TY  - JOUR
AB  - Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) and PyClone to detect clones that are present at a â ‰1 10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.
AU  - Andor, N.
AU  - Graham, T.A.*
AU  - Jansen, M.A.*
AU  - Xia, L.C.*
AU  - Aktipis, C.A.*
AU  - Petritsch, C.*
AU  - Ji, H.P.*
AU  - Maley, C.C.*
C1  - 47715
C2  - 39778
SP  - 105-113
TI  - Pan-cancer analysis of the extent and consequences of intratumor heterogeneity.
JO  - J. Nat. Med.
VL  - 22
IS  - 1
PY  - 2016
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - A new study shows that withaferin A, a steroidal lactone isolated from Withania somnifera, can exert profound metabolic benefits in mice, including body-weight loss, reduced hepatic steatosis and improved glucose control.
AU  - Pfluger, P.T.
AU  - Tschöp, M.H.
C1  - 49573
C2  - 40801
CY  - New York
SP  - 970-971
TI  - Obesity: Will withaferin win the war?
JO  - J. Nat. Med.
VL  - 22
IS  - 9
PB  - Nature Publishing Group
PY  - 2016
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.
AU  - Rohm, M.
AU  - Schäfer, M
AU  - Laurent, V.
AU  - Ekim Üstünel, B.
AU  - Niopek, K.
AU  - Algire, C.
AU  - Hautzinger, O.
AU  - Sijmonsma, T.P.
AU  - Zota, A.
AU  - Medrikova, D.
AU  - Pellegata, N.S.
AU  - Rydén, M.*
AU  - Kulyte, A.*
AU  - Dahlman, I.*
AU  - Arner, P.*
AU  - Petrovic, N.*
AU  - Cannon, B.*
AU  - Amri, E.Z.*
AU  - Kemp, B.E.*
AU  - Steinberg, G.R.*
AU  - Janovska, P.*
AU  - Kopecky, J.*
AU  - Wolfrum, C.*
AU  - Blüher, M.*
AU  - Berriel Diaz, M.
AU  - Herzig, S.
C1  - 49353
C2  - 41772
CY  - New York
SP  - 1120-1130
TI  - An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
JO  - J. Nat. Med.
VL  - 22
IS  - 10
PB  - Nature Publishing Group
PY  - 2016
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
AU  - Finan, B.
AU  - Yang, B.*
AU  - Ottaway, N.*
AU  - Smiley, D.L.*
AU  - Ma, T.*
AU  - Clemmensen, C.
AU  - Chabenne, J.*
AU  - Zhang, L.*
AU  - Habegger, K.M.*
AU  - Fischer, K.
AU  - Campbell, J.E.*
AU  - Sandoval, D.A.*
AU  - Seeley, R.J.*
AU  - Bleicher, K.*
AU  - Uhles, S.*
AU  - Riboulet, W.*
AU  - Funk, J.*
AU  - Hertel, C.*
AU  - Belli, S.*
AU  - Sebokova, E.*
AU  - Conde-Knape, K.*
AU  - Konkar, A.*
AU  - Drucker, D.J.*
AU  - Gelfanov, V.*
AU  - Pfluger, P.T.
AU  - Müller, T.D.
AU  - Perez-Tilve, D.*
AU  - DiMarchi, R.D.*
AU  - Tschöp, M.H.
C1  - 42922
C2  - 35860
CY  - New York
SP  - 27-36
TI  - A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.
JO  - J. Nat. Med.
VL  - 21
IS  - 1
PB  - Nature Publishing Group
PY  - 2015
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.
AU  - Riebold, M.*
AU  - Kozany, C.*
AU  - Freiburger, L.
AU  - Sattler, M.
AU  - Buchfelder, M.*
AU  - Hausch, F.*
AU  - Stalla, G.K.*
AU  - Paez-Pereda, M.*
C1  - 43263
C2  - 36372
SP  - 276-280
TI  - A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.
JO  - J. Nat. Med.
VL  - 21
IS  - 3
PY  - 2015
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
AU  - Yoda, A.*
AU  - Adelmant, G.*
AU  - Tamburini, J.*
AU  - Chapuy, B.*
AU  - Shindoh, N.*
AU  - Yoda, Y.*
AU  - Weigert, O.
