87 research outputs found
Exploiting Necroptosis for Therapy of Acute Lymphoblastic Leukemia
Get PDFEscape from chemotherapy-induced apoptosis is a hallmark of drug resistance in cancer. The recent identification of alternative programmed cell death pathways opens up for possibilities to circumvent the apoptotic blockade in drug resistant cancer and eliminate malignant cells. Indeed, we have recently shown that programmed necrosis, termed necroptosis, could be triggered to induce cell death in a subgroup of primary acute lymphoblastic leukemia (ALL) including highly refractory relapsed cases. In this review we focus on molecular mechanisms that drive drug resistance in ALL of childhood and discuss the potential of necroptosis activation to eradicate resistant disease
Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR
No full textAbstractMyosin regulatory light chain interacting protein (MIR) belongs to the ezrin, radixin, moesin (ERM) family of proteins involved in membrane cytoskeleton interactions and cell dynamics. MIR contains, beside the ERM domain, a RING zinc finger region. Immunocytochemistry showed that full-length MIR and the subdomains localize differently in cells. Cell fractionation revealed a similar distribution of full-length MIR and the RING domain protein in the Triton X-100-insoluble fraction. The neurite outgrowth inhibitory activity of MIR was attributed to the RING domain. MIR levels were controlled in the cells depending on the intact RING domain and proteasome activity. The dynamic regulation of MIR contributes to its effects on neurite outgrowth and cell motility
Mylip makes an Idol turn into regulation of LDL receptor
No full textHigh blood low-density-lipoprotein (LDL) cholesterol is a serious health problem among an increased number of patients in the Western world. Statins and other cholesterol lowering drugs have proven to be beneficial as therapy but are not optimal and show adverse effects in some patients. The LDL receptor is a crucial determinant of cholesterol metabolism in the body and amenable for drug interventions. Novel insights into the physiology of this receptor come from studies on the ubiquitination and degradation of LDL receptor by the ubiquitin ligase Mylip/Idol that is induced in cells by the nuclear receptor, LXR. This may open up new possibilities in the future to influence LDL receptor levels and cholesterol metabolism pharmacologically in various diseases.</p
A Hopeful Leap Forward by Multicentric Cooperation for Precision-Based Therapy for Very Resistant, Relapsed, or Refractory Childhood Leukemia
Get PDFPikman and colleagues report the results of a multicentric prospective clinical trial of the leukemia precision-based therapy (LEAP) consortium that combines identification of targetable lesions in drug-resistant childhood leukemia, tiered based on evidence for genomic lesions and drug target, validation of matching small-molecule targeted agents, and treatment of individual patients. The study demonstrates the impact of genomic information on disease classification, treatment guidance, and translational research, but also illustrates the challenges for target prediction and trial design for increasingly heterogeneous and smaller subgroups of patients.See related article by Pikman et al., p. 1424
Lo torcido ante todo lo recto
Get PDFResumen: Entrevista realizada por Zoltán Kulcsár-Szabó y Tamás Lénárt a Werner Hamacher en marzo de 2012 en Budapest, en la que este autor desgrana algunas de sus posiciones sobre la justicia lingüística. Se trata de una aportación en el ámbito de la teoría de la literatura, analizada desde un enfoque filosófico.El texto que aquí se presenta es la traducción de dicha entrevista al castellano y ha sido realizada por Niklas Bornhauser.Absatract: Interview conducted by Zoltán Kulcsár-Szabó and Tamás Lénárt to Werner Hamacher in March 2012 in Budapest, in which this author describes some of his positions on linguistic justice. It is a contribution in the field of literature theory, analyzed from a philosophical approach. The text presented here is the translation of said interview into Spanish and has been done by Niklas Bornhauser
Neuronal expression of the ERM-like protein MIR in rat brain and its localization to human chromosome 6
No full textThe ERM proteins, ezrin, radixin, and moesin, regulate cell motility by linking cortical F-actin to the plasma membrane in different cell types. Myosin regulatory light chain interacting protein (MIR) is a recently cloned ERM-like protein which was shown to be involved in neurite outgrowth. Here we have studied the occurrence and expression of MIR in rats during brain development. As Shown using Western blotting, MIR is present in different regions both in developing and adult brain, Immunohistochemistry and double labelling studies showed that MIR is localized especially to neurons in hippocampus and cerebellum. A search using the gene bank showed that the MIR gene localised to human chromosome 6 in the interval 6p22.3-23, the loss of which is characterized by mental retardation and different malformations in man. The presence of MIR in brain neurons during development together with its known effects on neurite outgrowth suggest an important function of the protein in the regulation of nerve cell motility and cytoskeletal interactions. (C) 2000 Academic Press.</p
Alternative technique for intrafemoral injection and bone marrow sampling in mouse transplant models
No full textCD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies.
Get PDFThe interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non-Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ-producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc-expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia
Tissue expression and actin binding of a novel N-terminal utrophin isoform
Get PDFUtrophin and dystrophin present two large proteins that link the intracellular actin cytoskeleton to the extracellular matrix via the C-terminal-associated protein complex. Here we describe a novel short N-terminal isoform of utrophin and its protein product in various rat tissues (N-utro, 62 kDa, amino acids 1-539, comprising the actin-binding domain plus the first two spectrin repeats). Using different N-terminal recombinant utrophin fragments, we show that actin binding exhibits pronounced negative cooperativity (affinity constants K(1) = ∼5 × 10(6) and K(2) = ∼1 × 10(5 )M(-1)) and is Ca(2+)-insensitive. Expression of the different fragments in COS7 cells and in myotubes indicates that the actin-binding domain alone binds exlusively to actin filaments. The recombinant N-utro analogue binds in vitro to actin and in the cells associates to the membranes. The results indicate that N-utro may be responsible for the anchoring of the cortical actin cytoskeleton to the membranes in muscle and other tissues
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