Cytosolic Ku70 regulates Bax-mediated cell death.

The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax-dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric. Interestingly, there is no free or monomeric Ku70 in the cytosol; most cytosolic Ku70 is in complex with other factors forming several high molecular weight complexes. A fraction of cytosolic Ku70 also binds to cytosolic Ku80, Ku70's binding partner in the nucleus. Ku70 may not be a survival factor in some cell types (Ku70-depletion less sensitive) because Ku70 depletion does not affect survival of these cells. These results indicate that, in addition to Ku70 acetylation, other factors may be involved in regulating Ku70-Bax binding in the Ku70-depletion less sensitive cells because Ku70 acetylation in these cells is not sufficient to dissociate Bax from Ku70 or to activate Bax.

Using Outcome Measures in Daily Practice: Development and Evaluation of an Implementation Strategy for Physiotherapists in the Netherlands.

PURPOSE: To describe the development of an educational programme for physiotherapists in the Netherlands, two toolkits of measurement instruments, and the evaluation of an implementation strategy. METHOD: The study used a controlled pre- and post-measurement design. A tailored educational programme for the use of outcome measures was developed that consisted of four training sessions and two toolkits of measurement instruments. Of 366 invited physiotherapists, 265 followed the educational programme (response rate 72.4%), and 235 randomly chosen control physiotherapists did not (28% response rate). The outcomes measured were participants' general attitude toward measurement instruments, their ability to choose measurement instruments, their use of measurement instruments, the applicability of the educational programme, and the changes in physiotherapy practice achieved as a result of the programme. RESULTS: Consistent (not occasional) use of measurement instruments increased from 26% to 41% in the intervention group; in the control group, use remained almost the same (45% vs 48%). Difficulty in choosing an appropriate measurement instrument decreased from 3.5 to 2.7 on a 5-point Likert-type scale. Finally, 91% of respondents found the educational programme useful, and 82% reported that it changed their physiotherapy practice. CONCLUSIONS: The educational programme and toolkits were useful and had a positive effect on physiotherapists' ability to choose among many possible outcome measures.

Objectif : Décrire l'élaboration d'un programme de formation pour des physiothérapeutes aux Pays-Bas, deux trousses d'instruments de mesure et l'évaluation d'une stratégie de mise en œuvre. Méthode : L'étude a utilisé un concept de mesure contrôlé de type avant-après. Un programme de formation personnalisé pour l'utilisation des mesures de résultats a été élaboré; il consistait en quatre séances de formation et deux trousses d'instruments de mesure. Des 366 physiothérapeutes invités, 265 ont suivi le programme de formation (taux de réponse de 72,4 %), en plus de 235 physiothérapeutes témoins sélectionnés de façon aléatoire qui ne l'ont pas fait (taux de réponse de 28 %). Les résultats mesurés étaient l'attitude générale des participants envers les instruments de mesure, leur capacité de choisir des instruments de mesure, leur utilisation des instruments, l'applicabilité du programme de formation et les changements entraînés dans la pratique de la physiothérapie grâce au programme. Résultats : L'utilisation constante (non occasionnelle) des instruments de mesure a augmenté de 26 % à 41 % dans le groupe d'intervention; dans le groupe témoin, l'utilisation est restée presque la même (45 % par rapport à 48 %). La difficulté de choisir un instrument de mesure approprié a diminué de 3,5 à 2,7 sur échelle Likert à 5 points. Finalement, 91 % des répondants ont trouvé le programme de formation utile et 82 % ont indiqué que ce programme a changé leur pratique de la physiothérapie. Conclusions : Le programme de formation et les trousses se sont avérés utiles et ont eu un effet positif sur la capacité des physiothérapeutes à faire un choix parmi les nombreuses possibilités de mesure de résultats.

CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma.

