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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 23 October 2018, Vol.115(43), pp.E10022-E10031
    Description: SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that depletes cellular dNTPs in noncycling cells to promote genome stability and to inhibit retroviral and herpes viral replication. In addition to being substrates, cellular nucleotides also allosterically regulate SAMHD1 activity. Recently, it was shown that high expression levels of SAMHD1 are also correlated with significantly worse patient responses to nucleotide analog drugs important for treating a variety of cancers, including acute myeloid leukemia (AML). In this study, we used biochemical, structural, and cellular methods to examine the interactions of various cancer drugs with SAMHD1. We found that both the catalytic and the allosteric sites of SAMHD1 are sensitive to sugar modifications of the nucleotide analogs, with the allosteric site being significantly more restrictive. We crystallized cladribine-TP, clofarabine-TP, fludarabine-TP, vidarabine-TP, cytarabine-TP, and gemcitabine-TP in the catalytic pocket of SAMHD1. We found that all of these drugs are substrates of SAMHD1 and that the efficacy of most of these drugs is affected by SAMHD1 activity. Of the nucleotide analogs tested, only cladribine-TP with a deoxyribose sugar efficiently induced the catalytically active SAMHD1 tetramer. Together, these results establish a detailed framework for understanding the substrate specificity and allosteric activation of SAMHD1 with regard to nucleotide analogs, which can be used to improve current cancer and antiviral therapies.
    Keywords: Samhd1 ; Allosteric Regulation ; Dntpase ; Nucleotide Analog Drugs ; Substrate Selection ; Allosteric Site -- Drug Effects ; Catalytic Domain -- Drug Effects ; Drug Interactions -- Physiology ; Leukemia, Myeloid, Acute -- Metabolism ; SAM Domain and HD Domain-Containing Protein 1 -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: BBA - Molecular Cell Research, December 2012, Vol.1823(12), pp.2287-2296
    Description: Posttranslational modification of proteins by lysine acetylation regulates many biological processes ranging from signal transduction to chromatin compaction. Here we identify the acetyl-transferases CBP/p300, Tip60 and PCAF as new substrates for the ubiquitin E3 ligases SIAH1 and SIAH2. While CBP/p300 can undergo ubiquitin/proteasome-dependent degradation by SIAH1 and SIAH2, the two other acetyl-transferases are exclusively degraded by SIAH2. Accordingly, SIAH-deficient cells show enhanced protein acetylation, thus revealing SIAH proteins as indirect regulators of the cellular acetylation status. Functional experiments show that Tip60/PCAF-mediated acetylation of the tumor suppressor p53 is antagonized by the p53 target gene SIAH2 which mediates ubiquitin/proteasome-mediated degradation of both acetyl-transferases and consequently diminishes p53 acetylation and transcriptional activity. The p53 kinase HIPK2 mediates hierarchical phosphorylation of SIAH2 at 5 sites, which further boosts its activity as a ubiquitin E3 ligase for several substrates and therefore dampens the late p53 response. ► The ubiquitin E3 ligase Siah controls the stability of various acetyl-transferases. ► HIPK2-mediated phosphorylation of Siah2 regulates its ubiquitinating activity. ► Siah2 contributes to the downregulation of the p53 response.
    Keywords: Siah ; Ubiquitin E3 Ligase ; P53 ; Protein Acetylation ; Hipk2 ; Biology ; Chemistry
    ISSN: 0167-4889
    E-ISSN: 1879-2596
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  • 3
    Language: English
    In: International Brazilian Journal of Urology, Vol.43(2), pp.202-208
    Description: ABSTRACT Purpose Renal cell carcinoma (RCC) is a malignant tumor that metastasizes early, and patients often present with metastatic disease at the time of diagnosis. The aim of our evaluation was to assess the diagnostic and differential diagnostic relevance of metastatic renal cell carcinoma (RCC) with particular emphasis on head and neck manifestations in a large patient series. Patients and methods We retrospectively evaluated 671 consecutive patients with RCC who were treated in our urology practice between 2000 and 2013. Results Twenty-four months after diagnosis, 200/671 (30%) of RCC had metastasized. Distant metastases were found in 172 cases, with 22 metastases (3.3%) in the head and neck. Cervical and cranial metastases were located in the lymph nodes (n=13) and in the parotid and the thyroid gland, tongue, the forehead skin, skull, and paranasal sinuses (n=9). All head and neck metastases were treated by surgical excision, with 14 patients receiving adjuvant radiotherapy and 9 patients receiving chemotherapy or targeted therapy at some point during the course of the disease. Five patients (23%) survived. The mean time of survival from diagnosis of a head and neck metastasis was 38 months, the shortest period of observation being 12 months and the longest 83 months. Discussion and conclusion Our findings show that while RCC metastases are rarely found in the neck, their proportion among distantly metastasized RCC amounts to 13%. Therefore, the neck should be included in staging investigations for RCC with distant metastases, and surgical management of neck disease considered in case of resectable metastatic disease. Similarly, in patients presenting with a neck mass with no corresponding tumor of the head and neck, a primary tumor below the clavicle should be considered and the appropriate staging investigations initiated.
