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Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials
Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.
We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0–2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64–88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4–20·2). Median duration of response was 24·6 months (95% CI 11·4–34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.
Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.
Ignyta/F Hoffmann-La Roche.
Journal Article
Structure of a pre-catalytic spliceosome
Intron removal requires assembly of the spliceosome on precursor mRNA (pre-mRNA) and extensive remodelling to form the spliceosome’s catalytic centre. Here we report the cryo-electron microscopy structure of the yeast
Saccharomyces cerevisiae
pre-catalytic B complex spliceosome at near-atomic resolution. The mobile U2 small nuclear ribonucleoprotein particle (snRNP) associates with U4/U6.U5 tri-snRNP through the U2/U6 helix II and an interface between U4/U6 di-snRNP and the U2 snRNP SF3b-containing domain, which also transiently contacts the helicase Brr2. The 3′ region of the U2 snRNP is flexibly attached to the SF3b-containing domain and protrudes over the concave surface of tri-snRNP, where the U1 snRNP may reside before its release from the pre-mRNA 5′ splice site. The U6 ACAGAGA sequence forms a hairpin that weakly tethers the 5′ splice site. The B complex proteins Prp38, Snu23 and Spp381 bind the Prp8 N-terminal domain and stabilize U6 ACAGAGA stem–pre-mRNA and Brr2–U4 small nuclear RNA interactions. These results provide important insights into the events leading to active site formation.
The cryo-electron microscopy structure of the yeast spliceosome in a pre-catalytic state provides insights into the molecular events leading to formation of the spliceosome active site.
Visualization of a poised spliceosome
Protein-coding regions of DNA can be interrupted by non-coding regions, or introns. A large multisubunit complex, the spliceosome, is used to excise introns from the messenger RNA before it is translated into protein. Formation of an active spliceosome complex on an intron requires stepwise assembly of subcomplexes, followed by their rearrangement and the loss of some factors. Kiyoshi Nagai and colleagues have solved the structure of the B complex spliceosome, poised in a pre-catalytic state. The detection of several factors that were not visualized in previous spliceosome structures provides new insights regarding the process by which the complex is activated.
Journal Article
Leadership and small business : the power of stories
\"This innovative book combines theoretical and practical perspectives with the power of storytelling to present a new understanding of leadership as a concept and endeavour in the small business organisation. With the assertion that leadership capability is a key function of small firm survival and growth, it underlines the importance of addressing the phenomenon within smal business. Employing storytelling as a fresh alternative to a traditional case study approach, the narrative of leading with purpose in real time is captured alongside relevant and current academic debate. In building upon the Harvard model of purpose driven leadership, the author offers a new definition and discussion of leadership that connects theory to real impact, based on research carried out with UK small business organisations. The overall aim of the book is to provoke interest in small business leadership and generate new knowledge of leading with purpose\"--Back cover.
Book
Continuous immunotherapy beyond disease progression in patients with advanced non-small cell and small cell lung cancer
Background
The benefits of continuing immunotherapy beyond disease progression in advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) remain uncertain, along with the specific patient subgroups that may gain the most from this approach. This retrospective study aims to evaluate the efficacy of this approach and identify target patient populations likely to benefit.
Methods
We collected data from patients with NSCLC and SCLC who experienced disease progression following initial immune checkpoint inhibitor (ICI) treatment from January 2020 to December 2023. Patients were categorized based on second-line treatment: those receiving immunotherapy beyond progression (IBP) and those receiving non-immunotherapy beyond progression (NIBP). Survival outcomes and treatment safety were compared between these two groups.
Results
A total of 150 patients were included, with 111 NSCLC patients (IBP:
n
= 78, NIBP:
n
= 33) and 39 SCLC patients (IBP:
n
= 31, NIBP:
n
= 8). Significant differences in median progression-free survival (PFS) and overall survival (OS) were found in patients with driver gene-negative NSCLC (mPFS: 4.7 vs 1.3 months, HR = 0.29,
P
< 0.01; mOS: 11.03 vs 2.63 months, HR = 0.13,
P
< 0.001) and SCLC (mPFS: 3.9 vs 2.1 months, HR = 0.38,
P
= 0.02; mOS: 9.28 vs 2.27 months, HR = 0.23,
P
< 0.01). Additionally, among driver gene-negative NSCLC patients, achieving a partial response (PR) or stable disease (SD) during initial immunotherapy was associated with improved effectiveness of continued immunotherapy beyond progression.
Conclusions
Continued immunotherapy as a second-line treatment may benefit patients with driver gene-negative NSCLC and SCLC who have progressed after initial immunotherapy.
Journal Article
Cryo-EM structure of the yeast U4/U6.U5 tri-snRNP at 3.7 Å resolution
U4/U6.U5 tri-snRNP represents a substantial part of the spliceosome before activation. A cryo-electron microscopy structure of
Saccharomyces cerevisiae
U4/U6.U5 tri-snRNP at 3.7 Å resolution led to an essentially complete atomic model comprising 30 proteins plus U4/U6 and U5 small nuclear RNAs (snRNAs). The structure reveals striking interweaving interactions of the protein and RNA components, including extended polypeptides penetrating into subunit interfaces. The invariant ACAGAGA sequence of U6 snRNA, which base-pairs with the 5′-splice site during catalytic activation, forms a hairpin stabilized by Dib1 and Prp8 while the adjacent nucleotides interact with the exon binding loop 1 of U5 snRNA. Snu114 harbours GTP, but its putative catalytic histidine is held away from the γ-phosphate by hydrogen bonding to a tyrosine in the amino-terminal domain of Prp8. Mutation of this histidine to alanine has no detectable effect on yeast growth. The structure provides important new insights into the spliceosome activation process leading to the formation of the catalytic centre.
A 3.7 Å resolution structure for the yeast U4/U6.U5 tri-snRNP, a complex involved in splicing, allows a better appreciation of the architecture of the tri-snRNP, and offers new functional insights into the activation of the spliceosome and the assembly of the catalytic core.
Yeast U4/U6.U5 tri-snRNP structure
Following up on their 5.9 Å cryo-electron microscopy structure published less than a year ago, Kiyoshi Nagai and colleagues have now achieved a resolution of 3.7 Å for the yeast U4/U6.U5 tri-snRNP, a complex involved in splicing of messenger RNA. The improved resolution allows a better appreciation of the architecture of the tri-snRNP, and offers new functional insights into the activation of the spliceosome and the assembly of the catalytic core.
Journal Article
Local farms and sustainable foods
Discusses the advantages of using organic farming methods on small local farms whose produce will be sold in the community
Book
Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer
Relapse is common in patients with locally advanced unresectable lung cancer after concurrent chemotherapy and radiation therapy. In a randomized study, addition of the anti–PD-L1 antibody durvalumab every 2 weeks for 12 months increased relapse-free survival by 47%.
Journal Article