Novel Heterocyclic Arylidene Derivatives as Anticancer Agents Against U87 Human Glioblastoma

The primary objectives of this interdisciplinary study were the synthesis of novel heterocyclic arylidenes and the investigation of their anticancer activity against U87 glioblastoma cell viability. Recently, novel hybrid derivatives have been considered as potential candidates for treating glioblastoma, demonstrating a synergistic anticancer effect in previous studies. 12 heterocyclic arylidenes with various functional groups, including halogens and boronic acid, were produced via a Knoevenagel condensation. These compounds and their starting reagents were then administered to U87 glioblastoma cancer cells at graded concentrations within a 12-well cell viability assay to determine each compound’s lethal concentration 50 (LC50). The LC50 of each compound was then compared to determine the effects of substituent type and position on anticancer activity. Although these arylidenes displayed some anticancer effects, their high LC50 suggest they have no significant effect on U87 glioblastoma cell viability and proliferation

Endovascular treatment of thoracoabdominal aortic aneurysms

ObjectiveThis study assessed the role of multibranched stent grafts for thoracoabdominal aortic aneurysm (TAAA) repair.MethodsSelf-expanding covered stents were used to connect the caudally directed cuffs of an aortic stent graft with the visceral branches of a TAAA in 22 patients (16 men, 6 women) with a mean age of 76 ± 7 years. All patients were unfit for open repair, and nine had undergone prior aortic surgery. Customized aortic stent grafts were inserted through surgically exposed femoral (n = 16) or iliac (n = 6) arteries. Covered stents were inserted through surgically exposed brachial arteries. Spinal catheters were used for cerebrospinal fluid pressure drainage in 22 patients and for and spinal anesthesia in 11.ResultsAll 22 stent grafts and all 81 branches were deployed successfully. Aortic coverage as a percentage of subclavian-to-bifurcation distance was 69% ± 20%. Mean contrast volume was 203 mL, mean blood loss was 714 mL, and mean hospital stay was 10.9 days. Two patients (9.1%) died perioperatively: one from guidewire injury to a renal arterial branch and the other from a medication error. Serious or potentially serious complications occurred in 9 of 22 patients (41%). There was no paraplegia, renal failure, stroke, or myocardial infarction among the 20 surviving patients. Two patients (9.1%) underwent successful reintervention: one for localized intimal disruption and the other for aortic dissection, type I endoleak, and stenosis of the superior mesenteric artery. One patient has a type II endoleak. Follow-up is >1 month in 19 patients, >6 months in 12, and >12 months in 8. One branch (renal artery) occluded for a 98.75% branch patency rate at 1 month. The other 80 branches remain patent. There are no signs of stent graft migration, component separation, or fracture.ConclusionsMultibranched stent graft implantation eliminates aneurysm flow, preserves visceral perfusion, and avoids many of the physiologic stresses associated with other forms of repair. The results support an expanded role for this technique in the treatment of TAAA

P-11 Novel Heterocyclic Arylidene Derivatives as Anticancer Agents against U87 Human Glioblastoma Cells

The primary objective of this research study was to investigate the efficacy of novel hybrid heterocyclic arylidenes as anticancer agents against the proliferation and invasiveness of glioblastoma cancer cells. A group of novel heterocyclic arylidenes were produced from a set of aryl aldehydes and rhodanine acetic acid in a pancreatin-catalyzed controlled reflux reaction. These compounds were subsequently administered to U87 glioblastoma cancer cells at different concentrations in a 12-well cell viability assay to determine each compound’s LC50. Compounds showed various levels of efficacy and were dependent upon the substituent composition

Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations