STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of ,, , and Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.
PRMT5, which regulates gene expression by symmetric dimethylation of histones and non-histone target proteins, is overexpressed and plays a pathogenic role in many cancers. In diffuse large B cell lymphoma (DLBCL), the mechanisms of PRMT5 dysregulation and its role in lymphomagenesis remain largely unknown. Here we demonstrate that B cell receptor (BCR) signaling regulates PRMT5 expression in DLBCL cells. Immunohistochemical analysis reveals elevated levels of PRMT5 expression in DLBCL cases and in germinal center (GC) B cells when compared to naive B cells. PRMT5 can be induced in naive B cells by BCR stimulation. We discovered that BTK-NF-κB signaling induces PRMT5 transcription in activated B cell-like (ABC) DLBCL cells while BCR downstream PI3K-AKT-MYC signaling upregulates PRMT5 expression in both ABC and GCB DLBCL cells. PRMT5 inhibition inhibits the growth of DLBCL *
Purpose: To characterize the relationships between disclosed conflicts of interest (COIs) and publication type in the Journal of Vascular and Interventional Radiology (JVIR) to identify opportunities to support the integrity of interventional radiology (IR) research. Materials and Methods: All JVIR publications in 2019 were cataloged based on publication category, official JVIR publication type, device focus, COI disclosure, and whether or not they were a part of CME and Society of Interventional Radiology (SIR) annual meetings. Publication categories included Primary Research, Systematic Review, and Other. Primary Research included the publication types Clinical Study, Laboratory Investigation, and Research in Translation; Systematic Review included Evidence-Based Review, Review Article, and Standards of Practice; Other included the remainder (e.g., Letter to the Editor or Commentary). Prevalence of COIs and device focus was characterized and compared within the various publication cohorts using Fisher's exact tests with statistical significance defined as P .05. Results: A total of 397 JVIR publications, 114 with COIs (29%) and 68 with device focus (17%), were evaluated. Prevalence of COIs was significantly lower in Other compared to Systematic Review (25% vs 50%, P ¼ .04), but not between Systematic Review and Primary Research (P ¼ .16) or between Other and Primary Research (P ¼ .21). Prevalence of device focus did not vary significantly among Primary Research, Systematic Review, and Other (c2-test P ¼ .20). COIs were more prevalent in device-focused papers (54% vs 23%, P< .0001), and this trend continued in Primary Research (61% vs 23%, P< .0001), Clinical Study (55% vs 23%, P ¼ .001), Laboratory Investigation (78% vs 23%, P ¼ .03), Letter to the Editor (45% vs 16%, P ¼ .01), and publications presented at SIR annual meetings (100% vs 30%, P ¼ .02). There was no significant relationship between COI and device focus among Systematic Review and publications that qualified for CME credit. Conclusions: Disclosed COIs are prevalent in IR research. They are more common in device-focused publications, especially in Laboratory Investigations and those presented at SIR annual meetings. Because previous work has suggested that bias associated with COIs is often incompletely managed, it may be particularly important for IR to develop innovative means of managing COIs to ensure the integrity of research in the field.
Introduction: Anemia is associated with increased morbidity and mortality in patients with acute ischemic stroke (AIS). However, it is unclear if management of anemia after stroke can improve outcomes. Objective: To assess the impact of anemia, and its treatment, on AIS patient outcomes. Methods: Adult AIS patients admitted to a rural academic medical center for primary stroke between 1/1/2012 - 12/31/2016 were included. Patient medical records were reviewed for relevant health information. Results: A sample of 753 patients treated for AIS was evaluated. Moderate or severe anemia (hemoglobin < 11 g/dL for both sexes) was associated with increased mortality at 6 months (57.6% [45.0-68.3], 80.3% [72.9-85.9], 86.9% [83.6-89.5] for moderate/severe, mild and no anemia, respectively; p< 0.0001). This difference in survival was still seen after adjustments for other covariables, such as age, renal insufficiency, atrial fibrillation, heart failure and diabetes mellitus, in multivariate analysis. Following AIS, only 41% (90/219) of patients with anemia had documented management of anemia. We did not detect a difference in long term survival or stroke recurrence for managed vs. unmanaged patients. However, the anemia management most often occurred in the months following stroke, while anemia had the largest impact on outcome in the initial weeks after stroke. Conclusions: This study confirmed the poor prognosis seen with moderate and severe anemia after AIS. The lack of difference in outcome for managed vs. unmanaged patients may reflect the fact that the adverse effect of anemia was greatest in the first days to weeks after stroke while management was undertaken later. Thus, more aggressive treatment of anemia in patients at risk for stroke may be beneficial. In conclusion, more investigation into the relationship between anemia treatment and stroke mortality is warranted, such as a prospective study looking at management of anemia in patients with stroke risk factors.
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