M.J.*
AU  - Sattar, N.*
AU  - Sharp, S.J.*
AU  - Sims, R.*
AU  - Slimani, N.*
AU  - Smith, J.A.*
AU  - Thompson, D.J.*
AU  - Trompet, S.*
AU  - Tumino, R.*
AU  - van der A, D.L.*
AU  - van der Schouw, Y.T.*
AU  - Virtamo, J.*
AU  - Walker, M.*
AU  - Walter, K.*
AU  - Abraham, J.E.*
AU  - Amundadottir, L.T.*
AU  - Aponte, J.L.*
AU  - Butterworth, A.S.*
AU  - Dupuis, J.*
AU  - Easton, D.F.*
AU  - Eeles, R.A.*
AU  - Erdmann, J.*
AU  - Franks, P.W.*
AU  - Frayling, T.M.*
AU  - Hansen, T.*
AU  - Howson, J.M.M.*
AU  - Jørgensen, T.*
AU  - Kooner, J.*
AU  - Laakso, M.*
AU  - Langenberg, C.*
AU  - McCarthy, M.I.*
AU  - Pankow, J.S.*
AU  - Pedersen, O.*
AU  - Riboli, E.*
AU  - Rotter, J.I.*
AU  - Saleheen, D.*
AU  - Samani, N.J.*
AU  - Schunkert, H.*
AU  - Vollenweider, P.*
AU  - O'Rahilly, S.*
AU  - Deloukas, P.*
AU  - Danesh, J.*
AU  - Goodarzi, M.O.*
AU  - Kathiresan, S.*
AU  - Meigs, J.B.*
AU  - Ehm, M.G.*
AU  - Wareham, N.J.*
AU  - Waterworth, D.M.*
C1  - 48732
C2  - 41291
CY  - Washington
TI  - A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease.
JO  - Sci. Transl. Med.
VL  - 8
IS  - 341
PB  - Amer Assoc Advancement Science
PY  - 2016
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADCC.
AU  - Bruns, H.*
AU  - Büttner, M.*
AU  - Fabri, M.*
AU  - Mougiakakos, D.*
AU  - Bittenbring, J.T.*
AU  - Hoffmann, M.H.*
AU  - Beier, F.*
AU  - Pasemann, S.*
AU  - Jitschin, R.*
AU  - Hofmann, A.D.*
AU  - Neumann, F.J.*
AU  - Daniel, C.*
AU  - Maurberger, A.*
AU  - Kempkes, B.
AU  - Amann, K.*
AU  - Mackensen, A.*
AU  - Gerbitz, A.*
C1  - 44338
C2  - 36875
CY  - Washington
TI  - Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma.
JO  - Sci. Transl. Med.
VL  - 7
IS  - 282
PB  - Amer Assoc Advancement Science
PY  - 2015
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - The research community can have confidence in data from well-executed phenotyping projects.
AU  - Lloyd, K.C.K.*
AU  - McKerlie, C.*
AU  - Seong, J.K.*
AU  - Neff, F.
C1  - 47538
C2  - 40653
TI  - Comment on "One health, one literature: Weaving together veterinary and medical research".
JO  - Sci. Transl. Med.
VL  - 7
IS  - 317
PY  - 2015
SN  - 1946-6234
ER  - 

TY  - JOUR
AU  - Rietschel, E.T.*
AU  - Bruckner-Tuderman, L.*
AU  - Schütte, G.*
AU  - Wess, G.
C1  - 43657
C2  - 36665
CY  - Washington
TI  - Moving medicine forward faster.
JO  - Sci. Transl. Med.