AU  - Kopp, N.*
AU  - Wu, S.C.*
AU  - Kim, S.S.*
AU  - Liu, H.*
AU  - Tivey, T.*
AU  - Christie, A.L.*
AU  - Elpek, K.G.*
AU  - Card, J.*
AU  - Gritsman, K.*
AU  - Gotlib, J.*
AU  - Deininger, M.W.*
AU  - Makishima, H.*
AU  - Turley, S.J.*
AU  - Javidi-Sharifi, N.*
AU  - Maciejewski, J.P.*
AU  - Jaiswal, S.*
AU  - Ebert, B.L.*
AU  - Rodig, S.J.*
AU  - Tyner, J.W.*
AU  - Marto, J.A.*
AU  - Weinstock, D.M.*
AU  - Lane, A.A.*
C1  - 42921
C2  - 35861
CY  - New York
SP  - 71-75
TI  - Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
JO  - J. Nat. Med.
VL  - 21
IS  - 1
PB  - Nature Publishing Group
PY  - 2015
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eμ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.
AU  - Baumann, U.*
AU  - Fernández-Sáiz, V.*
AU  - Rudelius, M.*
AU  - Lemeer, S.*
AU  - Rad, R.*
AU  - Knorn, A.M.*
AU  - Slawska, J.*
AU  - Engel, K.*
AU  - Jeremias, I.
AU  - Li, Z.*
AU  - Tomiatti, V.*
AU  - Illert, A.L.*
AU  - Targosz, B.S.*
AU  - Braun, M.*
AU  - Perner, S.*
AU  - Leitges, M.*
AU  - Klapper, W.*
AU  - Dreyling, M.*
AU  - Miething, C.*
AU  - Lenz, G.*
AU  - Rosenwald, A.*
AU  - Peschel, C.*
AU  - Keller, U.*
AU  - Kuster, B.*
AU  - Bassermann, F.*
C1  - 42827
C2  - 35540
SP  - 1401-1409
TI  - Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.
JO  - J. Nat. Med.
VL  - 20
IS  - 12
PY  - 2014
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Human epidemiological studies have revealed that maternal obesity predisposes offspring to metabolic disorders, though little is known about the mechanism that causes this phenomenon. In a step forward, Vogt et al. have shown in mice that the offspring of mothers fed a high-fat diet during lactation show an alteration in the number of projections in nerves in the hypothalamus in the brain and in the pancreas. These offspring are predisposed to be obese and develop diabetes, and the mechanism by which these connections are altered seems to be through insulin signaling. Here we asked three experts what the implications of these findings might be to humans.
AU  - Schwartz, M.W.*
AU  - Tschöp, M.H.
AU  - Zeltser, L.M.*
C1  - 31056
C2  - 34309
CY  - New York
SP  - 244-245
TI  - A mother's influence on metabolic disorders.
JO  - J. Nat. Med.
VL  - 20
IS  - 3
PB  - Nature Publishing Group
PY  - 2014
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Stefan, N.
AU  - Häring, H.-U.
C1  - 28733
C2  - 33616
SP  - 394-395
TI  - Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans.
JO  - J. Nat. Med.
VL  - 19
IS  - 4
PB  - Nature Publishing
PY  - 2013
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - This study reports on the determination of 11 elements in 33 medicinal plants from Sudan and discusses a possible correlation between their curative effects and their trace elements content. Further, a possible accumulation of adverse heavy metals could be excluded. A total of 11 elements (cadmium, lead, mercury, tin, copper, iron, manganese, zinc, chromium, selenium and magnesium) were determined using inductively coupled plasma (ICP)-optical emission spectrometry (ICP-OES), ICP-sector field-mass spectrometry (ICP-sf-MS) and hydride generation (HG)-ICP-OES techniques. The results of the present study showed no heavy metal accumulation in any of the plants. Cd, Pb, Hg and Sn were found only in trace concentrations significantly below the global limits. This indicates the possibility of a safe use of these medicinal plants. Elevated chromium concentrations were found in those phytopharmaca which are employed for the treatment of diabetes mellitus in Sudanese traditional medicine. Cr was detected in the same range as in other plants reported to be applied for diabetes mellitus treatment. Aside from these medicinal plants, some others were identified which could be potential sources for providing reasonable amounts of Cr, Zn, Mn, Se and Mg for the treatment of diabetes mellitus, smooth muscle relaxation and/or against gastro-intestinal cramps.
AU  - Ebrahim, A.M.*
AU  - Eltayeb, M.H.*
AU  - Khalid, H.*
AU  - Mohamed, H.*
AU  - Abdalla, W.*
AU  - Grill, P.
AU  - Michalke, B.
C1  - 7562
C2  - 29860
SP  - 671-679
TI  - Study on selected trace elements and heavy metals in some popular medicinal plants from Sudan.
