Kettering University

About: Kettering University is a education organization based out in Flint, Michigan, United States. It is known for research contribution in the topics: Cancer & RNA. The organization has 6842 authors who have published 7689 publications receiving 337503 citations. The organization is also known as: GMI Engineering & Management Institute & General Motors Institute.

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.

Abstract: Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL) 1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2–4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2–4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2–9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.

Intestinal Domination and the Risk of Bacteremia in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for a range of malignant and nonmalignant disorders. Pre-transplant conditioning transiently ablates circulating granulocytes and monocytes and markedly increases susceptibility to disseminated infections [1, 2]. Mucosal barrier injury is also a complication of allo-HSCT and enables commensal microbes to invade underlying tissues and the bloodstream [3]. As a result, systemic bacterial infections are frequent during the early transplant period [4–6]. Vancomycin-resistant Enterococcus (VRE), viridians-group Streptococcus, and aerobic gram-negative bacteria are the most common causes of bloodstream infection following allo-HSCT [5–8]. Why some patients develop bacteremia while others do not is unclear. The complex microbial populations colonizing the human intestine provide resistance to infection. The intestinal microbiota also serves as a sanctuary for highly antibiotic-resistant bacteria [9]. Prior studies using in vitro culture methods have characterized microbial populations inhabiting the intestine [10]; more recently, massively parallel pyrosequencing of bacterial 16S ribosomal RNA (rRNA) encoding genes has provided new insights into the composition and complexity of the intestinal microbiota by identifying bacterial taxons that are not readily cultivated in vitro [11–14]. These approaches have demonstrated the compositional changes and resilience of the intestinal microbiota of healthy individuals after antibiotic treatment [12]. Studies with mice demonstrated dramatic changes in the microbiota of the ileum and cecum following antibiotic treatment, and dramatic expansion of antibiotic-resistant microbes such as vancomycin-resistant Enterococcus (VRE) [15]. Intestinal expansion of VRE following antibiotic treatment is also seen in humans, with episodes of VRE domination in patients undergoing allo-HSCT preceding the development of VRE bacteremia in 2 patients [15]. Because the effect of allo-HSCT conditioning, prolonged neutropenia, and antibiotic administration on the gastrointestinal tract microbiota is unknown, we characterized the fecal microbiota of patients undergoing transplant at multiple time points using 454 pyrosequencing of 16S rRNA genes. (Data deposition: 454 pyrosequencing reads have been deposited in the National Center for Biotechnology Information Sequence Read Archive.)

Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation

Abstract: Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.

Serum glutamic pyruvic transaminase in cardiac with hepatic disease.

Abstract: SummaryThe measurement of SGP-T alterations has been found to be a useful tool in the diagnosis and study of acute hepatic disease and appears to be more sensitive than SGO-T in depicting acute hep...