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"Mcneill, Robert"
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Mosquito empires : ecology and war in the Greater Caribbean, 1620 - 1914
\"This book explores the links among ecology, disease, and international politics in the context of the Greater Caribbean - the landscapes lying between Surinam and the Chesapeake - in the seventeenth through early twentieth centuries. Ecological changes made these landscapes especially suitable for the vector mosquitoes of yellow fever and malaria, and these diseases wrought systematic havoc among armies and would-be settlers. Because yellow fever confers immunity on survivors of the disease, and because malaria confers resistance, these diseases played partisan roles in the struggles for empire and revolution, attacking some populations more severely than others. In particular, yellow fever and malaria attacked newcomers to the region, which helped keep the Spanish Empire Spanish in the face of predatory rivals in the seventeenth and early eighteenth centuries. In the late eighteenth and through the nineteenth century, these diseases helped revolutions to succeed by decimating forces sent out from Europe to prevent them\"--Provided by publisher.
Book
Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process
How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.
Significance How malignant gliomas arise in a mature brain remains a mystery, which hinders the development of effective treatments. Which cell types can escape their quiescent, adult state and how they do so is unknown. Additionally, because gliomas are only detected at advanced stages, the full course of transformation remains uncharacterized. Here we report that adult oligodendrocyte precursor cells, despite their relatively quiescent properties, can be reactivated to a highly proliferative state by p53 and NF1 mutations and give rise to malignant gliomas. Furthermore, we describe the early phase of gliomagenesis for the first time, revealing a multistep process of reactivation, dormancy, and final transformation in which mammalian target of rapamycin signaling plays a critical role at both early and late steps.
Journal Article
PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition
Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients.
We used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro.
PIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations.
PIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment.
Journal Article
A Companion to Global Environmental History
The Companion to Global Environmental History offers multiple points of entry into the history and historiography of this dynamic and fast-growing field, to provide an essential road map to past developments, current controversies, and future developments for specialists and newcomers alike.
* Combines temporal, geographic, thematic and contextual approaches from prehistory to the present day
* Explores environmental thought and action around the world, to give readers a cultural, intellectual and political context for engagement with the environment in modern times
* Brings together environmental historians from around the world, including scholars from South Africa, Brazil, Germany, and China
eBook
The global condition : conquerors, catastrophes, and community
William H. McNeill is known for his ability to portray the grand sweep of history. The Global Condition is a classic work for understanding the grand sweep of world history in brief compass. Now with a new foreword by J. R. McNeill, this book brings together two of William Hardy McNeill's popular short books and an essay. The Human Condition provides a provocative interpretation of history as a competition of parasites, both biological and human; The Great Frontier questions the notion of \"frontier freedom\" through an examination of European expansion; the concluding essay speculates on the role of catastrophe in our lives. -- Provided by publisher.
Book
Retrospective Analysis of the Real-World Utilization of 4-Factor Prothrombin Complex Concentrate and Plasma in Oral Anticoagulant-Associated Bleeding in US Hospitals
Real-world utilization of 4-factor prothrombin complex concentrate (4F-PCC) and plasma for the management of oral anticoagulant (OAC)-associated bleeding in US trauma hospitals was described.
This is amulticenter, retrospective chart review evaluating the use of 4F-PCC and plasma in OAC reversal across medical specialties. Physicians completed a survey and extracted data from 3 to 5 patient charts. Variables of interest included medical specialty, urgency, and bleed type. Two hundred and thirty-five physicians completed the survey, and 861 patient charts were included in the study. 4F-PCC was commonly used in life-threatening or emergent indications, whereas plasma was used in emergent and urgent indications. Plasma was used mostly for patients on warfarin (53% vs 47% 4F-PCC) and 4F-PCC for those on apixaban (82% vs 18% plasma) and rivaroxaban (77% vs 23% plasma). This retrospective analysis showed that 4F-PCC was predominantly used for OAC reversal despite available specific reversal agents for some of the OAC. Although it is not recommended by any reversal guidelines, plasma is still used for OAC reversal. Plasma should be avoided in the management of OAC-associated bleeding.
Journal Article
Mining North America : an environmental history since 1522
\"Over the past five hundred years, North Americans have increasingly turned to mining to produce many of their basic social and cultural objects. From cell phones to cars and roadways, metal pots to wall tile and even talcum powder, minerals products have become central to modern North American life. As this process has unfolded, mining has also indelibly shaped the natural world and North Americans' relationship with it. Mountains have been honeycombed, rivers poisoned, and forests leveled. The effects of these environmental transformations have fallen unevenly across North American societies. Mining North America examines these developments. Drawing on the work of scholars from Mexico, the United States, and Canada, this book explores how mining has shaped North America over the last half millennium. It covers an array of minerals and geographies while seeking to draw mining into the core debates that animate North American environmental history generally. Taken together, the authors' contributions make a powerful case for the centrality of mining in forging North American environments and societies\"--Provided by publisher.
Book
The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2 diabetes mellitus: a randomized controlled trial
Background
The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks.
Methods
365 treatment-naïve patients with T2DM (HbA
1c
7.0%–10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA
1c
≥7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control.
Results
At week 24, placebo-subtracted mean HbA
1c
reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]).
Conclusions
In treatment-naïve patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA
1c
compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks.
Trial registration
ClinicalTrials.gov Identifier: NCT00316082
Journal Article