Ku70 was originally described as an autoantigen, but it also functions as a DNA repair protein in the nucleus and as an antiapoptotic protein by binding to Bax in the cytoplasm, blocking Bax-mediated cell death. In neuroblastoma (NB) cells, Ku70's binding with Bax is regulated by Ku70 acetylation such that increasing Ku70 acetylation results in Bax release, triggering cell death. Although regulating cytoplasmic Ku70 acetylation is important for cell survival, the role of nuclear Ku70 acetylation in DNA repair is unclear. Here, we showed that Ku70 acetylation in the nucleus is regulated by the CREB-binding protein (CBP), and that Ku70 acetylation plays an important role in DNA repair in NB cells. We treated NB cells with ionization radiation and measured DNA repair activity as well as Ku70 acetylation status. Cytoplasmic and nuclear Ku70 were acetylated after ionization radiation in NB cells. Interestingly, cytoplasmic Ku70 was redistributed to the nucleus following irradiation. Depleting CBP in NB cells results in reducing Ku70 acetylation and enhancing DNA repair activity in NB cells, suggesting nuclear Ku70 acetylation may have an inhibitory role in DNA repair. These results provide support for the hypothesis that enhancing Ku70 acetylation, through deacetylase inhibition, may potentiate the effect of ionization radiation in NB cells.

HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma.

Ku70 was first characterized as a nuclear factor that binds DNA double-strand breaks in nonhomolog end-joining DNA repair. However, recent studies have shown that Ku70 is also found in the cytoplasm and binds Bax, preventing Bax-induced cell death. We have shown that, in neuroblastoma cells, the binding between Ku70 and Bax depends on the acetylation status of Ku70, such that, when Ku70 is acetylated, Bax is released from Ku70, triggering cell death. Thus, to survive, in neuroblastoma cells, cytoplasmic Ku70 acetylation status is carefully regulated such that Ku70 is maintained in a deacetylated state, keeping Bax complexed with Ku70. We have shown that overexpression of CREB-binding protein (CBP), a known acetyltransferase that acetylates Ku70, releases Bax from Ku70, triggering apoptosis. Although we have shown that blocking deacetylase activity using non-type-specific inhibitors also triggers Ku70 acetylation and Bax-dependent cell death, the targets of these deacetylase inhibitors in neuroblastoma cells remain unknown. Here, we demonstrate that, in neuroblastoma cells, histone deacetylase 6 (HDAC6) binds Ku70 and Bax in the cytoplasm and that knocking down HDAC6 or using an HDAC6-specific inhibitor triggers Bax-dependent cell death. Our results show that HDAC6 regulates the interaction between Ku70 and Bax in neuroblastoma cells and may be a therapeutic target in this pediatric solid tumor.

Current use and barriers and facilitators for implementation of standardised measures in physical therapy in the Netherlands.

BACKGROUND: In many countries, the need for physical therapists to use standardised measures has been recognised and is recommended in clinical practice guidelines. Research has shown a lack of clinimetric knowledge and clinical application of measurement instruments in daily practice may hamper implementation of these guidelines. OBJECTIVES: The aims of our study were a) to investigate the current use of measurement instruments by Dutch physical therapists; b) to investigate the facilitators and barriers in using measurement instruments. METHODS: To get a complete and valid overview of relevant barriers and facilitators, different methods of data collection were used. We conducted a literature search, semi-structured interviews with 20 physical therapists and an online survey. RESULTS: Facilitators are the fact that most therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. The most important barriers to the use of measurement instruments included physical therapists' competence and problems in changing behaviour, practice organisation (no room; no time) and the unavailability and feasibility of measurement instruments. Furthermore, physical therapists indicated the need to have a core set of measurement instruments with a short user's instruction on application, scoring and interpretation. CONCLUSIONS: The main barriers are on the level of the physical therapist (lack of knowledge; not focusing on the use of outcome measures) and organisation (lack of time; availability; lack of management support).There seems to be a disparity between what physical therapists say and what they do. The majority of participating physical therapists indicated a positive attitude and were convinced of the advantages of the use of measurement instruments. However, the main problem for physical therapists is when to use which instrument for what patient (lack of knowledge). Furthermore, physical therapists indicated a need to compile a core set of measurement instruments with instructions concerning application, scoring and interpretation. Based on the identified factors, a number of strategies will be developed and evaluated in future studies.

