Modulation of autoimmune arthritis by environmental 'hygiene' and commensal microbiota.

Observations in patients with autoimmune diseases and studies in animal models of autoimmunity have revealed that external environmental factors including exposure to microbes and the state of the host gut microbiota can influence susceptibility to autoimmunity and subsequent disease development. Mechanisms underlying these outcomes continue to be elucidated. These include deviation of the cytokine response and imbalance between pathogenic versus regulatory T cell subsets. Furthermore, specific commensal organisms are associated with enhanced severity of arthritis in susceptible individuals, while exposure to certain microbes or helminths can afford protection against this disease. In addition, the role of metabolites (e.g., short-chain fatty acids, tryptophan catabolites), produced either by the microbes themselves or from their action on dietary products, in modulation of arthritis is increasingly being realized. In this context, re-setting of the microbial dysbiosis in RA using prebiotics, probiotics, or fecal microbial transplant is emerging as a promising approach for the prevention and treatment of arthritis. It is hoped that advances in defining the interplay between gut microbiota, dietary products, and bioactive metabolites would help in the development of therapeutic regimen customized for the needs of individual patients in the near future.

Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

Rheumatoid arthritis (RA) is characterized by hyperplastic pannus formation mediated by activated synovial fibroblasts (RASFs) that cause joint destruction. We have shown earlier that RASFs exhibit resistance to apoptosis, primarily as a result of enhanced expression of myeloid cell leukemia-1 (Mcl-1). In this study, we discovered that ursolic acid (UA), a plant-derived pentacyclic triterpenoid, selectively induces B-cell lymphoma 2 homology 3-only protein Noxa in human RASFs. We observed that UA-induced Noxa expression was followed by a consequent decrease in Mcl-1 expression in a dose-dependent manner. Subsequent evaluation of the signaling pathways showed that UA-induced Noxa is primarily mediated by the JNK pathway in human RASFs. Chromatin immunoprecipitation (IP) studies into the promoter region of Noxa indicated the role of transcription factor specificity protein 1 in JNK-mediated Noxa expression. Furthermore, the results from IP studies and proximity ligation assays indicated that UA-induced Noxa colocalizes and associates with Mcl-1 to prime it for proteasomal degradation through K48-linked ubiquitination by the selective recruitment of Mcl-1 ubiquitin ligase E3, a homologous to E6-associated protein C terminus domain-containing E3 ubiquitin ligase. These findings unveil a novel mechanism of inducing apoptosis in RASFs and a potential adjunct therapeutic strategy of regulating synovial hyperplasia in RA.-Kim, E. Y., Sudini, K., Singh, A. K., Haque, M., Leaman, D., Khuder, S., Ahmed, S. Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1-mediated Noxa expression and proteasomal degradation of Mcl-1.

Syndecans in chronic inflammatory and autoimmune diseases: Pathological insights and therapeutic opportunities.

Syndecans (SDCs) are a family of heparan sulfate proteoglycans (HSPGs) glycoproteins ubiquitously expressed on the cell surfaces and extracellular matrix of all mammalian tissues. There are four mammalian syndecans, SDC-1 thorough 4, which play a critical role in cell adhesion, migration, proliferation, differentiation, and angiogenesis through independent and growth factor mediated signaling. An altered expression of SDCs is often observed in autoimmune disorders, cancer, HIV infection, and many other pathological conditions. SDCs modulate disease progression by interacting with a diverse array of ligands, receptors, and other proteins, including extracellular matrix, glycoproteins, integrins, morphogens, and various growth factors and chemokines, along with their receptors and kinases. Specifically, SDCs present on cell surface can bind directly to chemokines to enhance their binding to receptors, downstream signaling, and migration. Alternatively, SDCs can be cleaved and shed to mediate negative regulation of chemokine and growth factor signaling pathways and ligand sequestration. Importantly, SDC shedding may be a biomarker of inflammation, especially in chronic inflammatory diseases. While the current therapies for cancer and several autoimmune disorders have revolutionized treatment outcomes, understanding the pathophysiological role of SDCs and the use of HSPG mimetic or antagonists on cytokine signaling networks may uncover potentially novel targeted therapeutic approaches. This review mainly summarizes the current findings on the role of individual SDCs in disease processes, mechanisms through which SDCs mediate their biological functions, and the possibility of targeting SDCs as future potential therapeutic approaches.