    Keywords: Carcinoma, Renal Cell ; Neoplasm Metastasis ; Carcinoma, Squamous Cell of Head and Neck [Supplementary Concept]
    ISSN: 1677-6119
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  • 4
    In: Schneider, Constanze and Oellerich, Thomas and Baldauf, Hanna-Mari and Schwarz, Sarah-Marie and Thomas, Dominique and Flick, Robert and Bohnenberger, Hanibal and Kaderali, Lars and Stegmann, Lena and Cremer, Anjali and Martin, Margarethe and Lohmeyer, Julian and Michaelis, Martin and Hornung, Veit and Schliemann, Christoph and Berdel, Wolfgang E and Hartmann, Wolfgang and Wardelmann, Eva and Comoglio, Federico and Hansmann, Martin-Leo and Yakunin, Alexander F and Geisslinger, Gerd and Ströbel, Philipp and Ferreirós, Nerea and Serve, Hubert and Keppler, Oliver T and Cinatl, Jindrich (2016) SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nature medicine, 23 (2). pp. 250-255.
    Description: The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 1078-8956
    Source: University of Kent
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  • 5
    In: Nature Medicine, 2016
    Description: The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells1. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking2, 3. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate4, 5. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs6, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity--through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles7, 8--potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.
    Keywords: Leukemia ; Chemotherapy ; Biomarkers ; Medical Prognosis ; Cytotoxicity;
    ISSN: 1078-8956
    E-ISSN: 1546-170X
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  • 6
    In: Nature Medicine, 2017, Vol.23(6), p.788
    Description: Corrigendum: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
    Keywords: Medicine ; Biology;
    ISSN: 1078-8956
    E-ISSN: 1546-170X
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  • 7
    Language: English
    In: Arthroscopy: The Journal of Arthroscopic and Related Surgery, June 1, 2006, Vol.22(6), p.680.e1-680.e4
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.arthro.2005.10.023 Byline: Eduard Buess, Constanze Schneider Keywords: SLAP lesion; SLAP repair; Portals; Shoulder arthroscopy Abstract: We present a simplified and cost-effective method for repair of a type II SLAP lesion that requires only 1 working portal in the rotator interval -- the lateral anterosuperior portal (LASP) -- which is about 3 cm more lateral than the standard ASP. The rotator cuff tendon or muscle are not violated when using this portal, which provides an unproblematic 30[degrees] angle for the drill hole. The biceps root can be firmly reattached anteriorly and posteriorly using 1 double-loaded absorbable bone anchor with a suture eyelet. The first stitch is performed using a straight suture hook to pierce the anterior biceps root from the front. A PDS utility suture helps to shuttle the braided suture in a retrograde manner through the labrum. We then tie a sliding knot seating solidly on top of the labrum. The second stitch is placed with a 45[degrees] curved suture hook allowing us to pierce the labrum posteriorly to the biceps from above. Again, a sliding knot will be seated on top of the posterior biceps root, pressing it firmly onto the previously abraded bone. The completed repair looks like a V and produces secure fixation of the biceps, thus eliminating the peel-back phenomenon. Author Affiliation: Orthopedic Department, Sonnenhof Clinic, Berne, Switzerland Article Note: (footnote) Cite this article as: Buess E, Schneider C. Simplified single-portal V-shaped SLAP repair. Arthroscopy 2006;22:680.e1-680.e4 [doi:10.1016/j.arthro.2005.10.023].
    ISSN: 0749-8063
    Source: Cengage Learning, Inc.
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  • 8
    In: Voges, Yvonne and Michaelis, Martin and Rothweiler, Florian and Schaller, Torsten and Schneider, Constanze and Politt, Katharina and Mernberger, Marco and Nist, Andrea and Stiewe, Thorsten and Wass, Mark N. and Rödel, Franz and Cinatl, Jindrich (2016) Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance. Cell death & disease, 7 (10). e2410.
    Description: Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.
    Keywords: RM Therapeutics. Pharmacology
    ISSN: 2041-4889
    Source: University of Kent
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  • 9
    Language: English
    In: Cell death & disease, 13 October 2016, Vol.7(10), pp.e2410
    Description: Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.
    Keywords: Drug Resistance, Neoplasm -- Drug Effects ; Imidazoles -- Pharmacology ; Inhibitor of Apoptosis Proteins -- Metabolism ; Naphthoquinones -- Pharmacology ; Neuroblastoma -- Metabolism
    E-ISSN: 2041-4889
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  • 10
    Language: English
    In: Arthroscopy: The Journal of Arthroscopic and Related Surgery, 2006, Vol.22(6), pp.680.e1-680.e4
    Description: We present a simplified and cost-effective method for repair of a type II SLAP lesion that requires only 1 working portal in the rotator interval—the lateral anterosuperior portal (LASP)—which is about 3 cm more lateral than the standard ASP. The rotator cuff tendon or muscle are not violated when using this portal, which provides an unproblematic 30° angle for the drill hole. The biceps root can be firmly reattached anteriorly and posteriorly using 1 double-loaded absorbable bone anchor with a suture eyelet. The first stitch is performed using a straight suture hook to pierce the anterior biceps root from the front. A PDS utility suture helps to shuttle the braided suture in a retrograde manner through the labrum. We then tie a sliding knot seating solidly on top of the labrum. The second stitch is placed with a 45° curved suture hook allowing us to pierce the labrum posteriorly to the biceps from above. Again, a sliding knot will be seated on top of the posterior biceps root, pressing it firmly onto the previously abraded bone. The completed repair looks like a V and produces secure fixation of the biceps, thus eliminating the peel-back phenomenon.
    Keywords: Slap Lesion ; Slap Repair ; Portals ; Shoulder Arthroscopy
    ISSN: 0749-8063
    E-ISSN: 1526-3231
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