24 research outputs found
Role of the amino terminal RHAU-specific motif in the recognition and resolution of guanine quadruplex-RNA by the DEAH-box RNA helicase RHAU
Under physiological conditions, guanine-rich sequences of DNA and RNA can adopt stable and atypical four-stranded helical structures called G-quadruplexes (G4). Such G4 structures have been shown to occur in vivo and to play a role in various processes such as transcription, translation and telomere maintenance. Owing to their high-thermodynamic stability, resolution of G4 structures in vivo requires specialized enzymes. RHAU is a human RNA helicase of the DEAH-box family that exhibits a unique ATP-dependent G4-resolvase activity with a high affinity and specificity for its substrate in vitro. How RHAU recognizes G4-RNAs has not yet been established. Here, we show that the amino-terminal region of RHAU is essential for RHAU to bind G4 structures and further identify within this region the evolutionary conserved RSM (RHAU-specific motif) domain as a major affinity and specificity determinant. G4-resolvase activity and strict RSM dependency are also observed with CG9323, the Drosophila orthologue of RHAU, in the amino terminal region of which the RSM is the only conserved motif. Thus, these results reveal a novel motif in RHAU protein that plays an important role in recognizing and resolving G4-RNA structures, properties unique to RHAU among many known RNA helicases
Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Background
Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving
patients with previously treated metastatic melanoma. We conducted a phase 3 study
of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously
untreated metastatic melanoma.
Methods
We randomly assigned 502 patients with previously untreated metastatic melanoma,
in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per
square meter of body-surface area) or dacarbazine (850 mg per square meter) plus
placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks
through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as
maintenance therapy. The primary end point was overall survival.
Results
Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1
months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year
(47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard
ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of
patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated
with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal
perforations occurred in the ipilimumab–dacarbazine group.
Conclusions
Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as
compared with dacarbazine plus placebo, improved overall survival in patients with
previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were
lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb;
ClinicalTrials.gov number, NCT00324155.
Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma
Enhanced Humoral Immune Response Correlates With Improved Disease-Free and Overall Survival in American Joint Committee on Cancer Stage II Melanoma Patients Receiving Adjuvant Polyvalent Vaccine
Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma
Abstract
Background
In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population.
Methods
Baseline and 4-week follow-up 18F-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months.
Results
Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR.
Conclusions
Metabolic response by 18F-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. 18F-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this.
Clinical trial registration
NCT0042451