Bouncing Back Elsewhere: Multilevel Analysis of Return Visits to the Same or a Different Hospital After Initial Emergency Department Presentation.

STUDY OBJECTIVE: Analyses of 72-hour emergency department (ED) return visits are frequently used for quality assurance purposes and have been proposed as a means of measuring provider performance. These analyses have traditionally examined only patients returning to the same hospital as the initial visit. We use a health information exchange network to describe differences between ED visits resulting in 72-hour revisits to the same hospital and those resulting in revisits to a different site. METHODS: We examined data from a 31-hospital health information exchange of all ED visits during a 5-year period to identify 72-hour return visits and collected available encounter, patient, and hospital variables. Next, we used multilevel analysis of encounter-level, patient-level, and hospital-level data to describe differences between initial ED visits resulting in different-site and same-site return visits. RESULTS: We identified 12,621,159 patient visits to the 31 study EDs, including 841,259 same-site and 107,713 different-site return visits within 72 hours of initial ED presentation. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the initial-visit characteristics' predictive relationship that any return visit would be at a different site: daytime visit (OR 1.10; 95% CI 1.07 to 1.12), patient-hospital county concordance (OR 1.40; 95% CI 1.36 to 1.44), male sex (OR 1.27; 95% CI 1.24 to 1.30), aged 65 years or older (OR 0.55; 95% CI 0.53 to 0.57), sites with an ED residency (OR 0.41; 95% CI 0.40 to 0.43), sites at an academic hospital (OR 1.12; 95% CI 1.08 to 1.15), sites with high density of surrounding EDs (OR 1.73; 95% CI 1.68 to 1.77), and sites with a high frequency of same-site return visits (OR 0.10; 95% CI 0.10 to 0.11). CONCLUSION: This analysis describes how ED encounters with early revisits to the same hospital differ from those with revisits to a second hospital. These findings challenge the use of single-site return-visit frequency as a quality measure, and, more constructively, describe how hospitals can use health information exchange to more accurately identify early ED return visits and to support programs related to these revisits.

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines.

Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.

Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2.

Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-kappaB signalling triggered by TNF-alpha. Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1) that then serves as a platform for recruitment and stimulation of IkappaB kinase, leading to activation of the transcription factor NF-kappaB. Although TRAF2 is a RING domain ubiquitin ligase, direct evidence that TRAF2 catalyses the ubiquitination of RIP1 is lacking. TRAF2 binds to sphingosine kinase 1 (SphK1), one of the isoenzymes that generates the pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells. Here we show that SphK1 and the production of S1P is necessary for lysine-63-linked polyubiquitination of RIP1, phosphorylation of IkappaB kinase and IkappaBalpha, and IkappaBalpha degradation, leading to NF-kappaB activation. These responses were mediated by intracellular S1P independently of its cell surface G-protein-coupled receptors. S1P specifically binds to TRAF2 at the amino-terminal RING domain and stimulates its E3 ligase activity. S1P, but not dihydro-S1P, markedly increased recombinant TRAF2-catalysed lysine-63-linked, but not lysine-48-linked, polyubiquitination of RIP1 in vitro in the presence of the ubiquitin conjugating enzymes (E2) UbcH13 or UbcH5a. Our data show that TRAF2 is a novel intracellular target of S1P, and that S1P is the missing cofactor for TRAF2 E3 ubiquitin ligase activity, indicating a new paradigm for the regulation of lysine-63-linked polyubiquitination. These results also highlight the key role of SphK1 and its product S1P in TNF-alpha signalling and the canonical NF-kappaB activation pathway important in inflammatory, antiapoptotic and immune processes.

Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching.

The tumor necrosis factor (TNF) receptor family member CD40 plays an essential role in the activation of antigen-presenting cells, B cell maturation, and immunoglobulin (Ig) class switching critical for adaptive immunity. Although the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinase that produces it, sphingosine kinase 1 (SphK1), have long been implicated in the actions of TNF mediated by engagement of TNFR1, nothing is yet known of their role in CD40-mediated events. We have now found that ligation of CD40 activates and translocates SphK1 to the plasma membrane, leading to generation of S1P. SphK1 inhibition in human tonsil B cells, as well as inhibition or deletion of SphK1 in mouse splenic B cells, significantly reduced CD40-mediated Ig class switching and plasma cell differentiation ex vivo. Optimal activation of downstream CD40 signaling pathways, including NF-κB, p38, and JNK, also required SphK1. In mice treated with a SphK1 inhibitor or in SphK1(-/-) mice, isotype switching to antigen-specific IgE was decreased in vivo by 70 and 55%, respectively. Our results indicate that SphK1 is important for CD40-mediated B cell activation and regulation of humoral responses and suggest that targeting SphK1 might be a useful therapeutic approach to control antigen-specific IgE production.

Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.

Sphingosine-1-phosphate (S1P), a ligand for 5 specific receptors, is a potent lipid mediator that plays important roles in lymphocyte trafficking and immune responses. S1P is produced inside cells and therefore must be secreted to exert its effects through these receptors. Spinster 2 (Spns2) is one of the cell surface transporters thought to secrete S1P. We have shown that Spns2 can export endogenous S1P from cells and also dihydro-S1P, which is active at all cell surface S1P receptors. Moreover, Spns2 mice have decreased levels of both of these phosphorylated sphingoid bases in blood, accompanied by increases in very long chain ceramide species, and have defective lymphocyte trafficking. Surprisingly, levels of S1P and dihydro-S1P were increased in lymph from Spns2 mice as well as in specific tissues, including lymph nodes, and interstitial fluid. Moreover, lymph nodes from Spns2 mice have aberrant lymphatic sinus that appeared collapsed, with reduced numbers of lymphocytes. Our data suggest that Spns2 is an S1P transporter in vivo that plays a role in regulation not only of blood S1P but also lymph node and lymph S1P levels and consequently influences lymphocyte trafficking and lymphatic vessel network organization.

A Computational Framework to Evaluate Emergency Department Clinician Task Switching in the Electronic Health Record Using Event Logs.

Workflow fragmentation, defined as task switching, may be one proxy to quantify electronic health record (EHR) documentation burden in the emergency department (ED). Few measures have been operationalized to evaluate task switching at scale. Theoretically grounded in the time-based resource-sharing model (TBRSM) which conceives task switching as proportional to the cognitive load experienced, we describe the functional relationship between cognitive load and the time and effort constructs previously applied for measuring documentation burden. We present a computational framework, COMBINE, to evaluate multilevel task switching in the ED using EHR event logs. Based on this framework, we conducted a descriptive analysis on task switching among 63 full-time ED physicians from one ED site using EHR event logs extracted between April-June 2021 (n=2,068,605 events) which were matched to scheduled shifts (n=952). On average, we found a high volume of event-level (185.8±75.3/hr) and within-(6.6±1.7/chart) and between-patient chart (27.5±23.6/hr) switching per shift worked.

A Practical Approach to Optimize Computerized Provider Order Entry Systems and Reduce Clinician Burden: Pre-Post Evaluation of Vendor-Derived "Order Friction" Data.

