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Background and Objectives: The Albumin-to-Alkaline Phosphatase ratio (AAPR) is an easily applicable and cost-effective marker investigated as an outcome predictor in solid cancers. Preliminary evidence in breast cancer suggests that a low AAPR correlates with a poor response to neoadjuvant chemotherapy (NAC) in primary tumors. However, data regarding the axillary response are lacking. This study aims to evaluate whether the AAPR can predict the axillary response in initially nodal-positive (cN+) breast cancer patients undergoing NAC. Materials and Methods : Clinical and biochemical variables of cN+ breast cancer patients undergoing NAC were collected. Pre-NAC albumin and alkaline phosphatase serum values were utilized in the AAPR calculation. Fisher's exact test was performed to identify differences between the two groups of patients (high and low AAPR according to the cut-off reported in the literature). The primary outcome was the nodal pathologic complete response (pCR) rate in the two groups of patients. Results: Nodal pCR was achieved in 20/45 (44.4%) patients. A total of 36/45 (80%) patients had an AAPR > 0.583. Among patient and tumor characteristics, the only statistically significant difference between the two groups was the axillary pCR between the low and high AAPR groups ( p -value = 0.03, OR = 0.129, 95% CI = 0.00-0.835). Conclusions: This pilot study suggests that the pre-treatment AAPR might be an early predictor of axillary response in cN+ breast cancer patients undergoing NAC. This result justifies further investigation in larger prospective trials to validate this finding.

Background: Within the Open Biological and Biomedical Ontology (OBO) Foundry, many ontologies represent the execution of a plan specification as a process in which a realizable entity that concretizes the plan specification, a "realizable concretization" (RC), is realized. This representation, which we call the "RC-account", provides a straightforward way to relate a plan specification to the entity that bears the realizable concretization and the process that realizes the realizable concretization. However, the adequacy of the RC-account has not been evaluated in the scientific literature. In this manuscript, we provide this evaluation and, thereby, give ontology developers sound reasons to use or not use the RC-account pattern., Results: Analysis of the RC-account reveals that it is not adequate for representing failed plans. If the realizable concretization is flawed in some way, it is unclear what (if any) relation holds between the realizable entity and the plan specification. If the execution (i.e., realization) of the realizable concretization fails to carry out the actions given in the plan specification, it is unclear under the RC-account how to directly relate the failed execution to the entity carrying out the instructions given in the plan specification. These issues are exacerbated in the presence of changing plans., Conclusions: We propose two solutions for representing failed plans. The first uses the Common Core Ontologies 'prescribed by' relation to connect a plan specification to the entity or process that utilizes the plan specification as a guide. The second, more complex, solution incorporates the process of creating a plan (in the sense of an intention to execute a plan specification) into the representation of executing plan specifications. We hypothesize that the first solution (i.e., use of 'prescribed by') is adequate for most situations. However, more research is needed to test this hypothesis as well as explore the other solutions presented in this manuscript., (© 2024. The Author(s).)

