Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML.

Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi.

Somatic gene mutations expose cytoplasmic DNA to co-opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromes.

NLRP3 inflammasome and IFN-stimulated gene (ISG) induction are key biological drivers of ineffective hematopoiesis and inflammation in myelodysplastic syndromes (MDSs). Gene mutations involving mRNA splicing and epigenetic regulatory pathways induce inflammasome activation and myeloid lineage skewing in MDSs through undefined mechanisms. Using immortalized murine hematopoietic stem and progenitor cells harboring these somatic gene mutations and primary MDS BM specimens, we showed accumulation of unresolved R-loops and micronuclei with concurrent activation of the cytosolic sensor cyclic GMP-AMP synthase.

Loneliness in Bereavement: Measurement Matters.

The role of loneliness in the bereavement experience has been reported as substantial, with the death of a close person leaving a considerable void in the life of the bereaved. Yet, there is lack of agreement about its precise role and, notably, whether loneliness should be included as a core symptom for diagnosis of grief complications. The ongoing threat of heightened social isolation due to the COVID-19 pandemic underlines the need to understand the impact of loneliness, and to accurately chart its prevalence, intensity, duration, and associated difficulties in the context of bereavement.

A systematic review of loneliness in bereavement: Current research and future directions.

Bereaved people suffer from loneliness and loneliness is associated with poor mental health. In this study, this topic is reviewed. An agenda is suggested for future research.

RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis.

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia.

TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia.

MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism and tumorigenesis. A variety of alterations drive expression in acute myeloid leukemia (AML) and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy-lysosome pathway.

CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.

Casitas B-lineage lymphoma (CBL) encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and nonreceptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10% to 20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein's E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood.

Effects of on Engraftment of Patient-derived Chronic-Myelomonocytic Leukemia Cells in NSGS Mice.

Modeling chronic myelomonocytic leukemia (CMML) in immunodeficient NSGS mice relies on unique human CMML specimens and consistent murine engraftment. Only anecdotal comments have thus far supported the notion that research data may be altered by , an opportunistic cutaneous pathogen of immunodeficient mice. disseminated by asymptomatic and clinically affected mice with hyperkeratotic dermatitis, resulting in resilient facility contamination and infectious recurrence.

Intrapatient functional clonality deconvoluted by coupling intracellular flow cytometry and next-generation sequencing in human leukemia.

The interplay between tumor heterogeneity and microenvironmental factors is a critical mechanism for clonal selection in leukemia. Evidence of unique clonal capacities to engraft within patient-derived xenograft (PDX) models suggests that intrapatient genetic architecture may be defined by functional differences at the clonal level. However, methods to detect functional differences assigned to genetically defined clones remain limited.

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγ background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML.

Speed and Lateral Inhibition of Stimulus Processing Contribute to Individual Differences in Stroop-Task Performance.

The Stroop task is a popular neuropsychological test that measures executive control. Strong Stroop interference is commonly interpreted in neuropsychology as a diagnostic marker of impairment in executive control, possibly reflecting executive dysfunction. However, popular models of the Stroop task indicate that several other aspects of color and word processing may also account for individual differences in the Stroop task, independent of executive control.

Synchronization as a biological, psychological and social mechanism to create common time: A theoretical frame and a single case study.

Synchronizing neural processes, mental activities, and social interactions is considered to be fundamental for the creation of temporal order on the personal and interpersonal level. Several different types of synchronization are distinguished, and for each of them examples are given: self-organized synchronizations on the neural level giving rise to pre-semantically defined time windows of some tens of milliseconds and of approximately 3 s; time windows that are created by synchronizing different neural representations, as for instance in aesthetic appreciations or moral judgments; and synchronization of biological rhythms with geophysical cycles, like the circadian clock with the 24-hr rhythm of day and night. For the latter type of synchronization, an experiment is described that shows the importance of social interactions for sharing or avoiding common time.

Is it the picture or is it the frame? An fMRI study on the neurobiology of framing effects.

Using functional magnetic resonance imaging (fMRI) we investigated whether a culturally defined context modulates the neurocognitive processing of artworks. We presented subjects with paintings from the Museum of Modern Art (MoMA) in New York, and labeled them as being either from the MoMA or from an adult education center. Irrespective of aesthetic appreciation, we found higher neural activation in the left precuneus, superior and inferior parietal cortex for the MoMA condition compared to the control label condition.

Neurofunctional correlates of environmental cognition: an FMRI study with images from episodic memory.