Computerized provider order entry (CPOE) systems have been cited as a significant contributor to clinician burden. Vendor-derived measures and data sets have been developed to help with optimization of CPOE systems. We describe how we analyzed vendor-derived Order Friction (OF) EHR log data at our health system and propose a practical approach for optimizing CPOE systems by reducing OF. We also conducted a pre-post intervention study using OF data to evaluate the impact of defaulting the frequency of urine, stool and nasal swab tests and found that all modified orders had significantly fewer changes required per order (p<0.01). Our proposed approach is a six-step process: 1) understand the ordering process, 2) understand OF data elements contextually, 3) explore ordering user-level factors, 4) evaluate order volume and friction from different order sources, 5) optimize order-level design, 6) identify high volume alerts to evaluate for appropriateness.

Understanding the perceived role of electronic health records and workflow fragmentation on clinician documentation burden in emergency departments.

OBJECTIVE: Understand the perceived role of electronic health records (EHR) and workflow fragmentation on clinician documentation burden in the emergency department (ED). METHODS: From February to June 2022, we conducted semistructured interviews among a national sample of US prescribing providers and registered nurses who actively practice in the adult ED setting and use Epic Systems' EHR. We recruited participants through professional listservs, social media, and email invitations sent to healthcare professionals. We analyzed interview transcripts using inductive thematic analysis and interviewed participants until we achieved thematic saturation. We finalized themes through a consensus-building process. RESULTS: We conducted interviews with 12 prescribing providers and 12 registered nurses. Six themes were identified related to EHR factors perceived to contribute to documentation burden including lack of advanced EHR capabilities, absence of EHR optimization for clinicians, poor user interface design, hindered communication, increased manual work, and added workflow blockages, and five themes associated with cognitive load. Two themes emerged in the relationship between workflow fragmentation and EHR documentation burden: underlying sources and adverse consequences. DISCUSSION: Obtaining further stakeholder input and consensus is essential to determine whether these perceived burdensome EHR factors could be extended to broader contexts and addressed through optimizing existing EHR systems alone or through a broad overhaul of the EHR's architecture and primary purpose. CONCLUSION: While most clinicians perceived that the EHR added value to patient care and care quality, our findings underscore the importance of designing EHRs that are in harmony with ED clinical workflows to alleviate the clinician documentation burden.

Using Time Series Clustering to Segment and Infer Emergency Department Nursing Shifts from Electronic Health Record Log Files.

Few computational approaches exist for abstracting electronic health record (EHR) log files into clinically meaningful phenomena like clinician shifts. Because shifts are a fundamental unit of work recognized in clinical settings, shifts may serve as a primary unit of analysis in the study of documentation burden. We conducted a proof- of-concept study to investigate the feasibility of a novel approach using time series clustering to segment and infer clinician shifts from EHR log files. From 33,535,585 events captured between April-June 2021, we computationally identified 43,911 potential shifts among 2,285 (74.2%) emergency department nurses. On average, computationally-identified shifts were 10.6±3.1 hours long. Based on data distributions, we classified these shifts based on type: day, evening, night; and length: 12-hour, 8-hour, other. We validated our method through manual chart review of computationally-identified 12-hour shifts achieving 92.0% accuracy. Preliminary results suggest unsupervised clustering methods may be a reasonable approach for rapidly identifying clinician shifts.

A visual representation of microbiological culture data improves comprehension: a randomized controlled trial.

OBJECTIVE: While the judicious use of antibiotics takes past microbiological culture results into consideration, this data's typical format in the electronic health record (EHR) may be unwieldy when incorporated into clinical decision-making. We hypothesize that a visual representation of sensitivities may aid in their comprehension. MATERIALS AND METHODS: A prospective parallel unblinded randomized controlled trial was undertaken at an academic urban tertiary care center. Providers managing emergency department (ED) patients receiving antibiotics and having previous culture sensitivity testing were included. Providers were randomly selected to use standard EHR functionality or a visual representation of patients' past culture data as they answered questions about previous sensitivities. Concordance between provider responses and past cultures was assessed using the kappa statistic. Providers were surveyed about their decision-making and the usability of the tool using Likert scales. RESULTS: 518 ED encounters were screened from 3/5/2018 to 9/30/18, with providers from 144 visits enrolled and analyzed in the intervention arm and 129 in the control arm. Providers using the visualization tool had a kappa of 0.69 (95% CI: 0.65-0.73) when asked about past culture results while the control group had a kappa of 0.16 (95% CI: 0.12-0.20). Providers using the tool expressed improved understanding of previous cultures and found the tool easy to use (P < .001). Secondary outcomes showed no differences in prescribing practices. CONCLUSION: A visual representation of culture sensitivities improves comprehension when compared to standard text-based representations.

