The balance of STAT5 and NFκB or IKAROS at enhancer networks dictates progenitor B cell survival, proliferation, and differentiation

University of Minnesota Ph.D. dissertation. August 2015. Major: Microbiology, Immunology and Cancer Biology. Advisor: Michael Farrar. 1 computer file (PDF); viii, 119 pages.B cell Acute Lymphoblastic Leukemia (B-ALL) arises from transformation of progenitor B cells. The transcription factor STAT5 plays a critical role in B-ALL, as high STAT5 activation is correlated with poor patient survival. How STAT5 mediates this effect is unclear. Previous studies suggested that STAT5 simply promotes the survival of progenitor B cells. However, other roles for STAT5 in B-ALL have not been explored. This study demonstrates that STAT5 activation drives leukemia in cooperation with defects in a linear signaling pathway emanating from the pre-BCR, including Blnk, Btk, Prkcb, Nfkb1, and Ikaros. Using microarray analysis and chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we demonstrate that STAT5 antagonizes NFκB and IKAROS by opposing regulation of shared target genes. High levels of STAT5 binding was enriched at super-enhancers that are typically associated with an opposing network of B cell transcription factors including PAX5, EBF1, PU.1, IRF4, or IKAROS. The antagonism between STAT5 and NFκB or IKAROS has direct clinical relevance as the balance between these transcription factors affects patient outcome. Patients with high ratios of active STAT5 to NFκB or IKAROS have more aggressive disease characterized by decreased survival. Our studies illustrate how modest perturbations in two opposing transcriptional programs have dramatic consequences for B cell transformation, and that the degree of antagonism between these transcriptional programs correlates with patient survival

Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype

Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis

Severity of anxiety and work-related outcomes of patients with anxiety disorders

Background : This study examined associations between anxiety and work-related outcomes in an anxiety disorders clinic population, examining both pretreatment links and the impact of anxiety change over 12 weeks of treatment on work outcomes. Four validated instruments were used to also allow examination of their psychometric properties, with the goal of improving measurement of work-related quality of life in this population. Methods : Newly enrolled adult patients seeking treatment in a university-based anxiety clinic were administered four work performance measures: Work Limitations Questionnaire (WLQ), Work Productivity and Activity Impairment Questionnaire (WPAI), Endicott Work Productivity Scale (EWPS), and Functional Status Questionnaire Work Performance Scale (WPS). Anxiety severity was determined using the Beck Anxiety Inventory (BAI). The Clinical Global Impressions, Global Improvement Scale (CGI-I) was completed by patients to evaluate symptom change at a 12-week follow-up. Two severity groups (minimal/mild vs. moderate/severe, based on baseline BAI score) were compared to each other on work measures. Results : Eighty-one patients provided complete baseline data. Anxiety severity groups did not differ in job type, time on job, job satisfaction, or job choice. Patients with greater anxiety generally showed lower work performance on all instruments. Job advancement was impaired for the moderate/severe group. The multi-item performance scales demonstrated better validity and internal consistency. The WLQ and the WPAI detected change with symptom improvement. Conclusion : Level of work performance was generally associated with severity of anxiety. Of the instruments tested, the WLQ and the WPAI questionnaire demonstrated acceptable validity and internal reliability. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64535/1/20624_ftp.pd

Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein

Several canonical translocations produce oncofusion genes that can initiate acute myeloid leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase (TurboID) in-frame with 3 favorable-risk AML oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11) and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their nuclear localization. However, CBFB::MYH11-TurboID-interacting proteins were largely cytoplasmic, probably because of an interaction of the MYH11 domain with several cytoplasmic myosin-related proteins. Using a variety of methods, we showed that the CBFB domain of CBFB::MYH11 sequesters RUNX1 in cytoplasmic aggregates; these findings were confirmed in primary human AML cells. Paradoxically, CBFB::MYH11 expression was associated with increased RUNX1/2 expression, suggesting the presence of a sensor for reduced functional RUNX1 protein, and a feedback loop that may attempt to compensate by increasing RUNX1/2 transcription. These findings may have broad implications for AML pathogenesis

Inercia emocional: la clave para comprender el proceso y los resultados de la psicoterapia

