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  • 1
    Online Resource
    Online Resource
    Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
    Springer Science and Business Media LLC ; 2023
    In:  Nature Communications Vol. 14, No. 1 ( 2023-11-15)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-11-15)
    Abstract: Mucosal-associated invariant T (MAIT) cells have been implicated in various inflammatory diseases of barrier organs, but so far, their role in kidney disease is unclear. Here we report that MAIT cells that recognize their prototypical ligand, the vitamin B2 intermediate 5-OP-RU presented by MR1, reside in human and mouse kidneys. Single cell RNAseq analysis reveals several intrarenal MAIT subsets, and one, carrying the genetic fingerprint of tissue-resident MAIT17 cells, is activated and expanded in a murine model of crescentic glomerulonephritis (cGN). An equivalent subset is also present in kidney biopsies of patients with anti-neutrophil cytoplasmatic antibody (ANCA)-associated cGN. MAIT cell-deficient MR1 mice show aggravated disease, whereas B6-MAIT CAST mice, harboring higher MAIT cell numbers, are protected from cGN. The expanded MAIT17 cells express anti-inflammatory mediators known to suppress cGN, such as CTLA-4, PD-1, and TGF-β. Interactome analysis predicts CXCR6 – CXCL16-mediated cross-talk with renal mononuclear phagocytes, known to drive cGN progression. In line, we find that cGN is aggravated upon CXCL16 blockade. Finally, we present an optimized 5-OP-RU synthesis method which we apply to attenuating cGN in mice. In summary, we propose that CXCR6 + MAIT cells might play a protective role in cGN, implicating them as a potential target for anti-inflammatory therapies.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-023-43269-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2553671-0
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  • 2
    Online Resource
    Online Resource
    GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 2 ( 2012-07-12), p. 395-403
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 2 ( 2012-07-12), p. 395-403
    Abstract: Cytogenetically normal acute myeloid leukemia (CN-AML) with biallelic CEBPA gene mutations (biCEPBA) represents a distinct disease entity with a favorable clinical outcome. So far, it is not known whether other genetic alterations cooperate with biCEBPA mutations during leukemogenesis. To identify additional mutations, we performed whole exome sequencing of 5 biCEBPA patients and detected somatic GATA2 zinc finger 1 (ZF1) mutations in 2 of 5 cases. Both GATA2 and CEBPA are transcription factors crucial for hematopoietic development. Inherited or acquired mutations in both genes have been associated with leukemogenesis. Further mutational screening detected novel GATA2 ZF1 mutations in 13 of 33 biCEBPA-positive CN-AML patients (13/33, 39.4%). No GATA2 mutations were found in 38 CN-AML patients with a monoallelic CEBPA mutation and in 89 CN-AML patients with wild-type CEBPA status. The presence of additional GATA2 mutations (n=10) did not significantly influence the clinical outcome of 26 biCEBPA-positive patients. In reporter gene assays, all tested GATA2 ZF1 mutants showed reduced capacity to enhance CEBPA-mediated activation of transcription, suggesting that the GATA2 ZF1 mutations may collaborate with biCEPBA mutations to deregulate target genes during malignant transformation. We thus provide evidence for a genetically distinct subgroup of CN-AML. The German AML cooperative group trials 1999 and 2008 are registered with the identifiers NCT00266136 and NCT01382147 at www.clinicaltrials.gov.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2012-01-403220
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods
    Springer Science and Business Media LLC ; 2020
    In:  Archives of Toxicology Vol. 94, No. 7 ( 2020-07), p. 2435-2461
    Details
    In: Archives of Toxicology, Springer Science and Business Media LLC, Vol. 94, No. 7 ( 2020-07), p. 2435-2461
    Abstract: Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of  〉  20 assays (with  〉  50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.
