in BXH-2 acute myeloid leukemia. We also show that CalDAG-GEF I encodes two protein isoforms, a full-length isoform (CalDAG-GEF Ia) and a C-terminally truncated isoform (CalDAG-GEF Ib). Expression of the full-length CalDAG-GEF Ia isoform in Rat2 fibroblasts enhances growth in low serum, whereas expression in Swiss 3T3 cells causes morphological transformation and increased saturation density. In FDCP1 myeloid cells, CalDAG-GEF Ia expression increases growth and saturation density in the presence of the diacylglycerol analogs phorbol 12-myristate 13-acetate (PMA), which activates CalDAG-GEF Ia exchange activity. Likewise, in 32Dcl3 myeloblast cells, CalDAG-GEF Ia expression increases cell adherence to fibronectin in response to PMA and calcium ionophore and allows higher saturation densities and prolonged growth on fibronectin-coated plates. These effects were correlated with increased Rap1, but not Ras, protein activation following PMA and calcium ionophore treatment. Our results suggest that Rap1-GTP delivers signals that favor progression through the cell cycle and morphological transformation. The identification of CalDAG-GEF I as a proto-oncogene in BXH-2 acute myeloid leukemia is the first evidence implicating Rap1 signaling in myeloid leukemia.
Background: The objective of this study was to determine the prevalence of some thrombophilic factors and its relation to in vitro fertilization (IVF)-embryo transfer failure in women who had had three or more previously failed IVF-embryo transfer cycles. Methods: The study group included 51 consecutive women with three or more previously failed IVF-embryo transfer cycles (group 1). The control group included 50 women who conceived spontaneously with at least one uneventful pregnancy and no previous history of miscarriage. All women were tested for the presence of factor V Leiden, prothrombin (G20210A), and methylenetetrahydrofolate reductase (C677T) mutations. Results: A similar prevalence of factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase mutations was found in both groups. At least one inherited thrombophilic factor was detected in 62.7% of women with repeated IVF failure and in 53.9% of women in group 2. No association between repeated IVF failure and these thrombophilic factors was found statistically. Conclusion: These data suggest that factor V Leiden, methylenetetrahydrofolate reductase and prothrombin gene mutation do not have a significant role in IVF-embryo transfer implantation failure.
Chordomas are rare bone tumors arising from remnants of the notochord. Molecular studies to determine the pathways involved in their pathogenesis and develop better treatments are limited. Alterations in microRNAs (miRNAs) play important roles in cancer. miRNAs are small RNA sequences that affect transcriptional and post-transcriptional regulation of gene expression in most eukaryotic organisms. Studies show that miRNA dysregulation is important for tumor initiation and progression. We compared the expression profile of miRNAs in chordomas to that of healthy nucleus pulposus samples to gain insight into the molecular pathogenesis of chordomas. Results of functional studies on one of the altered miRNAs, miR-31, are presented. The comparison between the miRNA profile of chordoma samples and the profile of normal nucleus pulposus samples suggests dysregulation of 53 miRNAs. Thirty miRNAs were upregulated in our tumor samples, while 23 were downregulated. Notably, hsa-miR-140-3p and hsa-miR-148a were upregulated in most chordomas relative to levels in nucleus pulposus cells. Two other miRNAs, hsa-miR-31 and hsa-miR-222, were downregulated in chordomas compared with the control group. Quantification with real-time polymerase chain reaction confirmed up or downregulation of these miRNAs among all samples. Functional analyses showed that hsa-miR-31 has an apoptotic effect on chordoma cells and downregulates the expression of c-MET and radixin. miRNA profiling showed that hsa-miR-31, hsa-miR-222, hsa-miR-140-3p and hsa-miR-148a are differentially expressed in chordomas compared with healthy nucleus pulposus. Our profiling may be the first step toward delineating the differential regulation of cancer-related genes in chordomas, helping to reveal the mechanisms of initiation and progression.
