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: RNA & Antigen. 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.

Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido

Abstract: Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups

Abstract: Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4–52 years was studied for expression of four immunohistochemical markers: GAB1, β-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for β-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3–16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.

Precipitating antibody in human serum to an antigen present in cultured burkitt's lymphoma cells

Abstract: Burkitt's lymphomal has been the object of intense interest in recent years, particularly in view of epidemiological evidence suggesting that it may be caused by a virus.2 Herpes simplex virus,3' 4 reovirus,\" 6 and unidentified infectious agents7 have been isolated from the tissues of patients with Burkitt's lymphoma, but it is not known that any of them is etiologically related to the disease. Burkitt's lymphoma cells were established in continuous cultures first by Epstein and Barr8 and by Pulvertaft,9 and more recently by Stewart et al.,'0 Rabson et al.,\" and Osunkoya.12 Epstein, Achong, and Barrl3 observed particles resembling herpes virus in cultured Burkitt's lymphoma cells; similar particles have been seen by Stewart et al.'0 and Rabson et al.\" in the lines they established. In an extensive study, Epstein et al.'4 found no evidence of infectivity in preparations containing these particles. Stewart et al.,\" however, described a transmissible encephalitis in hamsters which was originally initiated by inoculating cultured lymphoma cells or extracts of these cells into thymectomized hamsters. These culture lines have been used to detect antibody in human serum by immunofluorescence tests on fixed cells'6 and by complement-fixation tests.'7 Positive reactions were observed in high frequency with the sera of patients with Burkitt's lymphoma and with sera from adult residents of the United States. The two tests did not give uniformly parallel results and so may be detecting different antigens. Using fresh Burkitt's lymphoma cells obtained by biopsy, Klein et al.'8 observed positive reactions in the indirect immunofluorescence test on viable cells with sera of patients with Burkitt's lymphoma, including in some instances the serum of the patient whose cells were used for the test. Positive reactions were observed also with sera from African patients with other diseases and infrequently with sera from healthy relatives of patients with Burkitt's lymphoma. We have examined approximately 400 sera from African and American donors for cytotoxic antibodies reactive with cultured Burkitt's lymphoma cells'9 by the same methods that led to the demonstration and description of several leukemia-specific antigens in the mouse (see review20). Positive reactions were found, but on further analysis these were attributed to isoantibodies or to naturally occurring antibody against a cell-attached component of the calf serum in which the cells were grown, the latter reactions disappearing when the cells were cultured in human serum. The purpose of this communication is to report the occurrence in human sera of precipitating antibody that reacts with antigen prepared from a culture line of Burkitt's lymphoma cells (Jiyoye).