Hypoxia and radiation therapy: past history, ongoing research, and future promise.

Tumor hypoxia influences the outcome of treatment with radiotherapy, chemotherapy and even surgery, not only for the treatment of large bulky tumors with extensive necrosis, but also in the treatment of very small primary tumors and recurrences, micrometastases, and surgical margins with microscopic tumor involvement. Because hypoxic tumor cells are resistant to radiation and to many anticancer drugs, many approaches to circumventing the therapeutic resistance induced by hypoxia have been examined in laboratory studies and clinical trials. In this review, these approaches and the results of past laboratory and clinical studies are described and the limitations of the past agents and their testing are discussed. We describe the importance of new technologies for measuring hypoxia in human tumors, which allow assessment of pretreatment tumor oxygen levels and changes in hypoxia over the course of prolonged treatment regimens. These offer the possibility of improving the design of clinical trials and the selection of patients who will benefit from hypoxia-directed therapies, as well as the possibility of facilitating the development of better agents and regimens for use in hypoxia-directed therapy. We also discuss how the improved understanding of the abnormal vascular beds in solid tumors and of the effects of hypoxia and related microenvironmental insults, resulting from recent and ongoing research, offers the potential for finding new therapeutic targets, that may lead to the development of new agents and novel therapeutic approaches for selectively targeting cells in the adverse microenvironments within solid tumors.

Roles of OB-Fold Proteins in Replication Stress.

Accurate DNA replication is essential for maintaining genome stability. However, this stability becomes vulnerable when replication fork progression is stalled or slowed - a condition known as replication stress. Prolonged fork stalling can cause DNA damage, leading to genome instabilities. Thus, cells have developed several pathways and a complex set of proteins to overcome the challenge at stalled replication forks. Oligonucleotide/oligosaccharide binding (OB)-fold containing proteins are a group of proteins that play a crucial role in fork protection and fork restart. These proteins bind to single-stranded DNA with high affinity and prevent premature annealing and unwanted nuclease digestion. Among these OB-fold containing proteins, the best studied in eukaryotic cells are replication protein A (RPA) and breast cancer susceptibility protein 2 (BRCA2). Recently, another RPA-like protein complex CTC1-STN1-TEN1 (CST) complex has been found to counter replication perturbation. In this review, we discuss the latest findings on how these OB-fold containing proteins (RPA, BRCA2, CST) cooperate to safeguard DNA replication and maintain genome stability.

Regulation of autoimmune inflammation by pro-inflammatory cytokines.

The pro-inflammatory cytokines play a critical role in the initiation and propagation of autoimmune arthritis and many other disorders resulting from a dysregulated self-directed immune response. These cytokines influence the interplay among the cellular, immunological and biochemical mediators of inflammation at multiple levels. Regulation of the pro-inflammatory activity of these cytokines is generally perceived to be mediated by the anti-inflammatory and immunosuppressive cytokines such as IL-4, IL-10, or TGF-beta. However, increasing evidence is accumulating in support of the regulatory attributes of the pro-inflammatory cytokines themselves, in studies conducted in animal models of diabetes, multiple sclerosis, uveitis, and lupus. The results of our recent studies have shown that the pro-inflammatory cytokines, TNF-alpha and IFN-gamma, can suppress arthritic inflammation in rats, and also contribute to resistance against arthritis. These results are of paramount significance not only in fully understanding the pathogenesis of autoimmune arthritis, but also in anticipating the full ramifications of the in vivo neutralization of the pro-inflammatory cytokines, including that for therapeutic purposes.

