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  • 1
    Online Resource
    Online Resource
    PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Neurology Vol. 268, No. 4 ( 2021-04), p. 1304-1315
    Details
    In: Journal of Neurology, Springer Science and Business Media LLC, Vol. 268, No. 4 ( 2021-04), p. 1304-1315
    Abstract: In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in—easily accessible—peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions.
    Type of Medium: Online Resource
    ISSN: 0340-5354 , 1432-1459
    URL: Article
    DOI: 10.1007/s00415-020-10274-y
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1421299-7
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  • 2
    Online Resource
    Online Resource
    Chlorin Index: A new parameter for organic matter freshness in sediments : CHLORIN INDEX
    American Geophysical Union (AGU) ; 2005
    In:  Geochemistry, Geophysics, Geosystems Vol. 6, No. 3 ( 2005-03), p. n/a-n/a
    Details
    In: Geochemistry, Geophysics, Geosystems, American Geophysical Union (AGU), Vol. 6, No. 3 ( 2005-03), p. n/a-n/a
    Type of Medium: Online Resource
    ISSN: 1525-2027
    URL: Article
    DOI: 10.1029/2004GC000837
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 2005
    detail.hit.zdb_id: 2027201-7
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  • 3
    Online Resource
    Online Resource
    Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy
    American Society of Clinical Oncology (ASCO) ; 2003
    In:  Journal of Clinical Oncology Vol. 21, No. 24 ( 2003-12-15), p. 4489-4495
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 21, No. 24 ( 2003-12-15), p. 4489-4495
    Abstract: Purpose: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)–based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. Results: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). Conclusion: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2003.04.056
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2003
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Nitrogen isotope effects induced by anammox bacteria
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 47 ( 2013-11-19), p. 18994-18999
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 47 ( 2013-11-19), p. 18994-18999
    Abstract: Nitrogen (N) isotope ratios ( 15 N/ 14 N) provide integrative constraints on the N inventory of the modern ocean. Anaerobic ammonium oxidation (anammox), which converts ammonium and nitrite to dinitrogen gas (N 2 ) and nitrate, is an important fixed N sink in marine ecosystems. We studied the so far unknown N isotope effects of anammox in batch culture experiments. Anammox preferentially removes 14 N from the ammonium pool with an isotope effect of +23.5‰ to +29.1‰, depending on factors controlling reversibility. The N isotope effects during the conversion of nitrite to N 2 and nitrate are ( i ) inverse kinetic N isotope fractionation associated with the oxidation of nitrite to nitrate (−31.1 ± 3.9‰), ( ii ) normal kinetic N isotope fractionation during the reduction of nitrite to N 2 (+16.0 ± 4.5‰), and ( iii ) an equilibrium N isotope effect between nitrate and nitrite (−60.5 ± 1.0‰), induced when anammox is exposed to environmental stress, leading to the superposition of N isotope exchange effects upon kinetic N isotope fractionation. Our findings indicate that anammox may be responsible for the unresolved large N isotope offsets between nitrate and nitrite in oceanic oxygen minimum zones. Irrespective of the extent of N isotope exchange between nitrate and nitrite, N removed from the combined nitrite and nitrate (NO x ) pool is depleted in 15 N relative to NO x . This net N isotope effect by anammox is superimposed on the N isotope fractionation by the co-occurring reduction of nitrate to nitrite in suboxic waters, possibly enhancing the overall N isotope effect for N loss from oxygen minimum zones.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1310488110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Twenty-year follow-up of a pilot/phase II trial on the Bonn protocol for primary CNS lymphoma
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Neurology Vol. 95, No. 23 ( 2020-12-08), p. e3138-e3144
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 95, No. 23 ( 2020-12-08), p. e3138-e3144
    Abstract: To determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years. Methods Sixty-five patients (median age 62 years, range 27–75; median Karnofsky performance score 70, range 20–90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation. Results Median follow-up for surviving patients was 19.6 years (17.5–23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9–5.9); for patients ≤60 years, 11.0 years (95% CI 4.8–17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years. Conclusion At a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL. Classification of evidence This work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000010949
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 6
    Online Resource
    Online Resource
    Polychemotherapy in patients with primary CNS lymphoma.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 3304-3304
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3304-3304
    Abstract: In primary CNS lymphoma (PCNSL) irradiation alone is no longer the primary treatment and combination with chemotherapy has significantly improved response and survival. However, patients treated with combined modality therapy suffer from significant neurotoxicity. Therefore, studies with chemotherapy alone have been carried out. We recently reported on a phase II multicenter trial to evaluate event-free survival, overall survival, response rate, response duration and toxicity of combination chemotherapy in patients with previously untreated PCNSL. 65 consecutive patients with histologically proven PCNSL received a total of 6 courses of combination chemotherapy with 3 different courses of chemotherapy. In patients with response these 3 cylces were repeated. The combination chemotherapy included high-dose methotrexate (MTX) (5g/m2, course 1,2,4,5) and cytarabine (ara-C) (3g/m2/d, d1-2, courses 3,6) combined with dexamethasone (courses 3–6), vinca alkaloids and ifosfamide alternating with cyclophosphamide. In addition, MTX, prednisolone and ara-C were applied via an Ommaya or Rickham reservoir in each course. The study population included 65 consecutive patients with a median age of 62 years with a range between 27 and 75. 62 patients are evaluable for response. There were 9% therapy-related deaths mainly due to neutropenic infections. Ommaya reservoir infections occurred in 12/64 (19%) and acute transient MTX related encephalopathy in 2 (subacute in 1) patients. The 5-year-survival of patients below 61 years was 75%, of patients of 61 years or older 17% (Pels H et al., J Clin Oncol21(24), 2003). The results for patients younger than 60 years could be superior to previously reported therapy regimes. The survival rates for patients above 60 years are comparable to those reported for combined radiochemotherapy. However, in contrast to radiochemotherapy permanent treatment-associated neurotoxicity is infrequent. Based on these data we constructed a follow-up trial. Patients below the age of 61 are treated as in the antecedent protocol without intraventricular therapy. Patients above 60 are treated in a protocol modified by the addition of procarbazine in 2 cycles and a maintenance therapy with procarbazine. First results of this follow-up trial will be presented.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.3304.3304
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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