Objective: To use software, datasets, and data formats in the domain of Infectious Disease Epidemiology as a test collection to evaluate a novel M1 use case, which we introduce in this paper. M1 is a machine that upon receipt of a new digital object of research exhaustively finds all valid compositions of it with existing objects., Method: We implemented a data-format-matching-only M1 using exhaustive search, which we refer to as M1 DFM . We then ran M1 DFM on the test collection and used error analysis to identify needed semantic constraints., Results: Precision of M1 DFM search was 61.7%. Error analysis identified needed semantic constraints and needed changes in handling of data services. Most semantic constraints were simple, but one data format was sufficiently complex to be practically impossible to represent semantic constraints over, from which we conclude limitatively that software developers will have to meet the machines halfway by engineering software whose inputs are sufficiently simple that their semantic constraints can be represented, akin to the simple APIs of services. We summarize these insights as M1-FAIR guiding principles for composability and suggest a roadmap for progressively capable devices in the service of reuse and accelerated scientific discovery., Conclusion: Algorithmic search of digital repositories for valid workflow compositions has potential to accelerate scientific discovery but requires a scalable solution to the problem of knowledge acquisition about semantic constraints on software inputs. Additionally, practical limitations on the logical complexity of semantic constraints must be respected, which has implications for the design of software., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Metabolic and bariatric surgery (MBS) venous thromboembolism (VTE) prescribing practices vary widely. Our institutional VTE prophylaxis protocol has historically been unstandardized., Objectives: To create a standardized MBS VTE prophylaxis protocol, track protocol compliance, and identify barriers to protocol compliance and address them with Plan-Do-Study-Act (PDSA) cycles., Setting: Single Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited academic hospital., Methods: We conducted a retrospective study for all patients undergoing MBS (January 2019 to September 2022). A multidisciplinary group of bariatric clinicians reviewed literature and developed the following standardized VTE prophylaxis protocol: 5000 units preoperative subcutaneous (SC) heparin within 60 minutes of anesthesia induction and postoperative 40 mg SC low molecular weight heparin (LMWH) within 24 hours of surgery. This protocol was distributed to relevant clinical stakeholders. We assessed monthly compliance rates through chart review. Goal compliance was ≥90%. We identified sources of noncompliance and addressed them with PDSA methodology., Results: A total of 796 patients were included. Preoperative heparin administration increased from a mean of 47% (107/228) preintervention to 96% (545/568) postintervention (P < .0001), and postoperative LMWH administration increased from 71% (47/66) to 96% (573/597, P = .0002). These compliance rates were sustained for 3 years. Barriers to protocol noncompliance included order set timing errors (n = 45), surgeon error (n = 44), surgeon discretion (n = 40), and nursing error (n = 20). No change in bleeding or VTE rates was observed., Conclusions: Developing a standardized VTE prophylaxis protocol, monitoring process measures, and engaging relevant stakeholders in PDSA cycles resulted in drastic and durable improvement in VTE prophylaxis compliance rates., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: It is critical to ensure appropriate and consistent sleeve size and orientation during laparoscopic sleeve gastrectomy (LSG). Various devices are used to achieve this, including weighted rubber bougies, esophagogastroduodenoscopy (EGD), and suction calibration systems (SCS). Prior reports suggest that SCSs may decrease operative time and stapler load firings but are limited by single-surgeon experience and retrospective design. We performed the first randomized controlled trial comparing SCS against EGD in patients undergoing LSG to investigate whether the SCS decreases the number of stapler load firings., Methods: This was a randomized, non-blinded study from a single MBSAQIP-accredited academic center. Appropriate LSG candidates ≥ 18 years of age were randomized to EGD or SCS calibration. Exclusion criteria included prior gastric or bariatric surgery, detection of hiatal hernia before surgery, and intraoperative hiatal hernia repair. A randomized block design was employed controlling for body mass index, gender, and race. Seven surgeons employed a standardized LSG operative technique. The primary endpoint was the number of stapler load firings. Secondary endpoints were operative duration, reflux symptoms, and change in total body weight (TBW). Endpoints were analyzed via t-test., Results: A total of 125 LSG patients (84% female) underwent study enrollment, with an average age of 44 ± 12 years and average BMI of 49 ± 8 kg/m 2 . Overall, 117 patients were randomized to receive EGD (n = 59) or SCS (n = 58) calibration. No significant differences in baseline characteristics were identified. The mean number of stapler load firings for EGD and SCS groups were 5.43 ± 0.89 and 5.31 ± 0.81, respectively (p = 0.463). The mean operative times for EGD and SCS groups were 94.4 ± 36.5 and 93.1 ± 27.9 min, respectively (p = 0.83). There were no significant differences in post-operative reflux, TBW loss, or complications., Conclusion: Use of EGD and SCS resulted in a similar number of LSG stapler load firings and operative duration. Additional research is needed to compare LSG calibration devices in different patients and settings to optimize surgical technique., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The use of integrative approaches for symptom management is highly prevalent among patients undergoing cancer treatment and among cancer survivors and is increasingly endorsed by clinical practice guidelines. However, access to and implementation of integrative oncology (IO) approaches are hindered by barriers at multiple levels, including logistic, geographic, financial, organizational, and cultural barriers. The goal of this mixed-method study was to examine oncology provider and patient knowledge, beliefs, and preferences in IO to identify facilitators, barriers, and recommendations for implementation of IO modalities., Materials and Methods: Data sources included patient surveys and provider semistructured interviews. Patients were in active treatment ( n  = 100) and survivors ( n  = 100) of heterogeneous cancer types. Patient and survivor surveys interrogated: (1) interest in types of IO approaches; and (2) preferences for delivery modality, frequency, and location. Providers ( n  = 18) were oncologists and nurse navigators working with diverse cancer types. Interviews queried their knowledge of and attitudes about IO, about their patients' needs for symptom management, and for recommendations for implementation of IO approaches in their clinic. We used the Consolidated Framework for Implementation Research framework to systematically analyze provider interviews., Results: The primary interests reported among actively treated patients and survivors were massage therapy, acupuncture, and wellness/exercise. Most patients expressed interest in both group and individual sessions and in telehealth or virtual reality options. Emergent themes from provider interviews identified barriers and facilitators to implementing IO approaches in both the internal and external settings, as well as for the implementation process., Conclusion: The emphasis on mind-body interventions as integrative rather than alternative highlights the importance of interventions as evidence-based, comprehensive, and integrated into health care. Gaining simultaneous perspectives from both patients and physicians generated insights for the implementation of IO care into complex clinical systems within a comprehensive cancer center., Competing Interests: No competing financial interests exist., (© Jennifer S. Mascaro et al., 2022; Published by Mary Ann Liebert, Inc.)