JO  - J. Nat. Med.
VL  - 66
IS  - 4
PB  - Springer 
PY  - 2012
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.
AU  - Finan, B.
AU  - Yang, B.*
AU  - Ottaway, N.*
AU  - Stemmer, K.
AU  - Müller, T.D.
AU  - Yi, C.-X.
AU  - Habegger, K.*
AU  - Schriever, S.C.
AU  - García-Cáceres, C.
AU  - Kabra, D.G.
AU  - Hembree, J.*
AU  - Holland, J.*
AU  - Raver, C.*
AU  - Seeley, R.J.*
AU  - Hans, W.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Hrabě de Angelis, M.
AU  - Tiano, J.P.*
AU  - Mauvais-Jarvis, F.*
AU  - Perez-Tilve, D.*
AU  - Pfluger, P.T.
AU  - Zhang, L.*
AU  - Gelfanov, V.*
AU  - DiMarchi, R.D.*
AU  - Tschöp, M.H.
C1  - 10863
C2  - 30375
SP  - 1847-1856
TI  - Targeted estrogen delivery reverses the metabolic syndrome.
JO  - J. Nat. Med.
VL  - 18
IS  - 12
PB  - Nature Publishing Company
PY  - 2012
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.
AU  - Walter, S.*
AU  - Weinschenk, T.*
AU  - Stenzl, A.*
AU  - Zdrojowy, R.*
AU  - Pluzanska, A.*
AU  - Szczylik, C.*
AU  - Staehler, M.*
AU  - Brugger, W.*
AU  - Dietrich, P.Y.*
AU  - Mendrzyk, R.*
AU  - Hilf, N.*
AU  - Schoor, O.*
AU  - Fritsche, J.*
AU  - Mahr, A.*
AU  - Maurer, D.*
AU  - Vass, V.*
AU  - Trautwein, C.*
AU  - Lewandrowski, P.*
AU  - Flohr, C.*
AU  - Pohla, H.
AU  - Stanczak, J.J.*
AU  - Bronte, V.*
AU  - Mandruzzato, S.*
AU  - Biedermann, T.*
AU  - Pawelec, G.*
AU  - Derhovanessian, E.*
AU  - Yamagishi, H.*
AU  - Miki, T.*
AU  - Hongo, F.*
AU  - Takaha, N.*
AU  - Hirakawa, K.*
AU  - Tanaka, H.*
AU  - Stevanovic, S.*
AU  - Frisch, J.*
AU  - Mayer-Mokler, A.*
AU  - Kirner, A.*
AU  - Rammensee, H.-G.*
AU  - Reinhardt, C.*
AU  - Singh-Jasuja, H.*
C1  - 26368
C2  - 32196
SP  - 1254-1261
TI  - Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.
JO  - J. Nat. Med.
VL  - 18
IS  - 8
PB  - Nature Publishing
PY  - 2012
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - The prognosis in advanced-stage ovarian cancer remains poor. Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis. The overexpression of folate receptor-α (FR-α) in 90-95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α-targeted fluorescent agent. In patients with ovarian cancer, intraoperative tumor-specific fluorescence imaging with an FR-α-targeted fluorescent agent showcased the potential applications in patients with ovarian cancer for improved intraoperative staging and more radical cytoreductive surgery.
AU  - van Dam, G.M.*
AU  - Themelis, G.
AU  - Crane, L.M.*
AU  - Harlaar, N.J.
AU  - Pleijhuis, R.G.*
AU  - Kelder, W.*
AU  - Sarantopoulos, A.
AU  - de Jong, J.S.*
AU  - Arts, H.J.*
AU  - van der Zee, A.G.*
AU  - Bart, J.*
AU  - Low, P.S.*
AU  - Ntziachristos, V.
C1  - 6527
C2  - 28910
SP  - 1315-1319
TI  - Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: First in-human results.
JO  - J. Nat. Med.
VL  - 17
IS  - 10
PB  - Nature Publ. Group
PY  - 2011
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Advancing understanding of human coronary artery disease requires new methods that can be used in patients for studying atherosclerotic plaque microstructure in relation to the molecular mechanisms that underlie its initiation, progression and clinical complications, including myocardial infarction and sudden cardiac death. Here we report a dual-modality intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo using a combination of optical frequency domain imaging (OFDI) and near-infrared fluorescence (NIRF) imaging. By providing simultaneous molecular information in the context of the surrounding tissue microstructure, this new catheter could provide new opportunities for investigating coronary atherosclerosis and stent healing and for identifying high-risk biological and structural coronary arterial plaques in vivo.