VL  - 7
IS  - 277
PB  - Amer Assoc Advancement Science
PY  - 2015
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Sentinel lymph node (SLN) excision is included in various cancer guidelines to identify microscopic metastatic disease. Although effective, SLN excision is an invasive procedure requiring radioactive tracing. Novel imaging approaches assessing SLN metastatic status could improve or replace conventional lymph node excision protocols. In our first-in-human study, we used noninvasive multispectral optoacoustic tomography (MSOT) to image SLNs ex vivo and in vivo in patients with melanoma, to determine metastatic status. MSOT significantly improved the tumor metastasis detection rate in excised SLN (506 SLNs from 214 melanoma patients) compared with the conventional EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group protocol (22.9% versus 14.2%). MSOT combined with the near-infrared fluorophore indocyanine green reliably visualized SLNs in vivo in 20 patients, up to 5-cm penetration and with 100% concordance with (99m)Tc-marked SLN lymphoscintigraphy. MSOT identified cancer-free SLNs in vivo and ex vivo without a single false negative (189 total lymph nodes), with 100% sensitivity and 48 to 62% specificity. Our findings indicate that a noninvasive, nonradioactive MSOT-based approach can identify and determine SLN status and confidently rule out the presence of metastasis. The study further demonstrates that optoacoustic imaging strategies can improve the identification of SLN metastasis as an alternative to current invasive SLN excision protocols.
AU  - Stoffels, I.*
AU  - Morscher, S.
AU  - Helfrich, I.*
AU  - Hillen, U.*
AU  - Lehy, J.*
AU  - Burton, N.C.B.*
AU  - Sardella, T.C.*
AU  - Claussen, J.*
AU  - Poeppel, T.D.*
AU  - Bachmann, H.S.*
AU  - Roesch, A.*
AU  - Griewank, K.*
AU  - Schadendorf, D.*
AU  - Gunzer, M.*
AU  - Klode, J.*
C1  - 47537
C2  - 40654
TI  - Metastatic status of sentinel lymph nodes in melanoma determined noninvasively with multispectral optoacoustic imaging.
JO  - Sci. Transl. Med.
VL  - 7
IS  - 317
PY  - 2015
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.
AU  - Bohne, F.
AU  - Londoño, M.C.*
AU  - Benítez, C.*
AU  - Miquel, R.*
AU  - Martínez-Llordella, M.*
AU  - Russo, C.
AU  - Ortiz, C.*
AU  - Bonaccorsi-Riani, E.*
AU  - Brander, C.*
AU  - Bauer, T.
AU  - Protzer, U.
AU  - Jaeckel, E.*
AU  - Taubert, R.*
AU  - Forns, X.*
AU  - Navasa, M.*
AU  - Berenguer, M.*
AU  - Rimola, A.*
AU  - Lozano, J.J.*
AU  - Sánchez-Fueyo, A.*
C1  - 31693
C2  - 34739
TI  - HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans.
JO  - Sci. Transl. Med.
VL  - 6
IS  - 242
PY  - 2014
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - A calculation grid developed by an international expert group was tested across biobanks in six countries to evaluate costs for collections of various types of biospecimens. The assessment yielded a tool for setting specimen-access prices that were transparently related to biobank costs, and the tool was applied across three models of collaborative partnership.
AU  - Clement, B.*
AU  - Yuille, M.*
AU  - Zaltoukal, K.*
AU  - Wichmann, H.-E.
AU  - Anton, G.
AU  - Parodi, B.*
AU  - Kozera, L.*
AU  - Bréchot, C.*
AU  - Hofman, P.*
AU  - Dagher, G.*
C1  - 34373
C2  - 35262
CY  - Washington
TI  - Public biobanks: Calculation and recovery of costs.
JO  - Sci. Transl. Med.
VL  - 6
IS  - 261
PB  - Amer Assoc Advancement Science
PY  - 2014
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.
AU  - Duda, G.N.*
AU  - Grainger, D.W.*
AU  - Frisk, M.L.*
AU  - Bruckner-Tuderman, L.*
AU  - Carr, A.*
AU  - Dirnagl, U.*
AU  - Einhäupl, K.M.*
AU  - Gottschalk, S.*
AU  - Gruskin, E.*
AU  - Huber, C.*
AU  - June, C.H.*
AU  - Mooney, D.J.*
AU  - Rietschel, E.T.*
AU  - Schütte, G.*
AU  - Seeger, W.*
AU  - Stevens, M.M.*
AU  - Urban, R.*
AU  - Veldman, A.*
AU  - Wess, G.