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage loss and reduced joint function. OA risk factors are age and obesity. Many adipokines are altered by obesity but also OA although systemic adipokine regulation in OA is not always clear. Therefore, metabolic effects of diet-induced obesity on OA development as well as the influence of obesity and OA progression on systemic vs. local adipokine expression in joints were compared. C57Bl/6-mice fed with HFD (high fat diet) or normal diet prior to destabilization of the medial meniscus (DMM) were sacrificed 4/6/8 weeks after surgery. Sera were evaluated for adiponectin, leptin, visfatin, cytokines. Liver grading and staging for non-alcoholic steatohepatitis (NASH) was performed and crown-like structures (CLS) in adipose tissue measured. OA progression was scored histologically. Adipokine-expressing cells and types were evaluated by immunohistochemistry. Time-dependent changes in DMM-progression were reflected by increased systemic adiponectin levels in DMM especially combined with HFD. While HFD increased serum leptin, DMM reduced systemic leptin significantly. OA scores correlated with bodyweight, leptin and hepatic scoring. Locally, increased numbers of adiponectin- and leptin-producing fibroblasts were observed in damaged menisci but visfatin was not changed. Local adipokine expression was independent from systemic levels, suggesting different mechanisms of action., (© 2021. The Author(s).)

An individual's health and conditions are associated with a complex interplay between the individual's genetics and his or her exposures to both internal and external environments. Much attention has been placed on characterizing of the genome in the past; nevertheless, genetics only account for about 10% of an individual's health conditions, while the remaining appears to be determined by environmental factors and gene-environment interactions. To comprehensively understand the causes of diseases and prevent them, environmental exposures, especially the external exposome, need to be systematically explored. However, the heterogeneity of the external exposome data sources (e.g., same exposure variables using different nomenclature in different data sources, or vice versa, two variables have the same or similar name but measure different exposures in reality) increases the difficulty of analyzing and understanding the associations between environmental exposures and health outcomes. To solve the issue, the development of semantic standards using an ontology-driven approach is inevitable because ontologies can (1) provide a unambiguous and consistent understanding of the variables in heterogeneous data sources, and (2) explicitly express and model the context of the variables and relationships between those variables. We conducted a review of existing ontology for the external exposome and found only four relevant ontologies. Further, the four existing ontologies are limited: they (1) often ignored the spatiotemporal characteristics of external exposome data, and (2) were developed in isolation from other conceptual frameworks (e.g., the socioecological model and the social determinants of health). Moving forward, the combination of multi-domain and multi-scale data (i.e., genome, phenome and exposome at different granularity) and different conceptual frameworks is the basis of health outcomes research in the future., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pain is a primary concern among patients with cancer and cancer survivors. Integrative interventions such as acupuncture, massage, and music therapy are effective nonpharmacologic approaches for cancer pain with low cost and minimal adverse events. Patient-reported outcomes (PROs) that have been validated in many clinical and research settings can be used to evaluate pain intensity, associated symptom burden, and quality of life. Clearly defined, reliable PROs can improve patient satisfaction and symptom control. As integrative oncology continues to evolve and expand, cancer-related pain PROs must be standardized to accurately guide clinicians and researchers. Well-validated pain PROs, such as the Brief Pain Inventory, are among the most commonly used for pain intensity assessment. Multiple symptom assessment tools such as the MD Anderson Symptom Inventory, the Memorial Symptom Assessment Scale, the Edmonton Symptom Assessment System, and the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events measurement system can also capture pain-associated symptom burden. Electronic PROs provide flexibility in collecting and analyzing PRO data. Clinical trials using carefully selected PROs and rigorous statistical analysis plans are fundamental to conducting high-quality integrative oncology research and promoting utilization of effective integrative interventions to improve patient outcomes. In this review, we aim to summarize current, validated PROs specific to cancer-related pain to aid integrative oncology clinicians and researchers in patient care and in study design and implementation.

