Network Analysis of Persistent Somatic Symptoms in Two Clinical Patient Samples.

OBJECTIVE: Previous attempts to group persistent somatic symptoms (PSSs) with factor-analytic approaches have obtained heterogeneous results. An alternative approach that seems to be more suitable is the network theory. Compared with factor analysis, which focuses on the underlying factor of symptoms, network analysis focuses on the dynamic relationships and interactions among different symptoms. The main aim of this study is to apply the network approach to examine the heterogeneous structure of PSS within two clinical samples. METHODS: The first data set consisted of n = 254 outpatients who were part of a multicenter study. The second data set included n = 574 inpatients, both with somatoform disorders. Somatic symptom severity was assessed with the Screening of Somatoform Disorder (SOMS-7T). RESULTS: Results indicate that there are five main symptom groups that were found in both samples: neurological, gastrointestinal, urogenital, cardiovascular, and musculoskeletal symptoms. Although patterns of symptoms with high connection to each other look quite similar in both networks, the order of the most central symptoms (e.g., symptoms with a high connection to other symptoms in the network) differs. CONCLUSIONS: This work is the first to estimate the structure of PSS using network analysis. A next step could be first to replicate our findings before translating them into clinical practice. Second, results may be useful for generating hypotheses to be tested in future studies, and the results open new opportunities for a better understanding for etiology, prevention, and intervention research.

Predicting optimal treatment outcomes using the Personalized Advantage Index for patients with persistent somatic symptoms.

Objective: Because individual patients with persistent somatic symptoms (PSS) respond differently to treatments, a better understanding of the factors that predict therapy outcomes are of high importance. Aggregating a wide selection of information into the treatment-decision process is a challenge for clinicians. Using the Personalized Advantage Index (PAI) this study aims to deal with this. Methods: Data from a multicentre RCT comparing CBT (N = 128) versus CBT enriched with emotion regulation training (ENCERT) (N = 126) for patients diagnosed with somatic symptom disorder were used to identify based on two machine learning approaches predictors of therapy outcomes. The identified predictors were used to calculate the PAI. Results: Five treatment unspecific predictors (pre-treatment somatic symptom severity, depression, symptom disability, health-related quality of life, age) and five treatment specific moderators (global functioning, early childhood traumatic events, gender, health anxiety, emotion regulation skills) were identified. Individuals assigned to their PAI-indicated optimal treatment had significantly lower somatic symptom severity at the end of therapy compared to those randomised to their non-optimal condition. Conclusion: Allowing patients to choose a personalised treatment seems to be meaningful. This could help to improve outcomes for PSS and reduce its high costs to the health care system.

Symptom change trajectories in patients with persistent somatic symptoms and their association to long-term treatment outcome.

OBJECTIVE: This study investigated symptom change trajectory for patients with persistent somatic symptoms (PSS) during psychotherapy and the association of these patterns with pre-treatment characteristics and long-term outcome. METHODS: Growth mixture modeling was used to identify trajectory curves in a sample of N = 210 outpatients diagnosed with PSS and treated either with conventional cognitive behavioral therapy (CBT) or CBT enriched with emotion regulation training (ENCERT). RESULTS: We identified three subgroups of patients with similar symptom change patterns over the course of treatment (a "no change," "strong response," and "slow change" subgroup). Higher initial anxiety symptoms were significantly associated with the no change and strong response subgroups; symptom-related disability in daily routine with no changes. Patients with a strong response had the highest proportion of reliable improvement at termination and at six-month-follow-up. CONCLUSION: Our results indicate that, instead of one common change pattern, patients with PSS respond differently to treatment. Due to the high association of symptom curves with long-term outcome, the identification and prediction of an individual's trajectory could provide important information for clinicians to identify non-responding patients that are at risk for failure. Selecting personalized treatment interventions could increase the effectiveness of psychotherapy.Trial registration: ClinicalTrials.gov identifier: NCT01908855..

Cdc42-Borg4-Septin7 axis regulates HSC polarity and function.

Aging of hematopoietic stem cells (HSCs) is caused by the elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (Borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal Septin network. Here, we show that Cdc42 interacts with Borg4, which in turn interacts with Septin7 to regulate the polar distribution of Cdc42, Borg4, and Septin7 within HSCs. Genetic deletion of either Borg4 or Septin7 results in a reduced frequency of HSCs polar for Cdc42 or Borg4 or Septin7, a reduced engraftment potential and decreased lymphoid-primed multipotent progenitor (LMPP) frequency in the bone marrow. Taken together, our data identify a Cdc42-Borg4-Septin7 axis essential for the maintenance of polarity within HSCs and for HSC function and provide a rationale for further investigating the role of Borgs and Septins in the regulation of compartmentalization within stem cells.