The processes underlying psychotherapeutic change have increasingly been emphasized in both research and clinical practice. Nonlinear dynamical systems theory (NDS) offers a transdisciplinary scientific approach to the study of these processes. This paper introduces the NDS concept of “emotional inertia”, the property of human emotion by which it retains its course so long as it is not acted upon by an external force, as a key to understanding moment-by-moment and also longer-term change processes within psychotherapy. A testable mathematical model of emotional inertia is presented that represents specific impacts of psychotherapeutic processes on emotional dynamics over time. Emotional trajectories in phase space, treatment energy, and the interaction between them are the essential elements of the model, and a detailed explanation is provided. Procedures for testing this model are described, such as by tracking the movement of emotion in phase space within and across therapy sessions, along with clinical implications of the model, which can potentially help to make more clear the complementary roles of therapeutic force, timing, and leverage.La importancia de los procesos subyacentes al cambio psicoterapéutico se ha ido enfatizando de forma creciente tanto en la investigación como en la práctica clínica. La Teoría de los sistemas dinámicos no lineales (TSD) permite una aproximación científica transdisciplinar para el estudio de dichos procesos. Este artículo presenta el concepto de “inercia emocional” derivado de la TSD, es decir, la propiedad de la emoción humana por la cual ésta sigue su curso mientras no incida en ella una fuerza externa, como clave para la comprensión de los procesos de cambio en la psicoterapia, tanto a corto como a largo plazo. Se presenta un modelo matemático contrastable que representa los impactos específicos de los procesos terapéuticos en la dinámica emocional a lo largo del tiempo. Los elementos esenciales del modelo son las trayectorias emocionales en el espacio de fase, la energía del tratamiento y la interacción entre ambos, y se ofrece una explicación detallada de los mismos. Se describen algunos procedimientos para contrastar el modelo, como monitorizar el movimiento emocional dentro y a través de las sesiones terapétuticas, así como sus posibles aplicaciones clínicas, que pueden potenciar el papel complementario de la fuerza y el momento de la intervención.Open Access funded by Asociación Española de Psicología Conductua

The Emergence of Translational Epidemiology: From Scientific Discovery to Population Health Impact

Recent emphasis on translational research (TR) is highlighting the role of epidemiology in translating scientific discoveries into population health impact. The authors present applications of epidemiology in TR through 4 phases designated T1–T4, illustrated by examples from human genomics. In T1, epidemiology explores the role of a basic scientific discovery (e.g., a disease risk factor or biomarker) in developing a “candidate application” for use in practice (e.g., a test used to guide interventions). In T2, epidemiology can help to evaluate the efficacy of a candidate application by using observational studies and randomized controlled trials. In T3, epidemiology can help to assess facilitators and barriers for uptake and implementation of candidate applications in practice. In T4, epidemiology can help to assess the impact of using candidate applications on population health outcomes. Epidemiology also has a leading role in knowledge synthesis, especially using quantitative methods (e.g., meta-analysis). To explore the emergence of TR in epidemiology, the authors compared articles published in selected issues of the Journal in 1999 and 2009. The proportion of articles identified as translational doubled from 16% (11/69) in 1999 to 33% (22/66) in 2009 (P = 0.02). Epidemiology is increasingly recognized as an important component of TR. By quantifying and integrating knowledge across disciplines, epidemiology provides crucial methods and tools for TR

Systematic review of measurement properties of questionnaires measuring somatization in primary care patients

Objective The aim of this review is to critically appraise the evidence on measurement properties of self-report questionnaires measuring somatization in adult primary care patients and to provide recommendations about which questionnaires are most useful for this purpose. Methods We assessed the methodological quality of included studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. To draw overall conclusions about the quality of the questionnaires, we conducted an evidence synthesis using predefined criteria for judging the measurement properties. Results We found 24 articles on 9 questionnaires. Studies on the Patient Health Questionnaire-15 (PHQ-15) and the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale prevailed and covered the broadest range of measurement properties. These questionnaires had the best internal consistency, test-retest reliability, structural validity, and construct validity. The PHQ-15 also had good criterion validity, whereas the 4DSQ somatization subscale was validated in several languages. The Bodily Distress Syndrome (BDS) checklist had good internal consistency and structural validity. Some evidence was found for good construct validity and criterion validity of the Physical Symptom Checklist (PSC-51) and good construct validity of the Symptom Check-List (SCL-90-R) somatization subscale. However, these three questionnaires were only studied in a small number of primary care studies. Conclusion Based on our findings, we recommend the use of either the PHQ-15 or 4DSQ somatization subscale for somatization in primary care. Other questionnaires, such as the BDS checklist, PSC-51 and the SCL-90-R somatization subscale show promising results but have not been studied extensively in primary care. © 2017 Elsevier Inc

Evidence-based pharmacotherapy of panic disorder: an update

The evidence-based pharmacotherapy of panic disorder continues to evolve. This paper reviews data on first-line pharmacotherapy, evidence for maintenance treatment, and management options for treatment-refractory patients. A Medline search of research on pharmacotherapy was undertaken, and a previous systematic review on the evidence-based pharmacotherapy of panic disorder was updated. Selective serotonin reuptake inhibitors remain a first-line pharmacotherapy of panic disorder, with the serotonin noradrenaline reuptake inhibitor venlafaxine also an acceptable early option. Temporary co-administration of benzodiazepines can be considered. Maintenance treatment reduces relapse rates, but further research to determine optimal duration is needed. For patients not responding to first-line agents several pharmacotherapy options are available, but there is a notable paucity of data on the optimal choice. © 2011 CINP