Background: Longitudinal studies have verified the pivotal role of mesenchymal stem/stromal cells (MSCs) in the bone marrow microenvironment for hematopoiesis and coordinate contribution to leukemia pathogenesis. However, the precise characteristics and alternation of MSCs during acquired aplastic anemia (AA) remain obscure. Methods: In this study, we originally collected samples from both healthy donors (HD) and AA patients to dissect the hematological changes. To systematically evaluate the biological defects of AA-derived MSCs (AA-MSCs), we analyzed alterations in cellular morphology, immunophenotype, multi-lineage differentiation, cell migration, cellular apoptosis, and chromosome karyocyte, together with the immunosuppressive effect on the activation and differentiation of lymphocytes. With the aid of whole genome sequencing and bioinformatic analysis, we try to compare the differences between AA-MSCs and HD-derived MSCs (HD-MSCs) upon the molecular genetics, especially the immune-associated gene expression pattern. In addition, the efficacy of umbilical cord-derived MSC (UC-MSC) transplantation on AA mice was evaluated by utilizing survivorship curve, histologic sections, and blood cell analyses. Results: In coincidence with the current reports, AA patients showed abnormal subsets of lymphocytes and higher contents of proinflammatory cytokines. Although with similar immunophenotype and chromosome karyotype to HD-MSCs, AA-MSCs showed distinguishable morphology and multiple distinct characteristics including genetic properties. In addition, the immunosuppressive effect on lymphocytes was significantly impaired in AA-MSCs. What is more, the cardinal symptoms of AA mice were largely rescued by systemic transplantation of UC-MSCs. Conclusions: Herein, we systematically investigated the signatures and efficacy of MSCs to dissect the alterations occurred in AA both at the cellular and molecular levels. Different from HD-MSCs, AA-MSCs exhibited multifaceted defects in biological characteristics and alterative molecular genetics in the whole genome. Our findings have provided systematic and overwhelming new evidence for the defects of AA-MSCs, together with effectiveness assessments of UC-MSCs on AA as well.

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IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...

Background Dementia is underdiagnosed in both the general population and among Veterans. This underdiagnosis decreases quality of life, reduces opportunities for interventions, and increases health-care costs. New approaches are therefore necessary to facilitate the timely detection of dementia. This study seeks to identify cases of undiagnosed dementia by developing and validating a weakly supervised machine-learning approach that incorporates the analysis of both structured and unstructured electronic health record (EHR) data. Methods A topic modeling approach that included latent Dirichlet allocation, stable topic extraction, and random sampling was applied to VHA EHRs. Topic features from unstructured data and features from structured data were compared between Veterans with ( n = 1861) and without ( n = 9305) ICD-9 dementia codes. A logistic regression model was used to develop dementia prediction scores, and manual reviews were conducted to validate the machine-learning results. Results A total of 853 features were identified (290 topics, 174 non-dementia ICD codes, 159 CPT codes, 59 medications, and 171 note types) for the development of logistic regression prediction scores. These scores were validated in a subset of Veterans without ICD-9 dementia codes ( n = 120) by experts in dementia who performed manual record reviews and achieved a high level of inter-rater agreement. The manual reviews were used to develop a receiver of characteristic (ROC) curve with different thresholds for case detection, including a threshold of 0.061, which produced an optimal sensitivity (0.825) and specificity (0.832). Conclusions Dementia is underdiagnosed, and thus, ICD codes alone cannot serve as a gold standard for diagnosis. However, this study suggests that imperfect data (e.g., ICD codes in combination with other EHR features) can serve as a silver standard to develop a risk model, apply that model to patients without dementia codes, and then select a case-detection threshold. The study is one of the first to utilize both structured and unstructured EHRs to develop risk scores for the diagnosis of dementia.

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We developed feasible and accurate methods for identifying axial SpA concepts in the free text of clinical notes. Additional research is required to determine combinations of concepts that will accurately identify axial SpA phenotypes. These novel methods will facilitate previously impractical observational research in axial SpA and may be applied to research with other diseases.

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