AU  - Yoo, H.*
AU  - Kim, J.W.*
AU  - Shishkov, M.*
AU  - Namati, E.*
AU  - Morse, T.*
AU  - Shubochkin, R.*
AU  - McCarthy, J.R.*
AU  - Ntziachristos, V.
AU  - Bouma, B.E.*
AU  - Jaffer, F.A.*
AU  - Tearney, G.J.*
C1  - 6788
C2  - 29273
SP  - 1680-1684
TI  - Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo.
JO  - J. Nat. Med.
VL  - 17
IS  - 12
PB  - Nature Publishing Group
PY  - 2011
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed that thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans.
AU  - Echtler, K.*
AU  - Stark, K.*
AU  - Lorenz, M.*
AU  - Kerstan, S.*
AU  - Walch, A.K.
AU  - Jennen, L.
AU  - Rudelius, M.*
AU  - Seidl, S.*
AU  - Kremmer, E.
AU  - Emambokus, N.R.*
AU  - von Bruehl, M.L.*
AU  - Frampton, J.*
AU  - Isermann, B.*
AU  - Genzel-Boroviczény, O.*
AU  - Schreiber, C.*
AU  - Mehilli, J.*
AU  - Kastrati, A.*
AU  - Schwaiger, M.*
AU  - Shivdasani, R.A.*
AU  - Massberg, S.*
C1  - 367
C2  - 27071
CY  - New York
SP  - 75-82
TI  - Platelets contribute to postnatal occlusion of the ductus arteriosus.
JO  - J. Nat. Med.
VL  - 16
IS  - 1
PB  - Nature Medicine
PY  - 2010
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.
AU  - Hartl, D.*
AU  - Latzin, P.*
AU  - Hordijk, P.*
AU  - Marcos, V.*
AU  - Rudolph, C.*
AU  - Woischnik, M.*
AU  - Krauss-Etschmann, S.
AU  - Koller, B.*
AU  - Reinhardt, D.*
AU  - Roscher, A.A.*
AU  - Roos, D.*
AU  - Griese, M.
C1  - 855
C2  - 24975
SP  - 1423-1430
TI  - Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease.
JO  - J. Nat. Med.
VL  - 13
IS  - 12
PB  - Nature Publ. Group
PY  - 2007
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - Genetic and epigenetic plasticity allows tumors to evade single-targeted treatments. Here we direct Bcl2-specific short interfering RNA (siRNA) with 5'-triphosphate ends (3p-siRNA) against melanoma. Recognition of 5'-triphosphate by the cytosolic antiviral helicase retinoic acid-induced protein I (Rig-I, encoded by Ddx58) activated innate immune cells such as dendritic cells and directly induced expression of interferons (IFNs) and apoptosis in tumor cells. These Rig-I-mediated activities synergized with siRNA-mediated Bcl2 silencing to provoke massive apoptosis of tumor cells in lung metastases in vivo. The therapeutic activity required natural killer cells and IFN, as well as silencing of Bcl2, as evidenced by rescue with a mutated Bcl2 target, by site-specific cleavage of Bcl2 messenger RNA in lung metastases and downregulation of Bcl-2 protein in tumor cells in vivo. Together, 3p-siRNA represents a single molecule-based approach in which Rig-I activation on both the immune- and tumor cell level corrects immune ignorance and in which gene silencing corrects key molecular events that govern tumor cell survival.
AU  - Poeck, H.*
AU  - Besch, R.*
AU  - Maihoefer, C.*
AU  - Renn, M.*
AU  - Tormo, D.*
AU  - Morskaya, S.S.*
AU  - Kirschnek, S.*
AU  - Gaffal, E.*
AU  - Landsberg, J.*
AU  - Hellmuth, J.*
AU  - Schmidt, A.*
AU  - Anz, D.*
AU  - Bscheider, M.*
AU  - Schwerd, T.*
AU  - Berking, C.*
AU  - Bourquin, C.*
AU  - Kalinke, U.*
AU  - Kremmer, E.
AU  - Kato, H.*
AU  - Akira, S.*
AU  - Meyers, R.*
AU  - Häcker, G.*
AU  - Neuenhahn, M.*
AU  - Busch, D.*
AU  - Ruland, J.*
AU  - Rothenfusser, S.*
AU  - Prinz, M.*
AU  - Hornung, V.*
AU  - Endres, S.*
AU  - Tüting, T.*
AU  - Hartmann, G.*
C1  - 2295
C2  - 25784
SP  - 1256-1263
TI  - 5'-Triphosphate-siRNA: Turning gene silencing and Rig-I activation against melanoma.
