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"Williams, James T"
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Antibodies to neutralising epitopes synergistically block the interaction of the receptor‐binding domain of SARS‐CoV‐2 to ACE 2
Objectives A major COVID‐19 vaccine strategy is to induce antibodies that prevent interaction between the Spike protein's receptor‐binding domain (RBD) and angiotensin‐converting enzyme 2 (ACE2). These vaccines will also induce T‐cell responses. However, concerns were raised that aberrant vaccine‐induced immune responses may exacerbate disease. We aimed to identify minimal epitopes on the RBD that would induce antibody responses that block the interaction of the RBD and ACE2 as a strategy leading to an effective vaccine with reduced risk of inducing immunopathology. Methods We procured a series of overlapping 20‐amino acid peptides spanning the RBD and asked which were recognised by plasma from COVID‐19 convalescent patients. Identified epitopes were conjugated to diphtheria‐toxoid and used to vaccinate mice. Immune sera were tested for binding to the RBD and for their ability to block the interaction of the RBD and ACE2. Results Seven putative vaccine epitopes were identified. Memory B‐cells (MBCs) specific for one of the epitopes were identified in the blood of convalescent patients. When used to vaccinate mice, six induced antibodies that bound recRBD and three induced antibodies that could partially block the interaction of the RBD and ACE2. However, when the sera were combined in pairs, we observed significantly enhanced inhibition of binding of RBD to ACE2. Two of the peptides were located in the main regions of the RBD known to contact ACE2. Of significant importance to vaccine development, two of the peptides were in regions that are invariant in the UK and South African strains. Conclusion COVID‐19 convalescent patients have SARS‐CoV‐2‐specific antibodies and MBCs, the specificities of which can be defined with short peptides. Epitope‐specific antibodies synergistically block RBD–ACE2 interaction. We identified SARS‐COV‐2 receptor‐binding domain (RBD)‐specific antibodies in convalescent patients, specificities of which could be defined with short peptides. These peptides when used as immunogens, induced neutralising antibodies which synergistically blocked RBD and ACE 2 interaction. Our approach will aid the design of a vaccine containing minimal antigenic material, thus improving the vaccine's safety profile.
Journal Article
Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer
PurposePreclinical studies support the JAK2–STAT3 signaling pathway as a key driver in CD44+ CD24− “stem-cell-like” breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).MethodsEligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10–25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D.ResultsNineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1–12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response.ConclusionThe combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429).Trial registrationNCT02041429. Date of registration: January 22, 2014.
Journal Article
Bronze Age Subsistence Change at Regional and Microscopic Scales in Northeast China
This article investigates Late Bronze Age mobile pastoralism in Northeast China. Analysis of the use-wear patterns provides direct evidence speaking to the subsistence economies during the Bronze Age. The patterns of use-wear are compared to the settlement patterning and environmental contexts to test proposed theories about whether and how subsistence change takes place. The results indicate continuity in mixed animal and plant based economies in both the Early and Late Bronze Age despite changes in climate and population. The relative intensity of economic practice is guided by the environmental context, but this is detected only at the sub-regional level.
Journal Article
Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer
Background
The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.
Methods
Through a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.
Results
We now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.
Conclusions
The interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.
Journal Article
Corporate Governance Failures
Corporate governance, the internal policies and leadership that guide the actions of corporations, played a major part in the recent global financial crisis. While much blame has been targeted at compensation arrangements that rewarded extreme risk-taking but did not punish failure, the performance of large, supposedly sophisticated institutional investors in this crisis has gone for the most part unexamined. Shareholding organizations, such as pension funds and mutual funds, hold considerable sway over the financial industry from Wall Street to the City of London. Corporate Governance Failures: The Role of Institutional Investors in the Global Financial Crisis exposes the misdeeds and lapses of these institutional investors leading up to the recent economic meltdown.In this collection of original essays, edited by pioneers in the field of fiduciary capitalism, top legal and financial practitioners and researchers discuss detrimental actions and inaction of institutional investors. Corporate Governance Failures reveals how these organizations exposed themselves and their clientele to extremely complex financial instruments, such as credit default swaps, through investments in hedge and private equity funds as well as more traditional equity investments in large financial institutions. The book's contributors critique fund executives for tolerating the \"pursuit of alpha\" culture that led managers to pursue risky financial strategies in hopes of outperforming the market. The volume also points out how and why institutional investors failed to effectively monitor such volatile investments, ignoring relatively well-established corporate governance principles and best practices.Along with detailed investigations of institutional investor missteps, Corporate Governance Failures offers nuanced and realistic proposals to mitigate future financial pitfalls. This volume provides fresh perspectives on ways institutional investors can best act as gatekeepers and promote responsible investment.
eBook
Gaining a Face
Contrary to the popular perception that C.S. Lewis was merely a religious writer, there is a good case to be made for Lewis being one of the major British writers of the twentieth century if we look at him as a prime member of a resurgent Romantic movement after the Second World War. Much has been written on Lewiss thoughts on joy, a central aspect of his Romanticism. However, Lewis was at the same time a rationalist, and managed to merge his Rationalism with his Romanticism in a unique and.
eBook
Translational Neuroscience
Translational neuroscience is at the heart of clinical advancement in the fields of psychiatry, neurology and neurodevelopmental disorders. Written and edited by leading scientists and clinicians, this is a comprehensive and authoritative analysis of this emerging strategy for developing more effective treatments for brain disorders. Introductory chapters bring together perspectives from both academia and industry, while subsequent sections focus on disease groups, including bipolar disorder and depression, attention deficit hyperactivity disorder, substance abuse, autism, Alzheimer's disease, pain, epilepsy, Parkinson's disease and multiple sclerosis. Each section includes topical introductory and summary chapters, providing an overview and synthesis of the field. Translational Neuroscience: Applications in Psychiatry, Neurology, and Neurodevelopmental Disorders is an important text for clinicians, scientists and students in academic settings, government agencies and industry, as well as those working in the fields of public health and the behavioural sciences.
eBook