KDM6A, a histone demethylase, regulates stress hematopoiesis and early B-cell differentiation.

Histone methylases and demethylases regulate gene expression programs in hematopoiesis. The molecular function of the demethylase KDM6A in normal hematopoiesis and, in particular, for the hematopoietic stem and progenitor cell (HSPC) compartment remains only partially understood. Female but not male Kdm6a-/- HSPCs were functionally impaired in adoptive transfer experiments as well as upon proliferative stress induced by 5-fluorouracil. Loss of Kdm6a affected primarily early B cells and erythroid and myeloid progenitor cells with respect to both number and function. Global gene expression analyses revealed a shared altered gene signature in Kdm6a-/- pro-B and pre-B cells that is also present in HSPCs, supporting that altered B-cell differentiation in Kdm6a-/- animals is already initiated in HSPCs. Interestingly, loss of KDM6A did not affect the global level of methylation of H3K27, its presumed target, in hematopoietic cells. Our data indicate a critical role for KDM6A in the regulation of hematopoietic differentiation and differentiation-specific gene expression programs, with a prominent role in early B-cell differentiation that is likely independent of H3K27 methylation status.

LaminA/C regulates epigenetic and chromatin architecture changes upon aging of hematopoietic stem cells.

BACKGROUND: The decline of hematopoietic stem cell (HSC) function upon aging contributes to aging-associated immune remodeling and leukemia pathogenesis. Aged HSCs show changes to their epigenome, such as alterations in DNA methylation and histone methylation and acetylation landscapes. We previously showed a correlation between high Cdc42 activity in aged HSCs and the loss of intranuclear epigenetic polarity, or epipolarity, as indicated by the specific distribution of H4K16ac. RESULTS: Here, we show that not all histone modifications display a polar localization and that a reduction in H4K16ac amount and loss of epipolarity are specific to aged HSCs. Increasing the levels of H4K16ac is not sufficient to restore polarity in aged HSCs and the restoration of HSC function. The changes in H4K16ac upon aging and rejuvenation of HSCs are correlated with a change in chromosome 11 architecture and alterations in nuclear volume and shape. Surprisingly, by taking advantage of knockout mouse models, we demonstrate that increased Cdc42 activity levels correlate with the repression of the nuclear envelope protein LaminA/C, which controls chromosome 11 distribution, H4K16ac polarity, and nuclear volume and shape in aged HSCs. CONCLUSIONS: Collectively, our data show that chromatin architecture changes in aged stem cells are reversible by decreasing the levels of Cdc42 activity, revealing an unanticipated way to pharmacologically target LaminA/C expression and revert alterations of the epigenetic architecture in aged HSCs.

Septin 6 regulates engraftment and lymphoid differentiation potential of murine long-term hematopoietic stem cells.

Septins are a family of filament-forming GTP-binding proteins that serve as scaffolds and diffusion barriers in various cellular processes. Septin 6 is known as a fusion partner of mixed-lineage leukemia in infant acute myeloid leukemia. The occurrence of the fusion gene is associated with a reduced expression of septin 6 itself. The role of septin 6 in hematopoiesis and whether it is involved in scaffolds within hematopoietic cells is not known. Septin 6-deficient hematopoietic stem cells (HSCs) present with an increased engraftment potential but altered lymphoid differentiation with a reduced contribution to the T-cell compartment and an increased B-cell contribution. Although multipotent progenitor cells showed a very distinct septin 6 filament organization and intracellular distribution, their function was not impaired by septin 6 deficiency. Our data therefore suggest a regulatory role for septin 6 in long-term HSC function and lymphoid lineage differentiation.

Aging of the microenvironment influences clonality in hematopoiesis.

The mechanisms of the age-associated exponential increase in the incidence of leukemia are not known in detail. Leukemia as well as aging are initiated and regulated in multi-factorial fashion by cell-intrinsic and extrinsic factors. The role of aging of the microenvironment for leukemia initiation/progression has not been investigated in great detail so far. Clonality in hematopoiesis is tightly linked to the initiation of leukemia. Based on a retroviral-insertion mutagenesis approach to generate primitive hematopoietic cells with an intrinsic potential for clonal expansion, we determined clonality of transduced hematopoietic progenitor cells (HPCs) exposed to a young or aged microenvironment in vivo. While HPCs displayed primarily oligo-clonality within a young microenvironment, aged animals transplanted with identical pool of cells displayed reduced clonality within transduced HPCs. Our data show that an aged niche exerts a distinct selection pressure on dominant HPC-clones thus facilitating the transition to mono-clonality, which might be one underlying cause for the increased age-associated incidence of leukemia.