Standardized Health data and Research Exchange (SHaRE): promoting a learning health system.

Aggregate de-identified data from electronic health records (EHRs) provide a valuable resource for research. The Standardized Health data and Research Exchange (SHaRE) is a diverse group of US healthcare organizations contributing to the Cerner Health Facts (HF) and Cerner Real-World Data (CRWD) initiatives. The 51 facilities at the 7 founding organizations have provided data about more than 4.8 million patients with 63 million encounters to HF and 7.4 million patients and 119 million encounters to CRWD. SHaRE organizations unmask their organization IDs and provide 3-digit zip code (zip3) data to support epidemiology and disparity research. SHaRE enables communication between members, facilitating data validation and collaboration as we demonstrate by comparing imputed EHR module usage to actual usage. Unlike other data sharing initiatives, no additional technology installation is required. SHaRE establishes a foundation for members to engage in discussions that bridge data science research and patient care, promoting the learning health system.

Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis.

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people world-wide. The aetiology of MS is not known and there is no medical treatment available that can cure MS. Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease model of MS. The pathogenesis of EAE/MS is a complex process involving activation of immune cells, secretion of inflammatory cytokines and destruction of myelin sheath in the central nervous system (CNS). Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptor transcription factors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown that PPARgamma, alpha and delta agonists inhibit CNS inflammation and demyelination in the EAE model of MS. In this study we show that the PPARdelta agonists GW501516 and L165041 ameliorate MOGp35-55-induced EAE in C57BL/6 mice by blocking interferon (IFN)-gamma and interleukin (IL)-17 production by T helper type 1 (Th1) and Th17 cells. The inhibition of EAE by PPARdelta agonists was also associated with a decrease in IL-12 and IL-23 and an increase in IL-4 and IL-10 expression in the CNS and lymphoid organs. These findings indicate that PPARdelta agonists modulate Th1 and Th17 responses in EAE and suggest their use in the treatment of MS and other autoimmune diseases.

Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis. Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by IL-12 and IL-23, two cytokines known to play important roles in the pathogenesis of EAE by inducing T cells to secrete IFN-gamma and IL-17, respectively. We and others have previously shown that therapeutic intervention or targeted disruption of Stat4 was effective in ameliorating EAE. Recently, a splice variant of Stat4 termed Stat4beta has been characterized that lacks 44 amino acids at the C terminus of the full-length Stat4alpha. In this study we examined whether T cells expressing either isoform could affect the pathogenesis of EAE. We found that transgenic mice expressing Stat4beta on a Stat4-deficient background develop an exacerbated EAE compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein peptide 35-55, while Stat4alpha transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFN-gamma and IL-17 in Stat4beta-expressing cells in situ, contrasting increased IL-10 production by Stat4alpha-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE.

Neural networks for mining the associations between diseases and symptoms in clinical notes.

There are challenges for analyzing the narrative clinical notes in Electronic Health Records (EHRs) because of their unstructured nature. Mining the associations between the clinical concepts within the clinical notes can support physicians in making decisions, and provide researchers evidence about disease development and treatment. In this paper, in order to model and analyze disease and symptom relationships in the clinical notes, we present a concept association mining framework that is based on word embedding learned through neural networks. The approach is tested using 154,738 clinical notes from 500 patients, which are extracted from the Indiana University Health's Electronic Health Records system. All patients are diagnosed with more than one type of disease. The results show that this concept association mining framework can identify related diseases and symptoms. We also propose a method to visualize a patients' diseases and related symptoms in chronological order. This visualization can provide physicians an overview of the medical history of a patient and support decision making. The presented approach can also be expanded to analyze the associations of other clinical concepts, such as social history, family history, medications, etc.

Dietary lutein modulates growth and survival genes in prostate cancer cells.