This study capitalizes on individual episodic memories to investigate the question, how dif-ferent environments affect us on a neural level. Instead of using predefined environmental stimuli, this study relied on individual representations of beauty and pleasure. Drawing upon episodic memories we conducted two experiments.

Tailored cognitive-behavioural therapy and exercise training improves the physical fitness of patients with fibromyalgia.

Objectives: Patients with fibromyalgia have diminished levels of physical fitness, which may lead to functional disability and exacerbating complaints. Multidisciplinary treatment comprising cognitive-behavioural therapy (CBT) and exercise training has been shown to be effective in improving physical fitness. However, due to the high drop-out rates and large variability in patients' functioning, it was proposed that a tailored treatment approach might yield more promising treatment outcomes.

Cognitive-behavioral mechanisms in a pain-avoidance and a pain-persistence treatment for high-risk fibromyalgia patients.

Objective: The heterogeneity of cognitive-behavioral patterns in patients with fibromyalgia (FM) has been proposed to underlie the variability in treatment outcomes. It has previously been shown that pain-avoidance and pain-persistence treatments tailored to the patient's pattern are effective in improving physical and psychological functioning and overall impact in high-risk patients with heightened psychological distress. In the present study, the cognitive-behavioral effects of these treatments were evaluated to provide insight into the main proposed mechanisms, specifically pain-avoidance behaviors and activity pacing in the pain-avoidance and pain-persistence treatments, respectively.

The effect of experience on children's ability to show response and place learning.

From a developmental perspective, it has been reasoned that over the course of development children make differential use of available landmarks in the surroundings to orient in space. The present study examined whether children can learn to apply different spatial strategies, focusing on different landmark cues. Children aged 7 and 10 years were tested on an object-location memory task in which they learned a location relative to a direct cue or to indirect cues.

Paediatric palliative home care by general paediatricians: a multimethod study on perceived barriers and incentives.

Background: Non-specialist palliative care, as it is delivered by general practitioners, is a basic component of a comprehensive palliative care infrastructure for adult patients with progressive and far advanced disease. Currently palliative care for children and adolescents is recognized as a distinct entity of care, requiring networks of service providers across different settings, including paediatricians working in general practice. In Germany, the medical home care for children and adolescents is to a large extent delivered by general paediatricians working in their own practice.

Tailored cognitive-behavioral therapy and exercise training for high-risk patients with fibromyalgia.

Objective: The treatment of patients with fibromyalgia (FM), a high-prevalence chronic pain condition with a high impact on both patients and society, poses a great challenge to clinicians due to a lack of effective treatments. In view of the large individual variability in outcome, selecting patients at risk of long-term dysfunction and offering tailored treatment may be promising for beneficial treatment effects.

Methods: High-risk patients were selected and classified into 2 groups (pain-persistence and pain-avoidance groups) and subsequently randomized in groups to either a treatment condition (TC) or a waiting list control condition (WLC).

Plasma markers of coagulation and endothelial activation in Fabry disease: impact of renal impairment.

Background: In Fabry disease, storage of globotriaosylceramide (Gb3) in arterial walls is one of the main pathogenetic factors that are thought to underlie the clinical manifestations of the disease. Abnormalities of the vessel wall, haemodynamics and pro- and anticoagulant factors may play a role, though the exact pathophysiology is incompletely understood. In this study, we try to clarify inconsistencies regarding coagulation activation, fibrinolysis, platelet activation and endothelial activation in 36 patients with Fabry disease.

Screening for pain-persistence and pain-avoidance patterns in fibromyalgia.

Background: The heterogeneity of patients regarding pain-related cognitive-behavioral mechanisms, such as pain-avoidance and pain-persistence patterns, has been proposed to underlie varying treatment outcomes in patients with fibromyalgia (FM).

Purpose: To investigate the validity of a screening instrument to discriminate between pain-persistence and pain-avoidance patterns in FM.

Method: In a three-part study, a self-reported screening instrument that assesses pain-avoidance behavior was used to distinguish patients with pain-persistence and pain-avoidance patterns.

Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3.

Two different enzyme preparations are used for the treatment of Fabry disease patients, agalsidase alpha (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme). Therapeutic efficacy of both products has been variable probably due to differences in gender, severity, age and other patient characteristics. We studied the occurrence of alpha-Gal A antibodies and their effect on urinary and plasma globotriaosylceramide (GL-3), plasma chitotriosidase and clinical outcome in 52 patients after 12 months of treatment with either 0.

Elevated globotriaosylsphingosine is a hallmark of Fabry disease.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium.