Citations

PURPOSE Electronic health records (EHRs) are created primarily for nonresearch purposes; thus, the amounts of data are enormous, and the data are crude, heterogeneous, incomplete, and largely unstructured, presenting challenges to effective analyses for timely, reliable results. Particularly, research dealing with clinical notes relevant to patient care and outcome is seldom conducted, due to the complexity of data extraction and accurate annotation in the past. RECIST is a set of widely accepted research criteria to evaluate tumor response in patients undergoing antineoplastic therapy. The aim for this study was to identify textual sources for RECIST information in EHRs and to develop a corpus of pharmacotherapy and response entities for development of natural language processing tools. METHODS We focused on pharmacotherapies and patient responses, using 55,120 medical notes (n = 72 types) in Mayo Clinic’s EHRs from 622 randomly selected patients who signed authorization for research. Using the Multidocument Annotation Environment tool, we applied and evaluated predefined keywords, and time interval and note-type filters for identifying RECIST information and established a gold standard data set for patient outcome research. RESULTS Key words reduced clinical notes to 37,406, and using four note types within 12 months postdiagnosis further reduced the number of notes to 5,005 that were manually annotated, which covered 97.9% of all cases (n = 609 of 622). The resulting data set of 609 cases (n = 503 for training and n = 106 for validation purpose), contains 736 fully annotated, deidentified clinical notes, with pharmacotherapies and four response end points: complete response, partial response, stable disease, and progressive disease. This resource is readily expandable to specific drugs, regimens, and most solid tumors. CONCLUSION We have established a gold standard data set to accommodate development of biomedical informatics tools in accelerating research into antineoplastic therapeutic response.

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.

Abstract The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

Abstract Stimulation of T lymphocytes with the ligand for the CXCR4 chemokine receptor stromal cell-derived factor-1α (SDF-1α/CXCL12), results in prolonged activation of the extracellular signal-regulated kinases (ERK) ERK1 and ERK2. Because SDF-1α is unique among several chemokines in its ability to stimulate prolonged ERK activation, this pathway is thought to mediate special functions of SDF-1α that are not shared with other chemokines. However, the molecular mechanisms of this response are poorly understood. In this study we show that SDF-1α stimulation of prolonged ERK activation in Jurkat T cells requires both the ZAP-70 tyrosine kinase and the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) scaffold protein. This pathway involves ZAP-70-dependent tyrosine phosphorylation of SLP-76 at one or more of its tyrosines, 113, 128, and 145. Because TCR activates ERK via SLP-76-mediated activation of the linker of activated T cells (LAT) scaffold protein, we examined the role of LAT in SDF-1α-mediated ERK activation. However, neither the SLP-76 proline-rich domain that links to GADS and LAT, nor LAT, itself are required for SDF-1α to stimulate SLP-76 tyrosine phosphorylation or to activate ERK. Together, our results describe the distinct mechanism by which SDF-1α stimulates prolonged ERK activation in T cells and indicate that this pathway is specific for cells expressing both ZAP-70 and SLP-76.

Abstract Costimulation by the chemokine, stromal cell-derived factor-1 (SDF-1)/CXCL12, has been shown to increase the amount of IL-10 secreted by TCR-stimulated human T cells; however, the molecular mechanisms of this response are unknown. Knowledge of this signaling pathway may be useful because extensive evidence indicates that deficient IL-10 secretion promotes autoimmunity. The human IL-10 locus is highly polymorphic. We report in this study that SDF-1 costimulates IL-10 secretion from T cells containing all three of the most common human IL-10 promoter haplotypes that are identified by single-nucleotide polymorphisms at −1082, −819, and −592 bp (numbering is relative to the transcription start site). We further show that SDF-1 primarily costimulates IL-10 secretion by a diverse population of CD45RA− (“memory”) phenotype T cells that includes cells expressing the presumed regulatory T cell marker, Foxp3. To address the molecular mechanisms of this response, we showed that SDF-1 costimulates the transcriptional activities in normal human T cells of reporter plasmids containing 1.1 kb of all three of the common IL-10 promoter haplotypes. IL-10 promoter activity was ablated by mutating two nonpolymorphic binding sites for the AP-1 transcription factor, and chromatin immunoprecipitation assays of primary human T cells revealed that SDF-1 costimulation enhances AP-1 binding to both of these sites. Together, these results delineate the molecular mechanisms responsible for SDF-1 costimulation of T cell IL-10 secretion. Because it is preserved among several human haplotypes and in diverse T cell populations including Foxp3+ T cells, this pathway of IL-10 regulation may represent a key mechanism for modulating expression of this important immunoregulatory cytokine.