Background: The symbiotic interactions that occur between humans and organisms in our environment have a tremendous impact on our health. Recently, there has been a surge in interest in understanding the complex relationships between the microbiome and human health and host immunity against microbial pathogens, among other things. To collect and manage data about these interactions and their complexity, scientists will need ontologies that represent symbiotic interactions as they occur in reality., Methods: We began with two papers that reviewed the usage of 'symbiosis' and related terms in the biology and ecology literature and prominent textbooks. We then analyzed several prominent standard terminologies and ontologies that contain representations of symbiotic interactions, to determine if they appropriately defined 'symbiosis' and related terms according to current scientific usage as identified by the review papers. In the process, we identified several subtypes of symbiotic interactions, as well as the characteristics that differentiate them, which we used to propose textual and axiomatic definitions for each subtype of interaction. To both illustrate how to use the ontological representations and definitions we created and provide additional quality assurance on key definitions, we carried out a referent tracking analysis and representation of three scenarios involving symbiotic interactions among organisms., Results: We found one definition of 'symbiosis' in an existing ontology that was consistent with the vast preponderance of scientific usage in biology and ecology. However, that ontology changed its definition during the course of our work, and discussions are ongoing. We present a new definition that we have proposed. We also define 34 subtypes of symbiosis. Our referent tracking analysis showed that it is necessary to define symbiotic interactions at the level of the individual, rather than at the species level, due to the complex nature in which organisms can go from participating in one type of symbiosis with one organism to participating in another type of symbiosis with a different organism., Conclusion: As a result of our efforts here, we have developed a robust representation of symbiotic interactions using a realism-based approach, which fills a gap in existing biomedical ontologies.

Objective: The long-distance migration of rheumatoid arthritis synovial fibroblasts (RASFs) in the severe combined immunodeficiency (SCID) mouse model of rheumatoid arthritis (RA) suggests that an interaction between RASFs and endothelial cells (EC) is critical in this process. Our objective was to assess whether immunomodulatory factors such as adipokines and antirheumatic drugs affect the adhesion of RASFs to ECs or the expression of surface molecules. Methods: Primary ECs or human umbilical vein endothelial cell (HUVEC) and primary RASFs were stimulated with adiponectin (10 μg/mL), visfatin (100 ng/mL), and resistin (20 ng/mL) or treated with methotrexate (1.5 and 1,000 μM) and the glucocorticoids prednisolone (1 μM) and dexamethasone (1 μM), respectively. The expression of adhesion molecules was analyzed by real-time polymerase chain reaction. The interaction of both cell types was analyzed under static (cell-to-cell binding assay) and dynamic conditions (flow-adhesion assay). Results: Under static conditions, adipokines increased mostly binding of RASFs to EC (adiponectin: 40%, visfatin: 28%, tumor necrosis factor α: 49%). Under flow conditions, visfatin increased RASF adhesion to HUVEC (e.g., 0.5 dyn/cm 2 : 75.2%). Reduced adhesion of RASFs to E-selectin was observed after treatment with dexamethasone (e.g., 0.9 dyn/cm 2 : -40%). In ECs, tumor necrosis factor α (TNF-α) increased expression of intercellular adhesion molecule 1 (20-fold) and vascular cell adhesion molecule 1 (77-fold), whereas P-selectin was downregulated after stimulation with TNF-α (-6-fold). Conclusion: The adhesion of RASFs to EC was increased by visfatin under static and flow conditions, whereas glucocorticoids were able to decrease adhesion to E-selectin. The process of migration and adhesion of RASFs to ECs could be enhanced by adipokines via adhesion molecules and seems to be targeted by therapeutic intervention with glucocorticoids., (Copyright © 2020 Hasseli, Frommer, Schwarz, Hülser, Schreiyäck, Arnold, Diller, Tarner, Lange, Pons-Kühnemann, Schönburg, Rehart, Müller-Ladner and Neumann.)

