Oncogene-induced senescence (OIS) is a cellular tumor-suppressive mechanism present in several premalignant conditions. Here, we analyze the possible impact of OIS on malignant transformation in plasma cell disorders. Tumor samples from 125 patients with different disease stages were analyzed immunohistochemically for expression of senescence markers.
View Article and Find Full Text PDFSingle-molecule localization based super-resolution microscopy has revolutionized optical microscopy and routinely allows for resolving structural details down to a few nanometers. However, there exists a rather large discrepancy between lateral and axial localization accuracy, the latter typically three to five times worse than the former. Here, we use single-molecule metal-induced energy transfer (smMIET) to localize single molecules along the optical axis, and to measure their axial distance with an accuracy of 5 nm.
View Article and Find Full Text PDFThe spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC).
View Article and Find Full Text PDFAim: The purpose of the study was to isolate the sources of variations in the rates of response-contingent learning among young children with multiple disabilities and significant developmental delays randomly assigned to contrasting types of early childhood intervention.
Method: Multilevel, hierarchical linear growth curve modelling was used to analyze four different measures of child response-contingent learning where repeated child learning measures were nested within individual children (Level-1), children were nested within practitioners (Level-2), and practitioners were nested within the contrasting types of intervention (Level-3).
Results: Findings showed that sources of variations in rates of child response-contingent learning were associated almost entirely with type of intervention after the variance associated with differences in practitioners nested within groups were accounted for.
In recent years, DNA origami nanorulers for superresolution (SR) fluorescence microscopy have been developed from fundamental proof-of-principle experiments to commercially available test structures. The self-assembled nanostructures allow placing a defined number of fluorescent dye molecules in defined geometries in the nanometer range. Besides the unprecedented control over matter on the nanoscale, robust DNA origami nanorulers are reproducibly obtained in high yields.
View Article and Find Full Text PDFA promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases.
View Article and Find Full Text PDFWe investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA.
View Article and Find Full Text PDFInt J Med Inform
June 2018
Introduction: ALMANACH (ALgorithms for the MANagement of Acute CHildhood illnesses) is an electronic version of IMCI (Integrated Management of Childhood Illness) running on tablets. ALMANACH enhances its concept, it integrates well into health staff's daily consultation work and facilitates diagnosis and treatment. ALMANACH informs when to refer a child or to perform a rapid diagnostic test (RDT), recommends the right treatment dosage and synchronizes collected data real time with a Health Management Information System (DHIS2) for epidemiological evaluation and decision making.
View Article and Find Full Text PDFThe goal of this study was to investigate the effect of predictability on dual-task performance in a continuous tracking task. Participants practiced either informed (explicit group) or uninformed (implicit group) about a repeated segment in the curves they had to track. In Experiment 1 participants practices the tracking task only, dual-task performance was assessed after by combining the tracking task with an auditory reaction time task.
View Article and Find Full Text PDFThe widespread use of high-dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long-term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first-line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long-term survivors.
View Article and Find Full Text PDFEmbodied cognition frameworks suggest a direct link between sensorimotor experience and cognitive representations of concepts ( Shapiro, 2011 ). We examined whether this holds also true for concepts that cannot be directly perceived with the sensorimotor system (i.e.
View Article and Find Full Text PDFAlthough multitasking has been the subject of a large number of papers and experiments, the term task is still not well defined. In this opinion paper, we adopt the ideomotor perspective to define the term task and distinguish it from the terms goal and action. In our opinion, actions are movements executed by an actor to achieve a concrete goal.
View Article and Find Full Text PDFPerformance decrements in multitasking have been explained by limitations in cognitive capacity, either modelled as static structural bottlenecks or as the scarcity of overall cognitive resources that prevent humans, or at least restrict them, from processing two tasks at the same time. However, recent research has shown that individual differences, flexible resource allocation, and prioritization of tasks cannot be fully explained by these accounts. We argue that understanding human multitasking as a choice and examining multitasking performance from the perspective of judgment and decision-making (JDM), may complement current dual-task theories.
View Article and Find Full Text PDFIn sport visual feedback is often used to enhance performance, mostly neglecting the auditory modality. However, athletes produce natural sounds when they move (acoustic reafferences) which they perceive and use to control their movements. We examined the short- and long-term effects of a training intervention on a complex movement by using acoustic reafferences.
View Article and Find Full Text PDFIn multiple myeloma (MM), the synergy between immunomodulatory drugs (IMiDs) and monoclonal antibodies (MABs) has been demonstrated in several pivotal trials. However, disease refractory to either class of compounds remains a major therapeutic challenge. We here report on 3 heavily pretreated MM patients who were refractory to pomalidomide as well as to MABs against CD38 (daratumumab) or CD20 (rituximab), respectively, but who responded to retreatment with the same agents in combination.
View Article and Find Full Text PDFChromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown.
View Article and Find Full Text PDFHuman performance requires choosing what to do and how to do it. The goal of this theoretical contribution is to advance understanding of how the motor and cognitive components of choices are intertwined. From a holistic perspective I extend simple heuristics that have been tested in cognitive tasks to motor tasks, coining the term motor heuristics.
View Article and Find Full Text PDFHepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC), mainly through cirrhosis induction, spurring research for a deeper understanding of HCV versus host interactions in cirrhosis. The present study investigated crosstalks between HCV infection and UNC5A, a netrin-1 dependence receptor that is inactivated in cancer. UNC5A and HCV parameters were monitored in patients samples (n=550) as well as in in vitro.
View Article and Find Full Text PDFThe Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.
View Article and Find Full Text PDFLymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering.
View Article and Find Full Text PDFThe histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49-87) and the median number of prior therapies was 5 (range 2-17).
View Article and Find Full Text PDFCell activation and apoptosis lead to the formation of extracellular vesicles (EVs) such as exosomes or microvesicles (MVs). EVs have been shown to modulate immune responses; recently, MVs were described to carry microRNA (miRNA) and a role for MVs in the pathogenesis of autoimmune diseases has been discussed. Here we systematically characterized MVs and exosomes according to their release stimuli.
View Article and Find Full Text PDFPurpose: The 6th Heidelberg Myeloma Workshop was held on May 5th and 6th, 2017 in the lecture hall of the University Hospital Heidelberg.
Methods And Results: Main topics of the meeting were (1) biology and genomics of multiple myeloma, (2) diagnostics and prognostic factors, (3) role of immunotherapy in multiple myeloma, as well as (4) therapy of multiple myeloma-drugs and treatment strategies.
Conclusion: The landscape for the treatment of newly diagnosed and relapsed disease has significantly changed since the last Heidelberg Myeloma Workshop in 2015.
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