CLU blocks HDACI-mediated killing of neuroblastoma.

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.

Effects of a high-intensity task-oriented training on gait performance early after stroke: a pilot study.

OBJECTIVE: To investigate the feasibility and the effects on gait of a high intensity task-oriented training, incorporating a high cardiovascular workload and large number of repetitions, in patients with subacute stroke, when compared to a low intensity physiotherapy-programme. DESIGN AND SUBJECTS: Randomized controlled clinical trial: Forty-four patients with stroke were recruited at 2 to 8 weeks after stroke onset. MEASURES: Maximal gait speed assessed with the 10-metre timed walking test (10MTWT), walking capacity assessed with the six-minute walk test (6MWT). Control of standing balance assessed with the Berg Balance Scale and the Functional Reach test. Group differences were analysed using a Mann-Whitney U-test. RESULTS: Between-group analysis showed a statistically significant difference in favour of the high intensity task-oriented training in performance on the 10MTWT (Z = -2.13, P = 0.03) and the 6MWT (Z = -2.26, P = 0.02). No between-group difference were found for the Berg Balance Scale (Z = -0.07, P = 0.45) and the Functional Reach test (Z = -0.21, P = 0.84). CONCLUSION: A high-intensity task-oriented training programme designed to improve hemiplegic gait and physical fitness was feasible in the present study and the effectiveness exceeds a low intensity physiotherapy-programme in terms of gait speed and walking capacity in patients with subacute stroke. In a future study, it seems appropriate to additionally use measures to evaluate physical fitness and energy expenditure while walking.

Outcome measures in physiotherapy management of patients with stroke: a survey into self-reported use, and barriers to and facilitators for use.

UNLABELLED: OBJECTIVE. To investigate physiotherapists' self-reported use of outcome measures as recommended in the Dutch Clinical Practice Guideline on Physiotherapy Management of Patients with Stroke (CPGPS) and to assess perceived barriers to and facilitators for the use of outcome measures in everyday practice. METHOD: A 41-item survey, including the barriers and facilitators questionnaire (BFQ), was sent by post to 400 physiotherapists in each of the following settings in the Netherlands: acute care hospitals (ACH; n = 100), rehabilitation centres (RC; n = 100), nursing homes (NH; n = 100) and private physiotherapy practices (PPP; n = 100). RESULTS: One hundred and eighty-nine physiotherapists returned the survey (47%; ACH, n = 57; RC, n = 67; NH, n = 26 and PPP, n = 39) and the surveys of 167 physiotherapists involved in stroke settings were analysed. These physiotherapists reported regularly using three (median; range 0-7) of the seven recommended outcome measures, with those working in RC or ACH reporting a significantly higher use than their colleagues in PPP (4 vs. 0 and 3 vs. 0; p < 0.001 and p = 0.02, respectively). The BFQ revealed that there were setting-specific facilitators, such as 'a positive attitude towards outcome measures' (as mentioned by 93% of the physiotherapists) and 'acquaintance with outcome measures' (90%), and barriers such as 'changing routines' (32%), 'time investment' (29%) and 'financial compensation' (21%). CONCLUSION: Despite an almost uniformly positive attitude, physiotherapists infrequently use the outcome measures recommended in the CPGPS. Robust setting-specific tailored implementation strategies based on the reported barriers and facilitators are needed.

Acetylation and deacetylation regulate CCAAT/enhancer binding protein beta at K39 in mediating gene transcription.

The transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) contains multiple acetylation sites, including lysine (K) 39. Mutation of C/EBPbeta at K39, an acetylation site in the transcriptional activation domain, impairs transcription of C/EBPbeta target genes in a dominant-negative fashion. Further, K39 of C/EBPbeta can be deacetylated by HDAC1, and HDAC1 may decrease C/EBPbeta-mediated transcription, suggesting that acetylation of C/EBPbeta at K39 is dynamically regulated in mediating gene transcription. Acetylation of endogenous C/EBPbeta at K39 is detected in adipose tissue, and also occurs in 3T3-L1 cells undergoing adipocyte conversion. In addition, mutation of K39 in C/EBPbeta impairs activation of its target genes encoding C/EBPalpha and PPARgamma, essential mediators of adipogenesis, as well as adipocyte genes for leptin and Glut4. These findings suggest that acetylation of C/EBPbeta at K39 is an important and dynamic regulatory event that contributes to its ability to transactivate target genes, including those associated with adipogenesis and adipocyte function.

CREB-binding protein is a mediator of neuroblastoma cell death induced by the histone deacetylase inhibitor trichostatin A.

The cytotoxic mechanism of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) was explored in a neuroblastoma (NB) model. TSA induces cell death in neuroblastic-type NB cells by increasing the acetylation of Ku70, a Bax-binding protein. Ku70 acetylation causes Bax release and activation, triggering cell death. This response to TSA depends on the CREB-binding protein (CBP) acetylating Ku70. TSA-induced cell death response correlates with CBP expression. In stromaltype NB cell lines with low levels of CBP and relative resistance to TSA, increasing CBP expression disrupts Bax-Ku70 binding and sensitizes them to TSA. Reducing CBP expression in neuroblastic cell types causes resistance. Cytotoxic response to TSA is Bax-dependent. Interestingly, depleting NB cells of Ku70 also triggers Bax-dependent cell death, suggesting that conditions that leave Bax unbound to Ku70 result in cell death. We also show that CBP, Ku70, and Bax are expressed in human NB tumors and that CBP expression varies across cell types comprising these tumors, with the highest expression observed in neuroblastic elements. Together, these results demonstrate that CBP, Bax, and Ku70 contribute to a therapeutic response to TSA against NB and identify the possibility of using these proteins to predict clinical responsiveness to HDACI treatment.

Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-kappaB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Paratonia: a Delphi procedure for consensus definition.

BACKGROUND AND PURPOSE: Paratonia is a motor problem that develops during the course of dementia. Definitions of paratonia used in the literature differ considerably, which has clinical implications and may lead to an undesirable heterogeneity in study populations. For this reason, we initiated a Delphi procedure with known experts in the field to establish an operational consensus definition of paratonia. METHODS: The Delphi procedure involved an anonymous and multistage approach presented as a questionnaire, with each stage building on the results of the previous one in order to reach consensus on the definition of paratonia. RESULTS: Eight of 17 experts agreed to participate in the study. After 4 rounds, the participants reached consensus on the following definition: paratonia is a form of hypertonia with an involuntary variable resistance during passive movement. The nature of paratonia may change with progression of dementia (eg, from active assistance (aka Mitgehen) to active resistance). The degree of resistance depends on the speed of movement (eg, slow > low resistance, fast > high resistance). The degree of paratonia is proportional to the amount of force applied and increases with progression of dementia. The resistance to passive movement is in any direction and there is no clasp-knife phenomenon. CONCLUSION: The Delphi procedure resulted in a comprehensive, operational definition of paratonia. Future research should focus on the reliability and validity of this definition.

Distribution of co-activators CBP and p300 during mouse oocyte and embryo development.

cAMP response element binding protein (CREB)-binding protein (CBP) and p300 are two structurally related transcriptional co-activators that activate expression of many eukaryotic genes. Current dogma would suggest that these transcriptional co-activators have similar mechanisms of transcription regulation. Studies of CBP or p300 homozygotic mouse mutants indicate that normal embryogenesis requires the existence of both factors. However, whether this is indicative of a dosage effect of these two proteins, or whether these proteins play different roles in mouse embryo development is not clear. Here we demonstrated that both factors are first found in the cytoplasm of oocytes within primordial follicles, and that they enter into the oocyte nucleus at different stages of oocyte growth, suggesting that they may play different roles in gene expression during oocyte growth and development. Consistent with this model, in the pre-implantation mouse embryos, from the two-cell stage to the blastocyst stage, the localizations of CBP and p300 are different, at times opposite, indicating that CBP and p300 also have different functions in early mouse embryogenesis.

