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991.
Karoline V Gleixner Yüksel Filik Daniela Berger Christina Schewzik Gabriele Stefanzl Irina Sadovnik Lina Degenfeld-Schonburg Gregor Eisenwort Mathias Schneeweiss-Gleixner Konstantin Byrgazov Wolfgang R Sperr Jií Mayer Thomas Lion Peter Valent 《American journal of cancer research》2021,11(9):4470
Ponatinib is a tyrosine kinase inhibitor (TKI) directed against BCR-ABL1 which is successfully used in patients with BCR-ABL1 T315I+ chronic myeloid leukemia (CML). However, BCR-ABL1 compound mutations may develop during therapy in these patients and may lead to drug resistance. Asciminib is a novel drug capable of targeting most BCR-ABL1 mutant-forms, including BCR-ABL1T315I, but remains ineffective against most BCR-ABL1T315I+ compound mutation-bearing sub-clones. We demonstrate that asciminib synergizes with ponatinib in inducing growth-arrest and apoptosis in patient-derived CML cell lines and murine Ba/F3 cells harboring BCR-ABL1 T315I or T315I-including compound mutations. Asciminib and ponatinib also produced cooperative effects on CRKL phosphorylation in BCR-ABL1-transformed cells. The growth-inhibitory effects of the drug combination ‘asciminib+ponatinib’ was further enhanced by hydroxyurea (HU), a drug which has lately been described to suppresses the proliferation of BCR-ABL1 T315I+ CML cells. Cooperative drug effects were also observed in patient-derived CML cells. Most importantly, we were able to show that the combinations ‘asciminib+ponatinib’ and ‘asciminib+ponatinib+HU’ produce synergistic apoptosis-inducing effects in CD34+/CD38- CML stem cells obtained from patients with chronic phase CML or BCR-ABL1 T315I+ CML blast phase. Together, asciminib, ponatinib and HU synergize in producing anti-leukemic effects in multi-resistant CML cells, including cells harboring T315I+ BCR-ABL1 compound mutations and CML stem cells. The clinical efficacy of this TKI combination needs to be evaluated within the frame of upcoming clinical trials. 相似文献
992.
993.
Stefanie Abel Katharina Dressel Ruth Bitzer Dorothee Kümmerer Irina Mader Cornelius Weiller Walter Huber 《NeuroImage》2009,44(3):1113-1124
In picture–word interference paradigms, the picture naming process is influenced by an additional presentation of linguistic distractors. Naming response times (RTs) are speeded (facilitation) by associatively-related and phonologically-related words when compared to unrelated words, while they are slowed down by categorically-related words (inhibition), given that distractor onsets occur at appropriate stimulus onset asynchronies (SOAs). In the present study with healthy subjects, we for the first time integrated all four auditorily presented distractor types into a single paradigm at an SOA of ? 200 ms, in order to directly compare behavioral and neural interference effects between them. The behavioral study corroborated results of previous studies and revealed that associatively-related distractors speeded RTs even more than phonologically-related distractors, thereby becoming equally fast as naming without distractors. Distractors were assumed to specifically enhance activation of brain areas corresponding to processing stages as determined in a cognitive model of word production (Indefrey, P., Levelt, W.J.M., 2004. The spatial and temporal signatures of word production components. Cognition 92, 101–144.). Functional magnetic resonance imaging (fMRI) at 3 T revealed activation of left superior temporal gyrus exclusively for phonologically-related distractors, and activation of left or right lingual gyrus exclusively for associatively-related and categorically-related distractors, respectively. Moreover, phonologically-related distractors elicited phonological–phonetic networks, and both semantic distractors evoked areas associated with mental imagery, semantics, and episodic memory retrieval and associations. While processes involved in distractor inhibition (e.g., conflict/competition monitoring) and high articulatory demands were observed for categorically-related distractors, priming of articulatory planning was revealed for associatively-related distractors. We conclude that activations of neural networks as obtained by the fMRI interference paradigm can be predicted from a cognitive model. 相似文献
994.