The American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO‐HNSF) has published a supplement to this issue featuring the new Clinical Practice Guideline: Bell's Palsy. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 11 recommendations developed encourage accurate and efficient diagnosis and treatment and, when applicable, facilitate patient follow‐up to address the management of long‐term sequelae or evaluation of new or worsening symptoms not indicative of Bell's palsy. There are myriad treatment options for Bell's palsy; some controversy exists regarding the effectiveness of several of these options, and there are consequent variations in care. In addition, there are numerous diagnostic tests available that are used in the evaluation of patients with Bell's palsy. Many of these tests are of questionable benefit in Bell's palsy. Furthermore, while patients with Bell's palsy enter the health care system with facial paresis/paralysis as a primary complaint, not all patients with facial paresis/paralysis have Bell's palsy. It is a concern that patients with alternative underlying etiologies may be misdiagnosed or have an unnecessary delay in diagnosis. All of these quality concerns provide an important opportunity for improvement in the diagnosis and management of patients with Bell's palsy.

Objective Bell's palsy, named after the Scottish anatomist, Sir Charles Bell, is the most common acute mono‐neuropathy, or disorder affecting a single nerve, and is the most common diagnosis associated with facial nerve weakness/paralysis. Bell's palsy is a rapid unilateral facial nerve paresis (weakness) or paralysis (complete loss of movement) of unknown cause. The condition leads to the partial or complete inability to voluntarily move facial muscles on the affected side of the face. Although typically self‐limited, the facial paresis/paralysis that occurs in Bell's palsy may cause significant temporary oral incompetence and an inability to close the eyelid, leading to potential eye injury. Additional long‐term poor outcomes do occur and can be devastating to the patient. Treatments are generally designed to improve facial function and facilitate recovery. There are myriad treatment options for Bell's palsy, and some controversy exists regarding the effectiveness of several of these options, and there are consequent variations in care. In addition, numerous diagnostic tests available are used in the evaluation of patients with Bell's palsy. Many of these tests are of questionable benefit in Bell's palsy. Furthermore, while patients with Bell's palsy enter the health care system with facial paresis/paralysis as a primary complaint, not all patients with facial paresis/paralysis have Bell's palsy. It is a concern that patients with alternative underlying etiologies may be misdiagnosed or have unnecessary delay in diagnosis. All of these quality concerns provide an important opportunity for improvement in the diagnosis and management of patients with Bell's palsy. Purpose The primary purpose of this guideline is to improve the accuracy of diagnosis for Bell's palsy, to improve the quality of care and outcomes for patients with Bell's palsy, and to decrease harmful variations in the evaluation and management of Bell's palsy. This guideline addresses these needs by encouraging accurate and efficient diagnosis and treatment and, when applicable, facilitating patient follow‐up to address the management of long‐term sequelae or evaluation of new or worsening symptoms not indicative of Bell's palsy. The guideline is intended for all clinicians in any setting who are likely to diagnose and manage patients with Bell's palsy. The target population is inclusive of both adults and children presenting with Bell's palsy. Action Statements The development group made a strong recommendation that (a) clinicians should assess the patient using history and physical examination to exclude identifiable causes of facial paresis or paralysis in patients presenting with acute‐onset unilateral facial paresis or paralysis, (b) clinicians should prescribe oral steroids within 72 hours of symptom onset for Bell's palsy patients 16 years and older, (c) clinicians should not prescribe oral antiviral therapy alone for patients with new‐onset Bell's palsy, and (d) clinicians should implement eye protection for Bell's palsy patients with impaired eye closure. The panel made recommendations that (a) clinicians should not obtain routine laboratory testing in patients with new‐onset Bell's palsy, (b) clinicians should not routinely perform diagnostic imaging for patients with new‐onset Bell's palsy, (c) clinicians should not perform electrodiagnostic testing in Bell's palsy patients with incomplete facial paralysis, and (d) clinicians should reassess or refer to a facial nerve specialist those Bell's palsy patients with (1) new or worsening neurologic findings at any point, (2) ocular symptoms developing at any point, or (3) incomplete facial recovery 3 months after initial symptom onset. The development group provided the following options : (a) clinicians may offer oral antiviral therapy in addition to oral steroids within 72 hours of symptom onset for patients with Bell's palsy, and (b) clinicians may offer electrodiagnostic testing to Bell's palsy patients with complete facial paralysis. The development group offered the following no recommendations : (a) no recommendation can be made regarding surgical decompression for patients with Bell's palsy, (b) no recommendation can be made regarding the effect of acupuncture in patients with Bell's palsy, and (c) no recommendation can be made regarding the effect of physical therapy in patients with Bell's palsy.

In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF-β and suppress mesenchymal cell adipogenesis. Using a tripotential mesenchymal cell line, we have examined whether estradiol suppression of adipocyte differentiation is due to stimulation of TGF-β and the mechanism by which TGF-β suppresses adipogenesis. We observed that estradiol-mediated suppression of adipogenic gene expression required at least 48 h treatment. TGF-β expression increased within 24 h of estradiol treatment, and TGF-β inhibition reversed estradiol influences on adipogenesis and adipocyte gene expression. Connective tissue growth factor (CTGF) mediates TGF-β suppression of adipogenesis in mouse 3T3-L1 cells. CTGF expression was induced within 24 h of TGF-β treatment, whereas estradiol-mediated induction required 48 h treatment. Moreover, estradiol-mediated induction of CTGF was abrogated by TGF-β inhibition. These data support that estradiol effects on adipogenesis involves TGF-β induction, which then induces CTGF to suppress adipogenesis.