SUMMARY Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by NF-κB accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA polymerase and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer mediated inflammatory transcription, atherogenic endothelial responses and atherosclerosis in vivo.
SUMMARY Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1.
Novel cancer therapies targeting tumor angiogenesis have revolutionized treatment options in a variety of tumors. Specifically, VEGF signaling pathway (VSP) inhibitors have been introduced into clinical practice at a rapid pace over the last decade. It is becoming increasingly clear that VSP inhibitors can cause cardiovascular toxicities including hypertension, thrombosis, and heart failure. This review highlights these toxicities and proposes several strategies in their prevention and treatment. However, we recognize the dearth of data in this area and advocate a multi-disciplinary approach involving cardiologists and oncologists, as well as clinical and translational studies, in understanding and treating VSP-inhibitor associated toxicities.
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Background. Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and Methods. Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progressionfree survival (PFS), duration of response, and overall survival (OS). Results. Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. Conclusion. In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials.
Iron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT), but the mechanisms leading to overload are unknown. Here, we determined iron levels and the expression of iron regulatory proteins in the liver and gut of nonobese diabeticsevere combined immunodeficient (NOD/ SCID) mice that underwent transplantation with syngeneic (histocompatible) or allogeneic (histoincompatible) T lymphocytes. Infusion of histoincompatible T cells resulted in a significant rise in serum iron levels and liver iron content. IntroductionIron overload is common in patients undergoing hematopoietic cell transplantation (HCT). 1-3 Many of these patients develop iron overload even without heavy red cell transfusion support; the mechanisms are largely unknown. High-dose conditioning preceding HCT may result in hyperferremia and increased non-transferrinbound iron, in association with the cessation of erythropoietic activity. 4,5 In many patients hyperferremia persists after HCT, 1,2 suggesting aberrant iron release into the circulation.The major regulator of iron release into the circulation is hepcidin (Hamp), secreted mainly by the liver. 6 Hepcidin binds to the iron transporter ferroportin 1 (Fpn), expressed on enterocytes and macrophages, which delivers iron from inside the cell to the circulation. 7 Hepcidin binding results in internalization and cytoplasmic degradation of ferroportin. As both the intestinal tract and liver are targets of graft-versus-host disease (GVHD), 2,8,9 we hypothesized that one effect of allogeneic transplantation may be direct or indirect interference by T lymphocytes with the expression or function of iron regulatory proteins in liver and gut, thereby contributing to iron overload. Here we characterized Hamp and Fpn expression and dietary iron uptake in a murine model of histoincompatible allogeneic T-lymphocyte transplantation. MethodsFemale NOD/LtSz-scid/scid (NOD/SCID [H-2d]), C57BL/6J (H-2b), and BALB/cJ mice (H-2d) were purchased from The Jackson Laboratory (Bar Harbor, ME). NOD/SCID mice were maintained in a pathogen-free environment and kept on normal chow (iron content ϳ35 ppm) or chow with low (Յ 1 ppm) or high (30 000 ppm) iron content (Test Diets, Richmond, IN), for 14 to 28 days before transplantation. Histocompatible Mice were euthanized at 7 or 14 days after transplantation (3-6 weeks after initiating a particular diet) by CO 2 inhalation. Blood was collected via cardiac puncture and total serum iron was measured. Hepatic iron content was determined using a colorimetric assay as described. 10 Tissue for histology was fixed in 10% formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin and with Perl Prussian blue to detect iron deposition.Hepatocyte suspensions were generated by mincing and straining liver tissue through a 75-m mesh. Enterocytes were obtained by scraping the mucosa off the inverted duodenum and mincing and straining through a 75-m mesh. Total RNA was isolated and cDNA synthesized using the MACS One-Step cDNA Sy...
Studies of chimeric antigen receptor (CAR) T‐cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions—and possibly cures—in some patients with heavily pretreated, high‐risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T‐cell fitness as well as the pre‐existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.
Patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) have limited options for salvage, and checkpoint blockade therapy (CBT) has little efficacy. Usage in solid malignancies suggests that CBT sensitises tumours to subsequent chemotherapy. We performed the first analysis of CBT on subsequent NHL treatment. Seventeen North American centres retrospectively queried records. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment. Secondary aims included progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Fifty-nine patients (68% aggressive NHL, 69% advanced disease) were included. Patients received a median of three therapies before CBT. Fifty-three (90%) discontinued CBT due to progression. Post-CBT regimens included chemotherapy (49%), targeted therapy (30%), clinical trial (17%), transplant conditioning (2%) and chimeric antigen receptor T cell (CAR-T) therapy (2%). The ORR to post-CBT treatment was 51%, with median PFS of 6Á1 months. In patients with at least stable disease (SD) to post-CBT, the median DOR was significantly longer than to pre-CBT (310 vs. 79 days, P = 0Á005) suggesting sensitisation. Nineteen patients were transplanted after post-CBT therapy. Median overall survival was not reached, nor affected by regimen. Prospective trials are warranted, as this may offer R/R NHL patients a novel therapeutic approach.
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