AU  - Volk, H.D.*
C1  - 42849
C2  - 35819
CY  - 1200 New York Ave, Nw, Washington, Dc 20005 Usa
SP  - 16-21
TI  - Changing the mindset in life sciences toward translation: A consensus.
JO  - Sci. Transl. Med.
VL  - 6
IS  - 264
PB  - Amer Assoc Advancement Science
PY  - 2014
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comparison of the molecular signatures of psoriasis and eczema identified genes and signaling pathways regulated in common and exclusive for each disease across all patients. Psoriasis-specific genes were important regulators of glucose and lipid metabolism, epidermal differentiation, as well as immune mediators of T helper 17 (TH17) responses, interleukin-10 (IL-10) family cytokines, and IL-36. Genes in eczema related to epidermal barrier, reduced innate immunity, increased IL-6, and a TH2 signature. Within eczema subtypes, a mutually exclusive regulation of epidermal differentiation genes was observed. Furthermore, only contact eczema was driven by inflammasome activation, apoptosis, and cellular adhesion. On the basis of this comprehensive picture of the pathogenesis of psoriasis and eczema, a disease classifier consisting of NOS2 and CCL27 was created. In an independent cohort of eczema (n = 28) and psoriasis patients (n = 25), respectively, this classifier diagnosed all patients correctly and also identified initially misdiagnosed or clinically undifferentiated patients.
AU  - Quaranta, M.
AU  - Knapp, B.
AU  - Garzorz-Stark, N.*
AU  - Mattii, M.
AU  - Pullabhatla, V.*
AU  - Pennino, D.
AU  - Andres, C.*
AU  - Traidl-Hoffmann, C.
AU  - Cavani, A.*
AU  - Theis, F.J.
AU  - Ring, J.*
AU  - Schmidt-Weber, C.B.
AU  - Eyerich, S.
AU  - Eyerich, K.*
C1  - 31748
C2  - 34724
CY  - Washington
TI  - Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.
JO  - Sci. Transl. Med.
VL  - 6
IS  - 244
PB  - Amer Assoc Advancement Science
PY  - 2014
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - White, beige, and brown adipocytes are developmentally and functionally distinct but often occur mixed together within individual depots. To target white, beige, and brown adipocytes for diagnostic or therapeutic purposes, a better understanding of the cell surface properties of these cell types is essential. Using a combination of in silico, in vitro, and in vivo methods, we have identified three new cell surface markers of adipose cell types. The amino acid transporter ASC-1 is a white adipocyte-specific cell surface protein, with little or no expression in brown adipocytes, whereas the amino acid transporter PAT2 and the purinergic receptor P2RX5 are cell surface markers expressed in classical brown and beige adipocytes in mice. These markers also selectively mark brown/beige and white adipocytes in human tissue. Thus, ASC-1, PAT2, and P2RX5 are membrane surface proteins that may serve as tools to identify and target white and brown/beige adipocytes for therapeutic purposes.
AU  - Ussar, S.
AU  - Lee, K.Y.*
AU  - Dankel, S.N.*
AU  - Boucher, J.*
AU  - Haering, M.-F.*
AU  - Kleinridders, A.*
AU  - Thomou, T.*
AU  - Xue, R.*
AU  - Macotela, Y.*
AU  - Cypess, A.M.*
AU  - Tseng, Y.H.*
AU  - Mellgren, G.*
AU  - Kahn, C.R.*
C1  - 32056
C2  - 34959
CY  - Washington
TI  - ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes.
JO  - Sci. Transl. Med.
VL  - 6
IS  - 245
PB  - Amer Assoc Advancement Science
PY  - 2014
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
AU  - Finan, B.
AU  - Ma, T.*
AU  - Ottaway, N.*
AU  - Müller, T.D.