Lutein is a carotenoid pigment present in fruits and vegetables that has anti-inflammatory and antitumor properties. In this study, we examined the effect of lutein on proliferation and survival-associated genes in prostate cancer (PC-3) cells. We found that in vitro culture of PC-3 cells with lutein induced mild decrease in proliferation that improved in combination treatment with peroxisome proliferator-activated receptor gamma (PPARγ) agonists and other chemotherapeutic agents. Flow cytometry analyses showed that lutein improved drug-induced cell cycle arrest and apoptosis in prostate cancer. Gene array and quantitative reverse transcription-polymerase chain reaction analyses showed that lutein altered the expression of growth and apoptosis-associated biomarker genes in PC-3 cells. These findings highlight that lutein modulates the expression of growth and survival-associated genes in prostate cancer cells.

Lycopene modulates growth and survival associated genes in prostate cancer.

Lycopene is a fat soluble red-orange carotenoid pigment present in tomato that reduces the risk for prostate cancer, a common malignancy among men. However, the mechanism by which lycopene attenuates prostate cancer is not fully defined. In this study we examined the effect of lycopene on proliferation, survival, and biomarker gene expression in prostate cancer (PC-3) cells in culture. WST-1 assay showed that lycopene induces a biphasic effect on PC-3 cells with a modest increase in proliferation at 1-5 µM, no change at 10-25 µM and a decrease at 50-100 µM doses in culture. Interestingly, combination treatment with lycopene induced anti-proliferative effect of Temozolomide on PC-3 cells. Lycopene also augmented the anti-proliferative effect of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, but not Doxorubicin or Taxol, in prostate cancer. Flow cytometry analyses showed that lycopene, in combination with chemotherapeutic agents and PPARγ agonists, induced modest cell cycle arrest with significant increase in cell death by apoptosis and necrosis on prostate cancer. Gene array and quantitative reverse transcription polymerase chain reaction analyses showed that lycopene alters the expression of growth and apoptosis associated biomarkers in PC-3 cells. These findings highlight that lycopene attenuates prostate cancer by modulating the expression of growth and survival associated genes.

PPARγ agonists promote oligodendrocyte differentiation of neural stem cells by modulating stemness and differentiation genes.

Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14)-Prostaglandin J(2) (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal ß-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.

Differential regulation of CD4(+) T helper cell responses by curcumin in experimental autoimmune encephalomyelitis.

Nutraceuticals and phytochemicals are important regulators of human health and diseases. Curcumin is a polyphenolic phytochemical isolated from the rhizome of the plant Curcuma longa (turmeric) that has been traditionally used for the treatment of inflammation and wound healing for centuries. Systematic analyses have shown that curcumin exerts its beneficial effects through antioxidant, antiproliferative and anti-inflammatory properties. We and others have shown earlier that curcumin ameliorates experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. In this study, we show that C57BL/6 mice induced to develop EAE express elevated levels of interferon (IFN) γ and interleukin (IL)-17 in the central nervous system (CNS) and lymphoid organs that decreased significantly following in vivo treatment with curcumin. The EAE mice also showed elevated expression of IL-12 and IL-23 that decreased after treatment with curcumin. Ex vivo and in vitro treatment with curcumin resulted in a dose-dependent decrease in the secretion of IFNγ, IL-17, IL-12 and IL-23 in culture. The inhibition of EAE by curcumin was also associated with an up-regulation of IL-10, peroxisome proliferator activated receptor γ and CD4(+)CD25(+-)Foxp3(+) Treg cells in the CNS and lymphoid organs. These findings highlight that curcumin differentially regulates CD4(+) T helper cell responses in EAE.

PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The etiology of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE). In this study we have used PPARδ deficient mice to determine its physiological role in the regulation of CNS EAE and MS. We found that PPARδ(-/-) mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ(-/-) mice showed prolonged EAE with resistance to remission and recovery. PPARδ(-/-) mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ(-/-) mice also developed augmented neural antigen-specific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ(-/-) mice develop prolonged EAE in association with augmented Th1/Th17 responses, suggesting a critical physiological role for PPARδ in the remission and recovery of EAE.

PPAR Regulation of Inflammatory Signaling in CNS Diseases.

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARalpha, gamma, and delta isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-kappaB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.