| 1. |
- Claussnitzer, Melina, et al.
(author)
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Leveraging cross-species transcription factor binding site patterns: from diabetes risk Loci to disease mechanisms.
- 2014
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 156:1-2, s. 343-358
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
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| 2. |
- Demichev, Vadim, et al.
(author)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Journal article (peer-reviewed)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 3. |
- Fassnacht, Martin, et al.
(author)
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Combination chemotherapy in advanced adrenocortical carcinoma
- 2012
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 366:23, s. 2189-2197
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Journal article (peer-reviewed)abstract
- BACKGROUND:Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment.METHODS:We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival.RESULTS:For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.CONCLUSIONS:Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival.
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| 4. |
- Harada, Nanase, et al.
(author)
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Starburst Energy Feedback Seen through HCO+/HOC+ Emission in NGC 253 from ALCHEMI
- 2021
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In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 923:1
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Journal article (peer-reviewed)abstract
- Molecular abundances are sensitive to the UV photon flux and cosmic-ray ionization rate. In starburst environments, the effects of high-energy photons and particles are expected to be stronger. We examine these astrochemical signatures through multiple transitions of HCO+ and its metastable isomer HOC+ in the center of the starburst galaxy NGC 253 using data from the Atacama Large Millimeter/submillimeter Array large program ALMA Comprehensive High-resolution Extragalactic Molecular inventory. The distribution of the HOC+(1-0) integrated intensity shows its association with "superbubbles," cavities created either by supernovae or expanding H ii regions. The observed HCO+/HOC+ abundance ratios are similar to 10-150, and the fractional abundance of HOC+ relative to H-2 is similar to 1.5 x 10(-11)-6 x 10(-10), which implies that the HOC+ abundance in the center of NGC 253 is significantly higher than in quiescent spiral arm dark clouds in the Galaxy and the Galactic center clouds. Comparison with chemical models implies either an interstellar radiation field of G (0) greater than or similar to 10(3) if the maximum visual extinction is greater than or similar to 5, or a cosmic-ray ionization rate of zeta greater than or similar to 10(-14) s(-1) (3-4 orders of magnitude higher than that within clouds in the Galactic spiral arms) to reproduce the observed results. From the difference in formation routes of HOC+, we propose that a low-excitation line of HOC+ traces cosmic-ray dominated regions, while high-excitation lines trace photodissociation regions. Our results suggest that the interstellar medium in the center of NGC 253 is significantly affected by energy input from UV photons and cosmic rays, sources of energy feedback.
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| 5. |
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| 6. |
- Kohshour, Mojtaba Oraki, et al.
(author)
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Comparative serum proteomic analysis of a selected protein panel in individuals with schizophrenia and bipolar disorder and the impact of genetic risk burden on serum proteomic profiles
- 2022
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In: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
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Journal article (peer-reviewed)abstract
- The diagnostic criteria for schizophrenia (SCZ) and bipolar disorder (BD) are based on clinical assessments of symptoms. In this pilot study, we applied high-throughput antibody-based protein profiling to serum samples of healthy controls and individuals with SCZ and BD with the aim of identifying differentially expressed proteins in these disorders. Moreover, we explored the influence of polygenic burden for SCZ and BD on the serum levels of these proteins. Serum samples from 113 individuals with SCZ and 125 with BD from the PsyCourse Study and from 44 healthy controls were analyzed by using a set of 155 antibodies in an antibody-based assay targeting a selected panel of 95 proteins. For the cases, genotyping and imputation were conducted for DNA samples and SCZ and BD polygenic risk scores (PRS) were calculated. Univariate linear and logistic models were used for association analyses. The comparison between SCZ and BD revealed two serum proteins that were significantly elevated in BD after multiple testing adjustment: "complement C9" and "Interleukin 1 Receptor Accessory Protein". Moreover, the first principal component of variance in the proteomics dataset differed significantly between SCZ and BD. After multiple testing correction, SCZ-PRS, BD-PRS, and SCZ-vs-BD-PRS were not significantly associated with the levels of the individual proteins or the values of the proteome principal components indicating no detectable genetic effects. Overall, our findings contribute to the evidence suggesting that the analysis of circulating proteins could lead to the identification of distinctive biomarkers for SCZ and BD. Our investigation warrants replication in large-scale studies to confirm these findings.
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| 7. |
- Ludwig, Monika, et al.
(author)
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Has gambling changed after major amendments of gambling regulations in Germany? A propensity score analysis
- 2012
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In: Journal of Behavioral Addictions. - 2062-5871 .- 2063-5303. ; 1:4, s. 151-161
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Journal article (peer-reviewed)abstract
- Aims: This study examined changes in general population gambling in the light of two major amendments of the German gambling regulation, the Fifth Amendment of the German Gambling Ordinance (AGO) for commercial amusement machines with prizes (AWP) and the State Treaty on Gambling (STG) for gambling activities subject to the state monopoly. Methods: Applying cross-sectional data from the 2006 and 2009 Epidemiological Survey of Substance Abuse (ESA), propensity-score-matched samples of 7,970 subjects and 3,624 12-month gamblers aged 18-64 years were used for analyses. Logistic regression was employed to examine changes in gambling controlling for possible confounding variables. Results: Overall participation in state gambling activities, participation in lotto as well as TV lottery decreased and gambling on Internet card games increased. No changes were found for any other gambling activity, 12-month prevalence of any gambling and pathological gambling. While weekly gambling declined, overall multiple gambling increased. Effects were similar in the total sample and among current gamblers. Conclusions: Prohibiting specific gambling activities, e. g., Internet gambling, seem to be insufficient approaches to change gambling behavior. Supply reduction might need to be enhanced by changes in game characteristics and implementation of early intervention measures. However, long-term consequences are uncertain and further monitoring is needed.
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| 8. |
- Längin, Matthias, et al.
(author)
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Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction after Orthotopic Pig-to-baboon Heart Transplantation
- 2023
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In: Transplantation. - 0041-1337. ; 107:12, s. 328-338
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Journal article (peer-reviewed)abstract
- Background. Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Methods. Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. Results. Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. Conclusions. After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.
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| 9. |
- Mohr, Sebastian, et al.
(author)
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Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemia.
- 2017
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In: Cancer cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 31:4
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Journal article (peer-reviewed)abstract
- The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression butis currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
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| 10. |
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