JO  - J. Nat. Med.
VL  - 14
IS  - 11
PB  - Nature Publ. Group
PY  - 2007
SN  - 1340-3443
ER  - 

TY  - JOUR
AB  - In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.
AU  - Trivedi, C.M.*
AU  - Luo, Y.*
AU  - Yin, Z.*
AU  - Zhang, M.*
AU  - Zhu, W.*
AU  - Wang, T.*
AU  - Floß, T.
AU  - Göttlicher, M.
AU  - Noppinger, P.R.*
AU  - Wurst, W.
AU  - Ferrari, VA.*
AU  - Abrams, C.S.*
AU  - Gruber, P.J.*
AU  - Epstein, J.A.*
C1  - 4405
C2  - 24407
SP  - 324-331
TI  - Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3ß activity.
JO  - J. Nat. Med.
VL  - 13
IS  - 3
PB  - Nature Publ. Group
PY  - 2007
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Hornung, V.*
AU  - Guenthner-Biller, M.*
AU  - Bourquin, C.*
AU  - Ablasser, A.*
AU  - Schlee, M.
AU  - Uematsu, S.*
AU  - Noronha, A.*
AU  - Manoharan, M.*
AU  - Akira, S.*
AU  - de Fougerolles, A.*
AU  - Endres, S.*
C1  - 4601
C2  - 22687
SP  - 263-270
TI  - Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.
JO  - J. Nat. Med.
VL  - 11
PY  - 2005
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Bonini, C.*
AU  - Grez, M.*
AU  - Traversari, C.*
AU  - Ciceri, F.*
AU  - Marktel, S.*
AU  - Ferrari, G.*
AU  - Dinauer, M.*
AU  - Sadat, M.*
AU  - Aiuti, A.*
AU  - Deola, S.*
AU  - Radrizzani, M.*
AU  - Hagenbeek, A.*
AU  - Apperley, J.*
C1  - 9713
C2  - 21636
SP  - 367-369
TI  - Safety of retroviral gene marking with a truncated NGF receptor. 
JO  - J. Nat. Med.
VL  - 9
PY  - 2003
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Ghoreschi, K.*
AU  - Thomas, P.*
AU  - Dugas, M.*
AU  - Mailhammer, R.
AU  - van Eden, W.*
AU  - van der Zee, R.*
AU  - Biedermann, T.*
AU  - Prinz, J.*
AU  - Mack, M.*
AU  - Mrowietz, U.*
AU  - Christophers, E.*
AU  - Schlöndorff, D.*
C1  - 9712
C2  - 21006
SP  - 40-46
TI  - Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.
JO  - J. Nat. Med.
VL  - 9
PY  - 2003
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Ghoreschi, K.*
AU  - Thomas, P.*
AU  - Breit, S.*
AU  - Dugas, M.*
AU  - Mailhammer, R.
AU  - van Eden, W.*
AU  - van der Zee, R.*
AU  - Biedermann, T.*
AU  - Prinz, J.*
AU  - Mack, M.*
AU  - Mrowietz, U.*
AU  - Christophers, E.*
AU  - Schlöndorff, D.*
AU  - Plewig, G.*
AU  - Sander, C.A.*
AU  - Röcken, M.*
C1  - 22029
C2  - 20603
SP  - 1-7
TI  - Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune  disease.
JO  - J. Nat. Med.
PY  - 2002
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Röcken, M.*
AU  - Hültner, L.
C1  - 21970
C2  - 20494
SP  - 668-670
TI  - Heavy functions for light chains.
JO  - J. Nat. Med.
VL  - 8
PY  - 2002
SN  - 1340-3443
ER  - 

TY  - JOUR
AU  - Calandra, T.*
AU  - Echtenacher, B.*
AU  - Roy, D. le*
AU  - Pugin, J.*
AU  - Metz, C.N.*
AU  - Hültner, L.
AU  - Heumann, D.*
AU  - Männel, D.*
AU  - Bucala, R.*
AU  - Glauser, M.P.*
C1  - 21259
C2  - 19370
SP  - 164-170
TI  - Protection from septic shock by neutralization of macrophage migration inhibitory factor.
JO  - J. Nat. Med.
VL  - 6
PY  - 2000
SN  - 1340-3443
ER  -