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"Long, John (John B.)"
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Characterizing the human hippocampus in aging and Alzheimer’s disease using a computational atlas derived from ex vivo MRI and histology
Although the hippocampus is one of the most studied structures in the human brain, limited quantitative data exist on its 3D organization, anatomical variability, and effects of disease on its subregions. Histological studies provide restricted reference information due to their 2D nature. In this paper, high-resolution (∼200 × 200 × 200 μm³) ex vivo MRI scans of 31 human hippocampal specimens are combined using a groupwise diffeomorphic registration approach into a 3D probabilistic atlas that captures average anatomy and anatomic variability of hippocampal subfields. Serial histological imaging in 9 of the 31 specimens was used to label hippocampal subfields in the atlas based on cytoarchitecture. Specimens were obtained from autopsies in patients with a clinical diagnosis of Alzheimer’s disease (AD; 9 subjects, 13 hemispheres), of other dementia (nine subjects, nine hemispheres), and in subjects without dementia (seven subjects, nine hemispheres), and morphometric analysis was performed in atlas space to measure effects of age and AD on hippocampal subfields. Disproportional involvement of the cornu ammonis (CA) 1 subfield and stratum radiatum lacunosum moleculare was found in AD, with lesser involvement of the dentate gyrus and CA2/3 subfields. An association with age was found for the dentate gyrus and, to a lesser extent, for CA1. Three-dimensional patterns of variability and disease and aging effects discovered via the ex vivo hippocampus atlas provide information highly relevant to the active field of in vivo hippocampal subfield imaging.
Journal Article
Teenage mutant ninja turtles. 7, The invasion
Read along and re-live the new Teenage Mutant Ninja Turtles cartoon-action with Leo, Don, Mikey, Raph, April, and Shredder in these young reader volumes. This volume adapts the season 2 two-part finale 'The Invasion.'
Book
Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure
In a randomized trial, 366 patients with advanced heart failure received a centrifugal- or axial-flow LVAD. At 2 years, the centrifugal-flow LVAD was superior with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device.
Journal Article
Transformers : lost light
\"Five years previously, Rodimus and a collection of traumatised, lovelorn and/or sarcastic Autobots set off on a quest to find Cyberutopia. So far, they've made a right hash of it. They've misplaced their map. They've lost their ship, the Lost Light, to a mutinous escapologist. Oh, and they're dead.\"-- page four of cover, v. 1.
Book
Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma
Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.
We randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo. Treatment was continued until the occurrence of disease progression, unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to
mutation status, metastasis stage, and programmed death ligand 1 expression. Here, we report the final, 10-year results of this trial, including results for overall survival and melanoma-specific survival, as well as durability of response.
With a minimum follow-up of 10 years, median overall survival was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI], 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52 to 0.76) for nivolumab as compared with ipilimumab. Median melanoma-specific survival was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the trial), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.
The final trial results showed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. (Funded by Bristol Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
Journal Article
Transformers : Optimus Prime
Explore the aftermath of Optimus Prime and his Autobots stopping an alien invasion of Earth. Diving into stories of war, peace, loss, regret, and redemption, this volume of Optimus Prime gives readers dramatic Transformers stories that spotlight the Autobots' present and past struggles while setting the stage for future surprises.
Book
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial
Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.
We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648.
Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2–not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2–23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55–0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0–13·9) in the dabrafenib and trametinib group and 8·8 months (5·9–9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53–0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.
The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.
GlaxoSmithKline.
Journal Article
Transformers, G.I. Joe : first strike. Champions
The Transformers, G.I. Joe, Micronauts, Rom, and M.A.S.K.: Mobile Armored Strike Kommand get to shine in standalone stories setting up the ultimate Hasbro comic book event! First, with Cybertron under seige from Baron Ironblood, it's up to Optimus Prime and Arcee to defend their homeland, and the Revolutionaries team is caught in the middle! Then, back on Earth, Rom finds himself teaming up with the world's smallest heroes, the Micronauts! Can they prevent catastrophe, or is it already too late? And, with the team divided, G.I. Joe must confront dangers both in space and Earthside. Looks like they'll need some help from M.A.S.K.!
Book
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
The addition of nivolumab (anti–PD-1) to ipilimumab (anti–CTLA-4) did not further improve response rate or progression-free survival among patients with PD-L1–positive tumors. The combination was much more effective in patients with PD-L1–negative tumors.
Considerable progress in the treatment of metastatic melanoma has been made in the past 5 years, with the approval of immune checkpoint–blocking antibodies and, in parallel, agents targeting aberrant signaling in the 40 to 50% of melanomas with
BRAF
mutations.
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Ipilimumab, an anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antibody, acts to up-regulate antitumor immunity and was the first agent to be associated with an improvement in overall survival in a phase 3 study involving patients with metastatic melanoma.
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Ipilimumab was associated with responses in 10% and 15% of patients
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; approximately 20% of treated patients had long-term survival. . . .
Journal Article