Modulation of Adjuvant Arthritis by Cellular and Humoral Immunity to Hsp65.

Heat shock proteins (Hsps) are highly conserved, and their expression is upregulated in cells by heat and other stressful stimuli. These proteins play a vital role in preserving the structural and functional integrity of cells under stress. Despite the ubiquitous expression of Hsps in an individual, the immune system is not fully tolerant to them. In fact, Hsps are highly immunogenic in nature, and immune response to these proteins is observed in various inflammatory and autoimmune diseases. Studies on the immunopathogenesis of autoimmune arthritis in the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA) as well as observations in patients with RA and juvenile idiopathic arthritis (JIA) have unraveled immunoregulatory attributes of self-Hsp65-directed immunity. Notable features of Hsp65 immunity in AA include protection rather than disease induction following immunization of Lewis rats with self (rat)-Hsp65; the diversification of T cell response to mycobacterial Hsp65 during the course of AA and its association with spontaneous induction of response to self-Hsp65; the cross-reactive T cells recognizing foreign and self homologs of Hsp65 and their role in disease suppression in rats; the suppressive effect of antibodies to Hsp65 in AA; and the use of Hsp65, its peptides, or altered peptide ligands in controlling autoimmune pathology. The results of studies in the AA model have relevance to RA and JIA. We believe that these insights into Hsp65 immunity would not only advance our understanding of the disease process in RA/JIA, but also lead to the development of novel therapeutic approaches for autoimmune arthritis.

Increased Identification of Emergency Department 72-hour Returns Using Multihospital Health Information Exchange.

OBJECTIVES: Emergency departments (EDs) commonly analyze cases of patients returning within 72 hours of initial ED discharge as potential opportunities for quality improvement. In this study, we tested the use of a health information exchange (HIE) to improve identification of 72-hour return visits compared to individual hospitals' site-specific data. METHODS: We collected deidentified patient data over a 5-year study period from Healthix, an HIE in the New York metropolitan area. We measured site-specific 72-hour ED returns and compared these data to those obtained from a regional 31-site HIE (Healthix) and to those from a smaller, antecedent 11-site HIE. Although only ED visits were counted as index visits, either ED or inpatient revisits within 72 hours of the index visit were considered as early returns. RESULTS: A total of 12,669,657 patient encounters were analyzed across the 31 HIE EDs, including 6,352,829 encounters from the antecedent 11-site HIE. Site-specific 72-hour return visit rates ranged from 1.1% to 15.2% (median = 5.8%) among the individual 31 sites. When the larger HIE was used to identify return visits to any site, individual EDs had a 72-hour return frequency of 1.8% to 15.5% (median = 6.8%). HIE increased the identification ability of 72-hour ED return analyses by a mean of 11.16% (95% confidence interval = 11.10% to 11.22%) compared with site-specific (no HIE) analyses. CONCLUSION: This analysis demonstrates incremental improvements in our ability to identify early ED returns using increasing levels of HIE data aggregation. Although intuitive, this has not been previously described using HIE. ED quality measurement and patient safety efforts may be aided by using HIE in 72-hour return analyses.

Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer.

Inflammatory bowel disease is an important risk factor for colorectal cancer. We show that sphingosine-1-phosphate (S1P) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of Sphk2. S1P is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor STAT3, and consequent upregulation of the S1P receptor, S1PR1. The prodrug FTY720 decreased SphK1 and S1PR1 expression and eliminated the NF-κB/IL-6/STAT3 amplification cascade and development of CAC, even in Sphk2(-/-) mice, and may be useful in treating colon cancer in individuals with ulcerative colitis. Thus, the SphK1/S1P/S1PR1 axis is at the nexus between NF-κB and STAT3 and connects chronic inflammation and CAC.