Assia L Angelova Marc Aprahamian Ginette Balboni Henri-Jacques Delecluse Regina Feederle Irina Kiprianova Svitlana P Grekova Angel S Galabov Mathias Witzens-Harig Anthony D Ho Jean Rommelaere Zahari Raykov 《Molecular therapy》2009,17(7):1164-1172
The incidence of lymphomas developing in both immunocompetent and immunosuppressed patients continues to steadily increase worldwide. Current chemotherapy and immunotherapy approaches have several limitations, such as severe side toxicity and selection of resistant cell variants. Autonomous parvoviruses (PVs), in particular the rat parvovirus H-1PV, have emerged as promising anticancer agents. Although it is apathogenic in humans, H-1PV has been shown to infect and suppress various rat and human tumors in animal models. In this study, we demonstrate the capacity of H-1PV for efficiently killing, through necrosis, cell cultures originating from Burkitt''s lymphoma (BL), while sparing normal B lymphocytes. The cytotoxic effect was generally accompanied by a productive H-1PV infection. Remarkably, parvovirus-based monotherapy efficiently suppressed established BL at an advanced stage in a severe combined immunodeficient (SCID) mouse model of the disease. The data show for the first time that an oncolytic parvovirus deserves further consideration as a potential tool for the treatment of some non-Hodgkin B-cell lymphomas, including those resistant to apoptosis induction by rituximab. 相似文献
995.
996.
The Immunosuppressive Properties of the HIV Vpr Protein Are Linked to a Single Highly Conserved Residue, R90
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997.
Grill S Banzola I Li Y Rekhviashvili T Legler TJ Müller SP Zhong XY Hahn S Holzgreve W 《Archives of gynecology and obstetrics》2009,279(4):533-537
Purpose To examine the potential high throughput capability and efficiency of an automated DNA extraction system in combination with
mass spectrometry for the non-invasive determination of the foetal Rhesus D status.
Methods A total of 178 maternal plasma samples from RHD-negative pregnant women were examined, from which DNA was extracted using the automated Roche MagNA Pure™ system. Presence
of the foetal RHD gene was detected by PCR for RHD exon 7 and subsequent analysis using the Sequenom MassArray™ mass spectrometric system.
Results We determined that as little as 15 pg of RHD-positive genomic DNA could be detected in a background of 585 pg of RHD-negative genomic DNA. The analysis of the clinical samples yielded a sensitivity and specificity of 96.1 and 96.1%, respectively.
Conclusion Our study indicated that automated DNA extraction in combination with mass spectrometry permits the determination of foetal
Rhesus D genotype with an accuracy comparable to the current approaches using real-time PCR. 相似文献
998.
Pollard I 《Seminars in Fetal & Neonatal Medicine》2007,12(2):106-113
Epidemiological evidence suggests that an adverse prenatal environment can have profound long-term health consequences throughout postnatal life. This chapter discusses the underlying mechanisms implicated in the consumption of mood-altering recreational drugs and teratogenicity in the fetus. The way metabolic parameters in pregnancy influence the pharmacokinetic characteristics of drugs and alcohol and the developmental stage of neurotoxicity are reviewed. The general underlying mechanisms that link multifaceted interactions between drug characteristics, gene polymorphisms, dietary deficiencies, changed endocrine indices and fetal programming are outlined, with specific examples throughout the text. As developmental injury is of significant social concern, the final section questions whether society provides adequate support for making appropriate and informed lifestyle choices to alleviate preventable transgenerational harm. 相似文献
999.
1000.
de Vries MC Rodenburg RJ Morava E van Kaauwen EP ter Laak H Mullaart RA Snoeck IN van Hasselt PM Harding P van den Heuvel LP Smeitink JA 《European journal of pediatrics》2007,166(3):229-234
Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia
were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex
deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients
fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes
I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities
were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture
is not Alpers syndrome. 相似文献