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"J. James"
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Novel therapies emerging in oncology to target the TGF-β pathway
The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.
Journal Article
Cleaner fuels for ships provide public health benefits with climate tradeoffs
We evaluate public health and climate impacts of low-sulphur fuels in global shipping. Using high-resolution emissions inventories, integrated atmospheric models, and health risk functions, we assess ship-related PM
2.5
pollution impacts in 2020 with and without the use of low-sulphur fuels. Cleaner marine fuels will reduce ship-related premature mortality and morbidity by 34 and 54%, respectively, representing a ~ 2.6% global reduction in PM
2.5
cardiovascular and lung cancer deaths and a ~3.6% global reduction in childhood asthma. Despite these reductions, low-sulphur marine fuels will still account for ~250k deaths and ~6.4 M childhood asthma cases annually, and more stringent standards beyond 2020 may provide additional health benefits. Lower sulphur fuels also reduce radiative cooling from ship aerosols by ~80%, equating to a ~3% increase in current estimates of total anthropogenic forcing. Therefore, stronger international shipping policies may need to achieve climate and health targets by jointly reducing greenhouse gases and air pollution.
Aerosol pollution from shipping contributes to cooling but also leads to premature mortality and morbidity. Here the authors combine emission inventories, atmospheric models and health risk functions to show how cleaner marine fuels will reduce premature deaths and childhood asthma but results in larger warming.
Journal Article
Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma
Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity.
Journal Article
Oxidation of the Guanine Nucleotide Pool Underlies Cell Death by Bactericidal Antibiotics
A detailed understanding of the mechanisms that underlie antibiotic killing is important for the derivation of new classes of antibiotics and clinically useful adjuvants for current antimicrobial therapies. Our efforts to understand why DinB (DNA polymerase IV) overproduction is cytotoxic to Escherichia coli led to the unexpected insight that oxidation of guanine to 8-oxo-guanine in the nucleotide pool underlies much of the cell death caused by both DinB overproduction and bactericidal antibiotics. We propose a model in which the cytotoxicity of beta-lactams and quinolones predominantly results from lethal double-strand DNA breaks caused by incomplete repair of closely spaced 8-oxo-deoxyguanosine lesions, whereas the cytotoxicity of aminoglycosides might additionally result from mistranslation due to the incorporation of 8-oxo-guanine into newly synthesized RNAs.
Journal Article
Russia's border wars and frozen conflicts
\"This book examines the origins and execution of Russian military and political activities in Moldova, Georgia, Ukraine, and Nagorno Karabakh. As the author argues, Russia has fomented ethnic tension in countries on its borders and provides military support to separatists. Moscow then use the peace process to deploy Russian 'peacekeepers' into the conflict zone. This book documents the origins of this ethnic unrest and the progress of the wars that followed. It begins with the current crisis in Ukraine, in which Russia used this pattern to seize Crimea. It follows with Moldova, Georgia, and Karabakh. Using a realist perspective, the author concludes that there are substantial similarities in the four case studies and places the conflicts in the context of international law and nationalism theory.\"--Cover.
Book
Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters
Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and Δ
H
f
for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in Δ
H
f
decreased by about 10 %; for organic solids, the AUE in Δ
H
f
dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol
-1
in PM6 and 10.8 kcal/mol
-1
in PM7 to 3.8 kcal/mol
-1
. The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved.
Journal Article