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"Paul, Elaine"
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Revisiting the polite and commercial people : essays in Georgian politics, society, and culture in honour of professor Paul Langford
\"For some time before his death in July 2015, former colleagues and students of Paul Langford had discussed the possibility of organising a festschrift to celebrate his remarkable contribution to eighteenth-century history. It was planned for 2019 to commemorate the thirtieth anniversary of the appearance of his seminal A Polite and Commercial People, the opening volume in the New Oxford History of England series, Paul's best-known and most influential publication. He was delighted to hear of these plans and the tragic news of his death only made the contributors more determined to see the project through to completion. 0The importance of A Polite and Commercial People within its own time is unquestionable. Not only did it provide a powerful new vision of eighteenth-century Britain, but it also played a vital part in reviving interest in, and expanding ways of thinking about, Georgian history. As the thirteen contributors to this volume amply testify, any review of the field from the 1980s onwards cannot ignore the profound effect Paul's research had on the social and political publications in his field. This collection of essays combines reflection on the impact of Paul's work with further engagement with the central questions he posed. In particular, it serves to re-connect various recent avenues of Georgian studies, bringing together diverse themes present in Paul's scholarship, but which are often studied independently of each other. As such, it aims to provide a fitting tribute to Paul's work and impact, and a wider reassessment of the current direction of eighteenth-century studies\"--Dust jacket.
Book
Assessment of brain penetration and tumor accumulation of niraparib and olaparib: insights from multimodal imaging in preclinical models
One of the most significant challenges in developing new treatments for primary and metastatic brain tumors is the requirement for crossing the blood-brain barrier (BBB). By examining the brain penetration and spatial distribution of drug candidates in animal models, we can gain valuable insights into their potential for clinical success. In this study, we used multimodal imaging alongside complementary analytical methods to assess the brain distribution of two clinically advanced poly(ADP-ribose) polymerase (PARP) inhibitors—niraparib and olaparib—across three preclinical models: healthy brain (nonhuman primates (NHPs)), primary brain tumors (mouse glioblastoma), and metastatic brain tumors (mouse breast cancer metastasis). The results suggest that niraparib has a superior ability (relative to olaparib) to penetrate the BBB, distribute widely throughout the brain, and accumulate in brain tumor lesions. These findings support further studies of niraparib as a potential treatment for tumors in the human brain.
Journal Article
Broader, bolder, better : how schools and communities help students overcome the disadvantages of poverty
With poverty and inequality on the rise and large achievement gaps remaining despite decades of school reform, Weiss and Reville make the case for a large-scale expansion of community-school partnerships in order to provide integrated student supports (ISS) from cradle to careers.-- Provided by publisher.
Book
First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1)
BackgroundThe phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors.MethodsGSK3174998 (0.003–10 mg/kg) ± pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity.Results138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 ≥0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) ≥24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR ≥24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56–CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response.ConclusionsGSK3174998±pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998±pembrolizumab in advanced cancers.Trial registration numberNCT02528357.
Journal Article
Sargent and Paris
\"Sargent and Paris explores the early career of American painter John Singer Sargent (1856-1925), from his arrival in Paris in 1874 as a precocious 18-year-old art student through the mid-1880s, when his infamous portrait Madame X was a scandalous success at the Paris Salon. Over the course of one extraordinary decade, Sargent achieved recognition by creating boldly ambitious portraits and figure paintings that pushed the boundaries of conventionality. Immersed in a cosmopolitan circle of artists, writers, and patrons, Sargent was able to navigate a successful path through the French exhibition system while achieving acclaim and awards. Beyond the portrait studio, he traveled in search of inspiration for his art--finding subjects in Italy, the Netherlands, Spain, and North Africa. This exhibition gathers Sargent's diverse works from this period to illuminate his path to becoming an artist, which was indelibly shaped by his experiences in the French capital. These visually stunning works provide a compelling view of the Paris art world of the late 19th century. The iconic Madame X, a beloved highlight of The Met collection, is the culmination of Sargent's early years in Paris. The exhibition will take an in-depth look at this captivating portrait and the numerous preparatory sketches, and it will be displayed alongside select portraits of Parisiennes by Sargent's contemporaries.\" -- Metropolitan Museum of Art website
BOOK
Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations
BackgroundOX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.MethodsAnti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.ResultsIsotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.ConclusionsThese findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.
Journal Article
Fashioned by Sargent
Fashioned by Sargent explores the complicated relationship of painting and dress through reproductions of portraits and other works by Sargent, alongside costumes of the period - including garments actually worn by his sitters. Essays illuminate topics such as portraits and performance, gender expression, the New Woman, and the pull of history and the excitement of new ideas.
Book
Expansion of epidemic dengue viral infections to Pakistan
Objectives: Antibodies to dengue viruses have occasionally been reported in individuals in Pakistan, but the frequency of occurrence of dengue infection in Pakistan is unclear. The first confirmed dengue hemorrhagic fever outbreak in Pakistan occurred in 1994. In October 1995, the authors investigated an outbreak of a febrile illness among employees of a construction contractor at a power generation plant in Baluchistan, Pakistan, to determine the cause of illness and recommend appropriate preventive measures.
Methods: The work site and living arrangements were inspected, a questionnaire was administered, and serum samples were collected from all consenting contractor employees and their families if they lived at the camp. Sera were analyzed for IgM against dengue virus, using an enzyme-linked immunosorbent assay.
Results: Interviews were conducted with 76 persons (mean age, 42 y); 95% were men. Forty-two persons (55%) reported having experienced fever, headache, or myalgia in the preceding 6 weeks. Fifty-seven subjects (75%) had IgM antibodies against at least one dengue serotype; 45 subjects (59%) had IgM antibodies against dengue serotype 2.
Conclusion: This was an outbreak of dengue fever due to multiple serotypes of dengue virus. This confirms that epidemic dengue infection was present in southern Pakistan for 2 consecutive years.
Journal Article
Celebrity philanthropy
Celebrities are some of the most prominent faces of philanthropic activity, yet their participation raises certain questions. This book presents case studies of international celebrity philanthropy, looking at the tensions between celebrity activism and ground-level work and the relationship between celebrity philanthropy and cultural citizenship.
eBook