Background: Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown., Methods: Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1β or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot., Results: In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1β and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin., Conclusion: The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment.

Objectives: The immunomodulatory properties of adipokines have previously been reported in autoimmune disorders. Less is known about the role of adipokines in systemic sclerosis (SSc). Lung and gastrointestinal tract are frequently involved in SSc; therefore, these organs were analyzed for adipokine expression as well as pulmonary samples of patients suffering from idiopathic pulmonary fibrosis (IPF) as comparison., Methods: Gastric samples (antrum, corpus) of SSc were analyzed immunohistochemically for adiponectin, resistin and visfatin compared with non-SSc related gastritis. Inflammatory cells were quantified in gastric samples and correlated with adipokine expression. Lung samples of SSc, IPF and healthy controls were also analyzed. Protein levels of lung tissue lysates and bronchoalveolar lavages (BAL) in minor fibrotic stages were measured by ELISA., Results: Lung sections of donor parenchyma showed significantly stronger adiponectin signals as IPF and SSc (donor vs. IPF: p < 0.0001). In SSc and IPF, resistin and visfatin were increased within immune cell infiltrates, but overall no difference in expression for resistin or visfatin compared to controls was observed. In BAL and lung protein lysates of early stages of fibrosis, adiponectin and visfatin were not reduced in IPF and SSc compared to controls. In gastric samples collected by standard endoscopic gastric biopsy, adiponectin was also significantly reduced in SSc- compared to non-SSc gastritis (p = 0.049) while resistin and visfatin were comparable although deeper fibrotic layers were not included in the respective samples. Adiponectin-positive tissues showed higher amounts of CD4 + but not CD8 + T cells. Controls showed no correlation between CD4 + T cells and resistin, whereas SSc showed significantly more CD4 + T cells in resistin-negative tissues., Conclusion: Adipokines are expressed in gastric and lung samples of patients with SSc and in lung samples affected by IPF. Prominently, adiponectin levels were reduced in fibrotic SSc gastritic tissue as well as in IPF and SSc lung tissue. Consequently, adiponectin expression seems to be associated with fibrotic progression in the context of SSc and IPF., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF. Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay. Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion. Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo . In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.

Background: The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication., Results: In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action., Conclusions: A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

Muskuloskeletal ultrasound and dual-energy-CT (DECT) findings are increasingly relevant for the establishment of the diagnosis of gout, and are therefore incorporated into the novel ACR / EULAR classification criteria. Canakinumab, a monoclonal antibody directed against interleukin-1β (IL-1β) has been approved in 2013 for the treatment of acute gout and for prophylaxis of flares. In patients demonstrating an inadequate response upon treatment with allopurinol or febuxostat, combination therapy with lesinurad might reduce uric acid levels to the target of < 6 mg / dl (< 5 mg / dl in tophaceous gout). Rapid lowering of uric acid levels and effective tophi reduction can be achieved with pegloticase, which can be utilized in selected patients presenting contraindications to xanthine oxidase inhibitors and uricosuric drugs. This article summarizes current scientific aspects of diagnosis, treatment and comorbidities of gout in the context of clinical relevance., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Local application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract breast cancer therapy. Thus, vaginal application of estriol (E3) has been recommended for these patients. However, it is unclear to what extent E3 stimulates breast cancer cell growth. In this study, we examined the effect of E3 on growth and gene expression of two human breast cancer cell lines., Methods: We used an established in vitro cell culture assay and compared the effect of E2 and E3 on growth of the estrogen receptor alpha-positive breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone concentrations of 10(-12)-10(-7)M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis., Results: E3 acted as a potent estrogen and exerted a mitogenic effect on T-47D and MCF-7 cells at concentrations of 10(-9)M (288 pg/ml) and higher. With regard to activation of an estrogen response element (ERE) in breast cancer cells, effects of E3 were visible at 10(-10)M. The same concentrations of E3 activated expression of the estrogen-responsive gene PR and of the proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing molecular mechanisms underlying the observed growth increase., Conclusions: Like E2, low levels of E3 were able to trigger a robust estrogenic response in breast cancer cells. Thus, our data suggest caution regarding use of E3 by breast cancer survivors., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)