Background Multimorbidity raises the number of essential information needed for delivery of high-quality care in patients with chronic diseases like rheumatoid arthritis (RA). We evaluated an innovative ICT platform for integrated care which orchestrates data from various health care providers to optimize care management processes. Methods The Horizon2020-funded research project PICASO (picaso-project.eu) established an ICT platform that offers integration of care services across providers and supports patients’ management along the continuum of care, leaving the data with the owner. Strict conformity with ethical and legal legislations was augmented with a usability-driven engineering process, user requirements gathering from relevant stakeholders, and expert walkthroughs guided developments. Developments based on the HL7/FHIR standard granting interoperability. Platform’s applicability in clinical routine was an essential aim. Thus, we evaluated the platform according to an evaluation framework in an observational 6-month proof-of-concept study with RA patients affected by cardiovascular comorbidities using questionnaires, interviews, and platform data. Results Thirty RA patients (80% female) participated, mean age 59 years, disease duration 13 years, average number of comorbidities 2.9. Home monitoring data demonstrated high platform adherence. Evaluations yielded predominantly positive feedback: The innovative dashboard-like design offering time-efficient data visualization, comprehension, and personalization was well accepted, i.e., patients rated the platform “overall” as 2.3 (1.1) (mean (SD), Likert scales 1–6) and clinicians recommended further platform use for 93% of their patients. They managed 86% of patients’ visits using the clinician dashboard. Dashboards were valued for a broader view of health status and patient-physician interactions. Platform use contributed to improved disease and comorbidity management (i.e., in 70% physicians reported usefulness to assess patients’ diseases and in 33% potential influence on treatment decisions; risk manager was used in 59%) and empowered patients (i.e., 48% set themselves new health-related goals, 92% stated easier patient-physician communications). Conclusion Comprehensive aggregation of clinical data from distributed sources in a modern, GDPR-compliant cloud platform can improve physicians’ and patients’ knowledge of the disease status and comorbidities as well as patients’ management. It empowers patients to monitor and positively contribute to their disease management. Effects on patients’ outcome, behavior, and changes in the health care systems should be explored by implementing ICT-based platforms enriched by upcoming Artificial Intelligence features where possible. Trial registration DRKS—German Clinical Trials Register, DRKS00013637, prospectively registered. 17 January 2018.
Background Mobile medical applications (Apps) offer innovative solutions for patients’ self-monitoring and new patient management opportunities. Prior to routine clinical application feasibility and acceptance of disease surveillance using an App that includes electronic (e) patient-reported outcome measures (PROMs) warrant evaluation. Therefore, we performed a proof-of-concept study in which rheumatoid arthritis (RA) patients used an App (RheumaLive) to document their disease. Methods Accurate PROM reporting via an App in comparison to paper-based versions was investigated to exclude media bias. Sixty participants recruited from 268 consecutive RA outpatients completed paper-based and electronic PROMs (Hannover Functional Questionnaire/derived HAQ; modified RA disease activity index) using the App at baseline and follow-up visits. Between visits, patients used their App on their own smartphone according to their preferences. The equivalence of PROM data and user experiences from patients and physicians were evaluated. Results Patients’ (78.3% female) mean (SD) age was 50.1 (13.1) years, disease duration 10.5 (9.1) years, and paper-based HAQ 0.78 (0.59). Mean confidence in Apps scored 3.5 (1.1, Likert scale 1 to 6). ePROMs’ scores obtained by patients’ data entry in the App were equivalent to paper-based ones and preferred by the patients. After 3 months, the App retention rate was 71.7%. Patients' overall satisfaction with the App was 2.2 (0.9, Likert scale 1 to 6). Patients and physicians valued the App, i.e., for patient-physician interaction: 87% reported that it was easier for them to document the course of the disease using the App than “only” answering questions about their current health during routine outpatient visits. Further App use was recommended in 77.3% of the patients, and according to physicians, in seven patients, the App use contributed to an increased adherence to therapy. Conclusion Our study provides an essential basis for the broader implementation of medical Apps in routine care. We demonstrated the feasibility and acceptance of disease surveillance using a smartphone App in RA. App use was convincing as a reliable option to perform continuous, remote monitoring of disease activity and treatment efficacy. Trial registration ClinicalTrials.gov, NCT02565225. Registered on September 16, 2015 (retrospectively registered).
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