    Type of Medium: Online Resource
    ISSN: 0340-5761 , 1432-0738
    URL: Article
    DOI: 10.1007/s00204-020-02802-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 1458459-1
    SSG: 15,3
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  • 4
    Online Resource
    Online Resource
    A multicohort phase I study of ramucirumab (R) plus pembrolizumab (P): Interim safety and clinical activity in patients with urothelial carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 6_suppl ( 2017-02-20), p. 349-349
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 6_suppl ( 2017-02-20), p. 349-349
    Abstract: 349 Background: Hallmarks of tumor growth include immunosuppression and angiogenesis. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the urothelial tumor microenvironment. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02443324) enrolled patients (pts) with histologically confirmed transitional cell carcinoma of the urothelium (bladder, urethra, or renal pelvis) with prior progression on platinum-based systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. Eligible pts received R at 10 mg/kg on Day 1 given with P 200 mg on Day 1 q3W. PD-L1 was classified as positive (≥1%) or negative using the DAKO PD-L1 22C3 IHC pharmDx assay. Tumor response was assessed every 6 wks (RECIST v1.1). The primary objective was to assess safety and tolerability of adding R to P and preliminary efficacy will be assessed as a secondary objective. Results: As of 23-June-2016, 24 pts have been treated. The median age was 63 years, 58% were male, 50% had ECOG PS 0, 50% were PD-L1 positive and 67% received study treatment as third or subsequent regimen. Median duration of treatment was 2.14 mo and 2.37 mo for R and P, respectively. All grades treatment-related AEs (TRAE) occurred in 13 (54%) pts; TRAEs occurring in ≥10% of pts were fatigue (21%), nausea (17%), pyrexia (13%), elevated alanine aminotransferase (13%) and elevated aspartate aminotransferase (13%). Three (13%) pts had grade 3 TRAEs (hypertension, colitis, pulmonary embolism; n=1 each). No treatment-related grade 4 or 5 events occurred. Preliminary efficacy data showed two (8%) PD-L1 positive pts had confirmed partial response, 10 (42%) pts had stable disease, and 10 (42%) had progressive disease as their best response. Two (8%) pts were not evaluable for response at the time of analysis. Median duration of response has not been reached ( 〉 2.92 mo). Median PFS was 1.87 mo (95% CI, 1.28 to 3.38). Five (21%) pts remain on treatment. Conclusions: R plus P generated no new safety signals and demonstrated antitumor activity in pts with previously treated advanced urothelial carcinoma. Clinical trial information: NCT02443324.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.6_suppl.349
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1 , DNMT3A, WT1 and low expression of TLE4
    Wiley ; 2017
    In:  Genes, Chromosomes and Cancer Vol. 56, No. 1 ( 2017-01), p. 75-86
    Details
    In: Genes, Chromosomes and Cancer, Wiley, Vol. 56, No. 1 ( 2017-01), p. 75-86
    Abstract: Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations. We detected frequent mutations in NPM1 (10/26; 38%), DNMT3A (8/26; 31%), and WT1 (8/26; 31%) but only few FLT3 ‐ITDs (2/26; 8%). All mutations affecting NPM1 and DNMT3A were exclusively identified in patients with del(9q) as the sole abnormality and were significantly more frequent compared to 111 patients classified as intermediate‐II according to the European LeukemiaNet (10/14, 71% vs. 22/111, 20%; P   〈  0.001, 8/14, 57% vs. 26/111, 23%; P  = 0.02). Furthermore, we identified DNMT3B to be rarely but recurrently targeted by truncating mutations in AML. Gene expression analysis of 13 patients with del(9q) and 454 patients with normal karyotype or various cytogenetic aberrations showed significant down regulation of TLE4 in patients with del(9q) ( P  = 0.02). Interestingly, downregulation of TLE4 was not limited to AML with del(9q), potentially representing a common mechanism in AML pathogenesis. Our comprehensive genetic analysis of the del(9q) subgroup reveals a unique mutational profile with the frequency of DNMT3A mutations in the del(9q) only subset being the highest reported so far in AML, indicating oncogenic cooperativity. © 2016 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 1045-2257 , 1098-2264
    URL: Issue
    URL: Article
    DOI: 10.1002/gcc.v56.1
    DOI: 10.1002/gcc.22418
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1018988-9
    detail.hit.zdb_id: 1492641-6
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Clinical characteristics of 172 children and adolescents with body dysmorphic disorder
    Springer Science and Business Media LLC ; 2022
    In:  European Child & Adolescent Psychiatry Vol. 31, No. 1 ( 2022-01), p. 133-144
    Details
    In: European Child & Adolescent Psychiatry, Springer Science and Business Media LLC, Vol. 31, No. 1 ( 2022-01), p. 133-144
    Abstract: Body dysmorphic disorder (BDD) often starts in childhood, with most cases developing symptoms before age 18. Yet, BDD research has primarily focused on adults. We report the clinical characteristics of the world’s largest cohort of carefully diagnosed youths with BDD and focus on previously unexplored sex and age differences. We systematically collected clinical data from 172 young people with BDD consecutively referred to 2 specialist pediatric obsessive–compulsive and related disorders outpatient clinics in Stockholm, Sweden and in London, England. A series of clinician-, self-, and parent-reported measures were administered. The cohort consisted of 136 girls, 32 boys, and 4 transgender individuals (age range 10–19 years). The mean severity of BDD symptoms was in the moderate to severe range, with more than one third presenting with severe symptoms and more than half showing poor or absent insight/delusional beliefs. We observed high rates of current psychiatric comorbidity (71.5%), past or current self-harm (52.1%), suicide attempts (11.0%), current desire for cosmetic procedures (53.7%), and complete school dropout (32.4%). Compared to boys, girls had significantly more severe self-reported BDD symptoms, depression, suicidal thoughts, and self-harm. Compared to the younger participants (14 or younger), older participants had significantly more severe compulsions and were more likely to report a desire for conducting cosmetic procedures. Adolescent BDD can be a severe and disabling disorder associated with significant risks and substantial functional impairment. The clinical presentation of the disorder is largely similar across sexes and age groups, indicating the importance of early detection and treatment. More research is needed specifically focusing on boys and pre-pubertal individuals with BDD.