AU  - Habegger, K.M.*
AU  - Heppner, K.M.*
AU  - Kirchner, H.*
AU  - Holland, J.*
AU  - Hembree, J.*
AU  - Raver, C.*
AU  - Lockie, S.H.*
AU  - Smiley, D.L.*
AU  - Gelfanov, V.*
AU  - Yang, B.*
AU  - Hofmann, S.
AU  - Bruemmer, D.*
AU  - Drucker, D.J.*
AU  - Pfluger, P.T.
AU  - Perez-Tilve, D.*
AU  - Gidda, J.*
AU  - Vignati, L.*
AU  - Zhang, L.*
AU  - Hauptman, J.B.*
AU  - Lau, M.*
AU  - Brecheisen, M.*
AU  - Uhles, S.*
AU  - Riboulet, W.*
AU  - Hainaut, E.*
AU  - Sebokova, E.*
AU  - Conde-Knape, K.*
AU  - Konkar, A.*
AU  - DiMarchi, R.D.*
AU  - Tschöp, M.H.
C1  - 28767
C2  - 33545
TI  - Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.
JO  - Sci. Transl. Med.
VL  - 5
IS  - 209
PB  - Amer. Assoc. Advancement Science
PY  - 2013
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (k(off) rate) of truly monomeric peptide-major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner. A first evaluation of this method on distinct human cytomegalovirus (CMV)-specific T cell populations revealed unexpected differences in the k(off) rates. CMV-specific T cells are currently being evaluated in clinical trials for efficacy in adoptive immunotherapy; therefore, determination of koff rates could guide selection of the most effective donor cells. Indeed, in two different murine infection models, we demonstrate that T cell populations with lower k(off) rates confer significantly better protection than populations with fast k(off) rates. These data indicate that k(off) rate measurements can improve the predictability of adoptive immunotherapy and provide diagnostic information on the in vivo quality of T cells.
AU  - Nauerth, M.*
AU  - Weißbrich, B.*
AU  - Knall, R.*
AU  - Franz, T.*
AU  - Dössinger, G.*
AU  - Bet, J.*
AU  - Paszkiewicz, P.J.*
AU  - Pfeifer, L.*
AU  - Bunse, M.*
AU  - Uckert, W.*
AU  - Holtappels, R.*
AU  - Gillert-Marien, D.*
AU  - Neuenhahn, M.
AU  - Krackhardt, A.M.
AU  - Reddehase, M.J.*
AU  - Riddell, S.R.*
AU  - Busch, D.H.
C1  - 26275
C2  - 32166
TI  - TCR-Ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer.
JO  - Sci. Transl. Med.
VL  - 5
IS  - 192
PB  - Amer. Assoc. Advancement Science
PY  - 2013
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Fluorescent agents with specificity to cellular and subcellular moieties present promise for enhancing diagnostics and theranostics, yet challenges associated with regulatory approvals of experimental agents stifle the clinical translation. As a result, targeted fluorescent agents have remained predominantly as preclinical imaging tools. We discuss the potential of using optically labeled drugs to accelerate the clinical acceptance of optical and optoacoustic agents, in analogy to nuclear medicine approaches. This strategy, corroborated with microdosing studies, outlines a promising approach for overcoming bottlenecks and advancing photonic clinical imaging.
AU  - Scheuer, W.*
AU  - van Dam, G.M.*
AU  - Dobosz, M.*
AU  - Schwaiger, M.*
AU  - Ntziachristos, V.
C1  - 8174
C2  - 30055
TI  - Drug-based optical agents: Infiltrating clinics at lower risk.
JO  - Sci. Transl. Med.
