1.
Etoposide combined with ruxolitinib for refractory hemophagocytic lymphohistiocytosis during pregnancy: a case report and literature review.
Wang, S, Wu, J, Jing, X, Zhang, Y, Tang, H, Wu, J
Hematology (Amsterdam, Netherlands). 2019;(1):751-756
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder caused by uncontrolled inflammatory responses and the activation of T lymphocytes. This life-threatening disease, characterized by fever, cytopenia and hepatosplenomegaly, is extremely rare during pregnancy with high mortality. Despite the improvement of treatment regimen in recent years, HLH is still a great challenge for clinicians. Here, we described a 26-year-old woman who admitted to our hospital at her first pregnancy with pyrexia. Her condition continued to deteriorate after receiving broad-spectrum antimicrobials, presenting with fever, pancytopenia, hepatosplenomegaly, ferritin ≥ 500 μg/L, hemophagocytosis and low NK-cell activity. HLH was eventually diagnosed by clinical manifestation and laboratory examination results. Then the patient recovered well after treatment with etoposide combined with ruxolitinib therapy and underwent successful induced-labor operation. Additionally, we summarized similar cases from the literature to improve the management of HLH during pregnancy. In conclusion, this study highlights the challenges and difficulties in the diagnosis and management of patients with HLH during pregnancy. Moreover, this is the first case report of etoposide combined with ruxolitinib in the treatment of patients with refractory secondary HLH during pregnancy.
2.
Cytokine changes in response to TPO receptor agonist treatment in primary immune thrombocytopenia.
Qu, MM, Liu, XN, Liu, XG, Feng, Q, Liu, Y, Zhang, X, Liu, S, Zhang, L, Li, GS, Zhu, YY, et al
Cytokine. 2017;:110-117
Abstract
Thrombopoietin receptor agonists (TPO-RAs) have been clinically used in primary immune thrombocytopenia (ITP) with favorable outcomes, while their effect on cytokine regulation in ITP remains unknown. In the present study, plasma and mRNA expression levels of interleukin (IL)-2, interferon gamma (IFN-γ), IL-4, IL-17A, and transforming growth factor-β1 (TGF-β1) were determined by ELISA and real-time quantitative PCR in 26 corticosteroid-resistant/relapsed ITP patients receiving eltrombopag or rhTPO therapy and 15 healthy controls (HCs). Results showed that plasma and mRNA levels of IL-2, IFN-γ, IL-4, and IL-17A in ITP patients did not change significantly after TPO-RA treatment, whereas TGF-β1 levels increased remarkably. The pre- and post-treatment plasma and mRNA levels of IFN-γ and IL-2 were significantly higher, while the pre- and post-treatment IL-4 levels as well as the pre-treatment TGF-β1 levels were remarkably lower in ITP patients compared with HCs. There was no significant difference in TGF-β1 levels between TPO-RA-treated ITP patients and HCs. No statistical difference was found in plasma levels of IL-17A between ITP patients before or after treatment and HCs. However, the pre- and post-treatment mRNA expression of IL-17A and retinoic orphan receptor (ROR) γt in ITP patients were higher than that in HCs. Overall, these findings indicated that TPO-RA treatment could promote the secretion of TGF-β1, while it could not correct the Th1 and Th17 polarization in ITP patients. This study might improve our understanding of the mechanism of action of TPO-RAs and provide important information for optimizing therapeutic strategies for ITP.
3.
Endocannabinoids regulate adipokine production and the immune balance of omental adipose tissue in human obesity.
Ge, Q, Maury, E, Rycken, L, Gérard, J, Noël, L, Detry, R, Navez, B, Brichard, SM
International journal of obesity (2005). 2013;(6):874-80
Abstract
OBJECTIVES (1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms. SUBJECTS AND METHODS OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m(-2)) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used. RESULTS In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1β was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation. CONCLUSIONS Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1β and IL-7. ApN regulation by the ES partly involves p38MAPK.
4.
COX-2 inhibitors celecoxib and rofecoxib prevent oxidative DNA fragmentation.
Matthias, C, Schuster, MT, Zieger, S, Harréus, U
Anticancer research. 2006;(3A):2003-7
Abstract
BACKGROUND Cyclooxygenase (COX) is the key regulatory enzyme in prostaglandin (PG) synthesis and is up-regulated in many premalignant and malignant lesions. The aim of this study was to investigate the in vitro DNA protective or damaging effects of COX-2 inhibitors using the single-cell gel electrophoresis (Comet) assay. MATERIALS AND METHODS Cells from miniorgan cultures of pharyngeal mucosa from 30 patients were incubated once or five times with the COX-2 inhibitors celecoxib and rofecoxib. After treatment with H2O2, DNA fragmentation was determined. RESULTS DNA strand-breaks were significantly reduced in cells pre-incubated with COX-2 inhibitors. Repeated incubation with celecoxib showed the strongest effect. This direct influence on DNA repair could be excluded by implementing DNA repair steps into the Comet assay. CONCLUSION The findings suggest that, in addition to the known influence of COX-2 inhibitors on immune surveillance, neo-angiogenesis and cell proliferation, these substances may express a direct antimutagenic effect in conditions of oxidative stress.