Effects of visual feedback therapy on postural control in bilateral standing after stroke: a systematic review.

OBJECTIVE: To establish whether bilateral standing with visual feedback therapy after stroke improves postural control compared with conventional therapy and to evaluate the generalization of the effects of visual feedback therapy on gait and gait-related activities. DESIGN: A systematic review. METHODS: A computer-aided literature search was performed. Randomized controlled trials and controlled clinical trials, comparing visual feedback therapy with conventional balance treatments were included up to April 2005. The methodological quality of each study was assessed with the the Physiotherapy Evidence Database scale. Depending on existing heterogeneity, studies with a common variable of outcome were pooled by calculating the summary effect-sizes using fixed or random effects models. RESULTS: Eight out of 78 studies, presenting 214 subjects, were included for qualitative and quantitative analysis. The methodological quality ranged from 3 to 6 points. The meta-analysis demonstrated non-significant summary effect-sizes in favour of visual feedback therapy for weight distribution and postural sway, as well as balance and gait performance, and gait speed. CONCLUSION: The additional value of visual feedback therapy in bilateral standing compared with conventional therapy shows no statistically significant effects on symmetry of weight distribution between paretic and non-paretic leg, postural sway in bilateral standing, gait and gait-related activities. Visual feedback therapy should not be favoured over conventional therapy. The question remains as to exactly how asymmetry in weight distribution while standing is related to balance control in patients with stroke.

Signaling from p53 to NF-kappa B determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-kappaB (I-KB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.

Histone deacetylase inhibition induces apoptosis in neuroblastoma.

Histone deacetylase inhibitors constitute a promising new treatment for cancer due to their novel site of action and low toxicity. Almost all histone deacetylase inhibitors currently in clinical development have anti-proliferate activities against cells in cultures, and specifically cause cell cycle arrest, differentiation and apoptosis. Interestingly, despite their rapid advance into clinical use, the cellular responses leading to these effects remain unclear. We recently reported that histone deacetylase inhibitor treatment induces apoptosis of neuroblastoma cells by increasing the acetylation of Ku70 in the cytoplasm, resulting in the release of Bax from Ku70. Subsequently, Bax releases cytochrome c from mitochondria causing apoptosis. Here we will discuss these findings and the implications of our model for the further clinical development of histone deacetylase inhibitors in the treatment of cancer.

SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx.

Small ubiquitin-like modifier (SUMO) modification is emerging as an important control in transcription regulation. Here, we show that CREB-binding protein (CBP), a versatile transcriptional coactivator for numerous transcription factors in response to diverse signaling events, can be modified by SUMO-1 at lysine residues 999, 1034, and 1057 both in vitro and in vivo. Mutation of the SUMO acceptor lysine residues either individually or in combination enhanced CBP transcriptional activity, and expression of a SUMO protease SENP2 potentiated the transcriptional activity of CBP wild-type but not its sumoylation mutant, indicating that SUMO modification negatively regulates CBP transcriptional activity. Furthermore, we demonstrated an interaction of SUMO-1-modified CBP with the transcriptional corepressor Daxx and an essential role of Daxx in mediating SUMO-dependent transcriptional regulation of CBP through histone deacetylase 2 recruitment. Together, our findings indicate that SUMO modification and subsequent recruitment of Daxx represent a previously undescribed mechanism in modulating CBP transcriptional potential.

p300/CBP-associated factor drives DEK into interchromatin granule clusters.

DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.