Dissociation of ras oncogene-induced gene expression and anchorage-independent growth in a series of somatic cell mutants

The mechanism or mechanisms by which ras oncogenes induce morphological transformation and anchorage-independent growth are poorly understood but are thought to involve stable alterations in gene expression. We previously described a genetically dominant, mutant rat fibroblast cell line (ER-1-2) that is resistant to ras-induced anchorage-independent growth. We now describe a cell line derived from ER-1-2 cells, termed ER-1-2T, that has apparently sustained a second, dominant mutation that conferred on these cells the ability to form colonies in soft agar. Analysis of these and control cell lines demonstrated that deregulation of many of the genes commonly associated with the transformed phenotype could be dissociated from anchorage-independent growth. After infection with a ras-expressing retrovirus, both control and ER-1-2 cell lines constitutively expressed elevated levels of the c-jun, junB, fosB, c-myc, collagenase, ornithine decarboxylase, osteopontin, stromelysin, cathepsin L, and insulin-like growth factor 1 genes. These data indicate that signaling events downstream of ras were largely intact in ER-1-2 cells and that the defect in these cells lies either on a pathway separate from those that control stable, ras-mediated expression of these genes or at a point in the cell-division cycle distinct from those that control expression of the genes. In contrast, only c-jun, junB, c-myc, and ornithine decarboxylase were expressed at a significantly elevated level in ER-1-2T cells. Thus, deregulated expression of the genes analyzed was not sufficient for anchorage-independent growth. Furthermore, deregulation of most of them was also not necessary. © 1996 Wiley-Liss, Inc.     

Utility and Limitations of Transient Elastography to Monitor Hepatic Steatosis,Hepatic Fibrosis,and Methotrexate-Associated Hepatic Disease in Psoriasis: A Systematic Review

ObjectivePsoriasis is associated with hepatic steatosis, fibrosis, and methotrexate-associated liver injury. There is a need for reliable methods to monitor liver disease in psoriasis. Transient elastography (TE) is a validated non-invasive method for assessing hepatic steatosis and fibrosis. Psoriasis-specific TE studies have been limited until recently. Here, we review the utility and limitations of TE to detect and monitor liver disease in the context of psoriasis.MethodsA comprehensive search using OVID, PubMed, and gray literature was conducted (2005–November 2019) to identify studies of TE use in psoriasis for assessment of hepatic steatosis and fibrosis.ResultsFifteen studies met inclusion criteria. A total of 1,536 patients with psoriasis or psoriatic arthritis were represented. TE-detected liver fibrosis is associated with age, diabetes, obesity, and severity of psoriasis. TE successfully evaluates hepatic steatosis and fibrosis. Elastography has a high negative predictive value and specificity in the context of methotrexate-associated liver fibrosis in psoriasis; however, reported associations between abnormal elastography results and cumulative methotrexate dose varied significantly despite methotrexate’s association with hepatotoxicity and fibrosis. The presence of central adiposity is associated with increased TE failure rate.LimitationThe TE studies included in this review date from 2007 to 2019, which could contribute to publication bias, as the technique of TE has improved over this time period.ConclusionTE is a useful and non-invasive modality to detect hepatic steatosis and fibrosis in psoriasis. Dermatologists might consider TE in psoriatic patients and concomitant risk factors for fibrosis with the understanding that failure rates may be higher in patients with central adiposity.     

Comparison of national antimicrobial treatment guidelines,African Union

ObjectiveTo identify and compare antimicrobial treatment guidelines from African Union (AU) Member States.MethodsWe reviewed national government agency and public health institutes’ websites and communicated with country or regional focal points to identify existing treatment guidelines from AU Member States. We included guidelines if they contained disease-, syndrome- or pathogen-specific treatment recommendations and if those recommendations included antimicrobial name or class, dosage and therapy duration. The scope of the review was limited to infections and clinical syndromes that often have a bacterial cause. We assessed treatment guidelines for alignment with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. We compared treatment recommendations for various common bacterial infections or clinical syndromes described across national guidelines and those described in three World Health Organization guidelines.FindingsWe identified 31 treatment guidelines from 20 of the 55 (36%) AU Member States; several countries had more than one treatment guideline that met our inclusion criteria. Fifteen (48%) guidelines from 10 countries have been published or updated since 2015. Methods used to develop the guidelines were not well described. No guidelines were developed according to the GRADE approach. Antimicrobial selection, dosage and duration of recommended therapies varied widely across guidelines for all infections and syndromes.ConclusionAU Member States lack antimicrobial treatment guidelines that meet internationally accepted methods and that draw from local evidence about disease burden and antimicrobial susceptibility.     

Clinical utility of postprocessed low-dose radiographs in skeletal imaging

Objectives:Radiography remains the mainstay of diagnostic and follow-up imaging. In view of the risks and the increasing use of ionizing radiation, dose reduction is a key issue for research and development. The introduction of digital radiography and the associated access to image postprocessing have opened up new opportunities to minimize the radiation dosage. These advances are contingent upon quality controls to ensure adequate image detail and maintenance of diagnostic confidence. The purpose of this study was to investigate the clinical applicability of postprocessed low-dose images in skeletal radiography.Methods:In our study setting, the median radiation dose for full dose X-rays was 9.61 dGy*cm2 for pelvis, 1.20 dGy*cm2 for shoulder and 18.64 dGy*cm2 for lumbar spine exams. Based on these values, we obtained 200 radiographs for each anatomic region in four consecutive steps, gradually reducing the dose to 84%, 71%, 60% and 50% of the baseline using an automatic exposure control (AEC). 549 patients were enrolled for a total of 600 images. All X-rays were postprocessed with a spatial noise reduction algorithm. Two radiologists assessed the diagnostic value of the radiographs by rating the visualization of anatomical landmarks and image elements on a five-point Likert scale. A mean-sum score was calculated by averaging the two reader’s total scores. Given the non-parametric distribution, we used the Mann-Whitney U test to evaluate the scores.Results:Median dosage at full dose accounted for 38.4%, 48 and 53.2% of the German reference dose area product for shoulder, pelvis and lumbar spine, respectively. The applied radiation was incrementally reduced to 21.5%, 18.4% and 18.7% of the respective reference value for shoulder, pelvis and lumbar spine. Throughout the study, we observed an estimable tendency of superior quality at higher dosage in overall image quality. Statistically significant differences in image quality were restricted to the 50% dose groups in shoulder and lumbar spine images. Regardless of the applied dosage, 598 out of 600 images were of sufficient diagnostic value.Conclusion:In digital radiography image postprocessing allows for extensive reduction of radiation dosage. Despite a trend of superior image detail at higher dose levels, overall quality and, more importantly, diagnostic utility of low-dose images was not significantly affected. Therefore, our results not only confirm the clinical utility of postprocessed low-dose radiographs, but also suggest a widespread deployment of this advanced technology to ensure further dose limitations in clinical practice.Advances in knowledge:The diagnostic image quality of postprocessed skeletal radiographs is not significantly impaired even after extensive dose reduction by up to 20% of the reference value.