    Type of Medium: Online Resource
    ISSN: 1018-8827 , 1435-165X
    URL: Article
    DOI: 10.1007/s00787-020-01677-3
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1463026-6
    SSG: 5,2
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  • 7
    Online Resource
    Online Resource
    Quality of inter-hospital transportation in 431 transport survivor patients suffering from acute respiratory distress syndrome referred to specialist centers
    Springer Science and Business Media LLC ; 2018
    In:  Annals of Intensive Care Vol. 8, No. 1 ( 2018-12)
    Details
    In: Annals of Intensive Care, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-12)
    Abstract: The acute respiratory distress syndrome (ARDS) is a life-threatening condition. In special situations, these critically ill patients must be transferred to specialized centers for escalating treatment. The aim of this study was to evaluate the quality of inter-hospital transport (IHT) of ARDS patients. Methods We evaluated medical and organizational aspects of structural and procedural quality relating to IHT of patients with ARDS in a prospective nationwide ARDS study. The qualification of emergency staff, the organizational aspects and the occurrence of critical events during transport were analyzed. Results Out of 1234 ARDS patients, 431 (34.9%) were transported, and 52 of these (12.1%) treated with extracorporeal membrane oxygenation. 63.1% of transferred patients were male, median age was 54 years, and 26.8% of patients were obese. All patients were mechanically ventilated during IHT. Pressure-controlled ventilation was the preferred mode (92.1%). Median duration to organize the IHT was 165 min. Median distance for IHT was 58 km, and median duration of IHT 60 min. Forty-two patient-related and 8 technology-related critical events (11.6%, 50 of 431 patients) were observed. When a critical event occurred, the PaO 2 /FiO 2 ratio before transport was significant lower (68 vs. 80 mmHg, p  = 0.017). 69.8% of physicians and 86.7% of paramedics confirmed all transfer qualifications according to requirements of the German faculty guidelines (DIVI). Conclusions The transport of critically ill patients is associated with potential risks. In our study the rate of patient- and technology-related critical events was relatively low. A severe ARDS with a PaO 2 /FiO 2 ratio  〈  70 mmHg seems to be a risk factor for the appearance of critical events during IHT. The majority of transport staff was well qualified. Time span for organization of IHT was relatively short. ECMO is an option to transport patients with a severe ARDS safely to specialized centers. Trial registration NCT02637011 (ClinicalTrials.gov, Registered 15 December 2015, retrospectively registered)
    Type of Medium: Online Resource
    ISSN: 2110-5820
    URL: Article
    DOI: 10.1186/s13613-018-0357-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2617094-2
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  • 8
    Online Resource
    Online Resource
    Tracheostomy in patients with acute respiratory distress syndrome is not related to quality of life, symptoms of psychiatric disorders or return-to-work: the prospective DACAPO cohort study
    Springer Science and Business Media LLC ; 2020
    In:  Annals of Intensive Care Vol. 10, No. 1 ( 2020-12)
    Details
    In: Annals of Intensive Care, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-12)
    Abstract: Acute respiratory distress syndrome (ARDS) is a life-threatening condition that often requires prolonged mechanical ventilation. Tracheostomy is a common procedure with some risks, on the other hand with potential advantages over orotracheal intubation in critically ill patients. This study investigated the association of tracheostomy with health-related quality of life (HRQoL), symptoms of psychiatric disorders and return-to-work of ARDS survivors. Methods Data were collected in the context of the prospective observational German-wide DACAPO study. Clinical and demographic patient data and treatment characteristics were obtained from the participating intensive care units (ICU). HRQoL and return-to-work were assessed using patient-reported questionnaires 3, 6 and 12 months after ICU discharge. HRQoL was measured with the Physical and Mental Component Scale of the Short-Form 12 Questionnaire (PCS-12, MCS-12). The prevalence of psychiatric symptoms (depression and post-traumatic stress disorder [PTSD]) was assessed using the Patient Health Questionnaire-9 and the Post-Traumatic Stress Syndrome-14. Physician-diagnosed anxiety and obsessive–compulsive disorder were recorded by patient self-report in the follow-up questionnaires. The associations of tracheostomy with HRQoL, psychiatric symptoms and return-to-work after 12 months were investigated by means of multivariable linear and logistic regression models. Results Primary 877 ARDS patients (mean ± standard deviation: 54 ± 16 years, 68% male) survived and were discharged from ICU. Out of these patients, 478 (54.5%) were tracheotomised during ICU treatment. After 12 months, patient-reported outcomes could be analysed of 388 (44.2%) respondents, 205 with tracheostomy and 183 without. One year after ICU discharge, tracheostomy showed no significant association with physical or mental health-related quality of life (PCS-12: − 0.73 [− 3.96, 2.51]; MCS-12: − 0.71 [− 4.92, 3.49] ), symptoms of psychiatric disorders (depression: 0.10 [− 1.43, 1.64]; PTSD: 3.31 [− 1.81, 8.43] ; anxiety: 1.26 [0.41, 3.86]; obsessive–compulsive disorder: 0.59 [0.05, 6.68] ) or return-to-work (0.71 [0.31, 1.64]) in the multivariable analysis (OR [95%-CI] ). Conclusions Up to 1 year after ICU discharge, neither HRQoL nor symptoms of psychiatric disorders nor return-to-work was affected by tracheostomy. Trial registration NCT02637011 (ClinicalTrials.gov, Registered 15 December 2015, retrospectively registered)
    Type of Medium: Online Resource
    ISSN: 2110-5820
    URL: Article
    DOI: 10.1186/s13613-020-00671-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2617094-2
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  • 9
    Online Resource
    Online Resource
    THEORIE UND METHODEN DER GESCHICHTSWISSENSCHAFT
    Peter Lang, International Academic Publishers ; 2017
    In:  Neue Politische Literatur Vol. 2017, No. 2 ( 2017-07-01), p. 305-396
    Details
    In: Neue Politische Literatur, Peter Lang, International Academic Publishers, Vol. 2017, No. 2 ( 2017-07-01), p. 305-396
    Type of Medium: Online Resource
    ISSN: 0028-3320
    URL: Article
    DOI: 10.3726/NPL2017-2_305
    RVK:
    MB 1500
    RVK:
    MA 1000
    Language: English
    Publisher: Peter Lang, International Academic Publishers
    Publication Date: 2017
    detail.hit.zdb_id: 3402-2
    detail.hit.zdb_id: 2053021-3
    SSG: 3,6
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  • 10
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    Online Resource
    Allelic Imbalance of Recurrently Mutated Genes in Acute Myeloid Leukaemia
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-08-13)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-08-13)
    Abstract: The patho-mechanism of somatic driver mutations in cancer usually involves transcription, but the proportion of mutations and wild-type alleles transcribed from DNA to RNA is largely unknown. We systematically compared the variant allele frequencies of recurrently mutated genes in DNA and RNA sequencing data of 246 acute myeloid leukaemia (AML) patients. We observed that 95% of all detected variants were transcribed while the rest were not detectable in RNA sequencing with a minimum read-depth cut-off (10x). Our analysis focusing on 11 genes harbouring recurring mutations demonstrated allelic imbalance (AI) in most patients. GATA2 , RUNX1 , TET2 , SRSF2 , IDH2 , PTPN11 , WT1 , NPM1 and CEBPA showed significant AIs. While the effect size was small in general, GATA2 exhibited the largest allelic imbalance. By pooling heterogeneous data from three independent AML cohorts with paired DNA and RNA sequencing (N = 253), we could validate the preferential transcription of GATA2 -mutated alleles. Differential expression analysis of the genes with significant AI showed no significant differential gene and isoform expression for the mutated genes, between mutated and wild-type patients. In conclusion, our analyses identified AI in nine out of eleven recurrently mutated genes. AI might be a common phenomenon in AML which potentially contributes to leukaemogenesis.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-48167-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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