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Exploring the NK cell platform for cancer immunotherapy
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.Natural killer (NK) cells have an innate potential to kill cancerous cells and considerable effort is being focused on innovative approaches to leverage these cells for cancer therapy. Herein, the authors discuss the variety of NK cell-based therapies that are being developed for the treatment of diverse cancers and identify future avenues for NK cell therapy research.
Journal Article
Crystal structure of a human GABAA receptor
Type-A γ-aminobutyric acid receptors (GABA
A
Rs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABA
A
R signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABA
A
R, the human β3 homopentamer, at 3 Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABA
A
R modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.
GABA
A
receptors are the principal mediators of rapid inhibitor synaptic transmission in the brain, and a decline in GABA
A
signalling leads to diseases including epilepsy, insomnia, anxiety and autism; here, the first X-ray crystal structure of a human GABA
A
receptor, the human β3 homopentamer, reveals structural features unique for this receptor class and uncovers the locations of key disease-causing mutations.
GABA
A
receptor structure
Paul Miller and Radu Aricescu report the first X-ray crystal structure of the human GABA
A
receptor, a pentameric ligand-gated ion channel and the principal mediator of rapid inhibitory synaptic transmission in the brain. The overall structure resembles those of other Cys-loop receptors but there are also several unique features, including the presence of an extended glycan sheath that would restrict interactions with other synaptic proteins. The authors discuss how specific mutations may be linked to specific diseases, and since the structure was obtained in the presence of benzamidine, a GABA
A
receptor agonist, it is hoped that this work could contribute to the design of new therapeutic agents.
Journal Article
Investor Relations and Information Assimilation
This paper examines whether investor relations (IR) officers provide value by facilitating the assimilation of firm information by the market. We find that firms with IR officers have lower stock price volatility, lower analyst forecast dispersion, higher analyst forecast accuracy, and quicker price discovery, consistent with IR officers aiding market participants in their assimilation of firm information. We also show that our findings are stronger for firms with longer-tenured IR officers. Finally, we find that when firms transition from a long-tenured IR officer to a new IR officer, stock price volatility increases, analyst forecasts become more disperse and less accurate, and the price discovery process slows, despite no significant change in the firm's disclosures, media coverage, or performance around the turnover. Collectively, these findings suggest that in-house IR officers, particularly those with greater experience, help facilitate information assimilation by the market, which has positive market effects.
Journal Article
Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer
Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician’s choice of chemotherapy (doxorubicin or paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.
Journal Article
Grizzly bears of Alaska : explore the wild world of bears
Describes grizzly bears' behaviors, habitats, and life cycles.
Book
Placental Pathology in COVID-19
Abstract
Objectives
To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy.
Methods
Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma.
Results
Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.
The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma.
Conclusions
Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.
Journal Article