VL  - 4
IS  - 134
PB  - American Assoc. for the Advancement of Science
PY  - 2012
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - Idiopathic pulmonary fibrosis (IPF) is a progressive, dysregulated response to alveolar injury that culminates in compromised lung function from excess extracellular matrix production. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. We examined fibrotic lungs from mice and from patients with IPF and detected increased expression of dimethylarginine dimethylaminohydrolases (DDAHs)--key enzymes that metabolize asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase, to form l-citrulline and dimethylamine. DDAHs are up-regulated in primary alveolar epithelial type II cells from these mice and patients where they are colocalized with inducible nitric oxide synthase. In cultured alveolar epithelial type II cells from bleomycin-induced fibrotic mouse lungs, inhibition of DDAH suppressed proliferation and induced apoptosis in an ADMA-dependent manner. In addition, DDAH inhibition reduced collagen production by fibroblasts in an ADMA-independent but transforming growth factor/SMAD-dependent manner. In mice with bleomycin-induced pulmonary fibrosis, the DDAH inhibitor L-291 reduced collagen deposition and normalized lung function. In bleomycin-induced fibrosis, inducible nitric oxide synthase inhibition decreased fibrosis, but an even stronger reduction was observed after inhibition of DDAH. Thus, DDAH inhibition reduces fibroblast-induced collagen deposition in an ADMA-independent manner and reduces abnormal epithelial proliferation in an ADMA-dependent manner, offering a possible therapeutic avenue for attenuation of pulmonary fibrosis.
AU  - Pullamsetti, S.S.*
AU  - Savai, R.*
AU  - Dumitrascu, R.*
AU  - Dahal, B.K.*
AU  - Wilhelm, J.*
AU  - Königshoff, M.
AU  - Zakrzewicz, D.*
AU  - Ghofrani, H.A.*
AU  - Weissmann, N.*
AU  - Eickelberg, O.
AU  - Guenther, A.*
AU  - Leiper, J.*
AU  - Seeger, W.*
AU  - Grimminger, F.*
AU  - Schermuly, R.T.*
C1  - 5788
C2  - 29028
CY  - Washington, DC, USA
TI  - The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis.
JO  - Sci. Transl. Med.
VL  - 3
IS  - 87
PB  - American Assoc. for the Advancement of Science
PY  - 2011
SN  - 1946-6234
ER  - 

TY  - JOUR
AB  - New high-resolution molecular and structural imaging strategies are needed to visualize high-risk plaques that are likely to cause acute myocardial infarction, because current diagnostic methods do not reliably identify at-risk subjects. Although molecular imaging agents are available for low-resolution detection of atherosclerosis in large arteries, a lack of imaging agents coupled to high-resolution modalities has limited molecular imaging of atherosclerosis in the smaller coronary arteries. Here, we have demonstrated that indocyanine green (ICG), a Food and Drug Administration-approved near-infrared fluorescence (NIRF)-emitting compound, targets atheromas within 20 min of injection and provides sufficient signal enhancement for in vivo detection of lipid-rich, inflamed, coronary-sized plaques in atherosclerotic rabbits. In vivo NIRF sensing was achieved with an intravascular wire in the aorta, a vessel of comparable caliber to human coronary arteries. Ex vivo fluorescence reflectance imaging showed high plaque target-to-background ratios in atheroma-bearing rabbits injected with ICG compared to atheroma-bearing rabbits injected with saline. In vitro studies using human macrophages established that ICG preferentially targets lipid-loaded macrophages. In an early clinical study of human atheroma specimens from four patients, we found that ICG colocalized with plaque macrophages and lipids. The atheroma-targeting capability of ICG has the potential to accelerate the clinical development of NIRF molecular imaging of high-risk plaques in humans.
AU  - Vinegoni, C.*
AU  - Botnaru, I.*
AU  - Aikawa, E.*
AU  - Calfon, M.A.*
AU  - Iwamoto, Y.*
AU  - Folco, E.J.*
AU  - Ntziachristos, V.
AU  - Weissleder, R.*
AU  - Libby, P.*
AU  - Jaffer, F.A.
C1  - 6159
C2  - 28574
TI  - Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques.
JO  - Sci. Transl. Med.
VL  - 3
IS  - 84
PB  - American Assoc. for the Advancement of Science
PY  - 2011
SN  - 1946-6234
ER  -