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"Miller, David S."
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Somatic LKB1 Mutations Promote Cervical Cancer Progression
Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence.
Journal Article
Injustice 2
\"The war is over. But a new battle is about to begin. After years of conflict and carnage, Batman and his rebel allies have finally triumphed over their tyrannical foe, Superman. Now the Man of Steel is behind bars, and the Dark Knight holds the future of the world in his hands. But that future is about to slip from his grasp. Superman still has many friends who will work tirelessly to free their leader from captivity. And a new force is about to emerge from the shadows. A winged warrior is assembling a Suicide Squad of the world's most dangerous villains to pursue plans of his own, by any means necessary. And this man in black is out to claim the mantle of the Batman himself. As old foes and new enemies collide, can Bruce Wayne preserve the fragile peace for which so many heroes have sacrificed? or is a new era of injustice about to dawn?\" -- Back cover of volume 1.
Book
Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms
Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.
Journal Article
Leading and managing in the social sector : strategies for advancing human dignity and social justice
\"This book explores leadership and management in social sector organizations, which include, NGOs, non-profits, social enterprises, social businesses, and cross-sector collaborations focusing on advancing human dignity and social justice. It provides social sector leaders with an overview of current trends, issues, and challenges in the field as well as best practices to foster effective programs, sustain organizations and meet the growing demands of the sector. The enclosed chapters cover topics such as cross-sector organizational design, innovation for client services, gender management dynamics, policy advocacy, and the growing social entrepreneurship movement.\"--Publisher's website.
Book
A Reexamination of the Relationship between Training Practices and Welfare in the Management of Ambassador Animals
There is an ethical need to document and develop best practices for meeting ambassador animals’ welfare needs within the context of meeting zoo and aquarium program objectives. This is because ambassador animals experience direct and frequent contact with humans. This paper rigorously synthesizes behavioral research and theory, contemporary practices, and personal experiences to offer key concepts that can be applied to meet ambassador animal welfare needs. These key concepts include addressing an animal’s recognition of choice and control, the use of the most positive and least intrusive effective interventions when training animals to participate in programming, and an overall reduction in aversive strategy use. Our model for increasing ambassador animal welfare focuses on seven main areas of concern, including the following: choosing the most suitable animal for the program; choosing the human with the right skills and knowledge for the program; using the most positive, least intrusive, effective training methods; developing a strong trusting relationship between trainer and animal; developing a comprehensive enrichment program; the need for institutional support; and creating opportunities for animals to practice species-appropriate behaviors. Our model will provide guidelines for improved ambassador animal welfare that can be refined with future research.
Journal Article
Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain
P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, ³H-verapamil (threefold increase), ³H-loperamide (fivefold increase), and ³H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain ¹⁴C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.
Journal Article
The new voices of science fiction
\"Your Future Is Bright! After all, your mother is a robot, your father has joined the alien hive mind, and your dinner will be counterfeit 3D-printed steak. Even though your worker bots have staged a mutiny, and your tour guide speaks only in memes, you can always sell your native language if you need some extra cash.\" -- From publisher's description.
Book
Assessment of humaneness using gunshot targeting the brain and cervical spine for cervid depopulation under field conditions
Population reduction or eradication of domestic or non-domestic species may be required to address their impacts on the environment, other species, or human interests. Firearms are often used to accomplish these practical management objectives, and there is increased concern that the methods used may compromise animal welfare. We document the accuracy and humaneness of gunshot placement to the brain and cervical vertebrae of Philippine deer (Rusa marianna) on Guam during depopulation activities as a model for meeting AVMA standards of euthanasia under field conditions (e.g., animal is not in hand). Deer were shot with a .223 caliber rifle from 10-125 m and approached immediately (<20 s) for assessment. A subset of adult deer was further evaluated for physiological responses including cessation of heart rate, respiration, ocular reflexes, and post-mortem spasms. All deer shot in the brain (n = 132) and upper cervical spine (C1-C3; n = 18) died immediately due to the destruction of the brain or spinal tissue. Shot placements were all within 1.9 cm of the point of aim (i.e., the center of the target region). The accuracy and immediate insensibility resulting from targeting of C1-C3 demonstrates that this is an alternative target site when animal positioning is not optimal for targeting the brain, or there is a need to preserve brain tissue (e.g., Chronic Wasting Disease testing). While targeting of C4 -C7 vertebrae (n = 6) was accurate and resulted in immediate incapacitation, the failure to produce immediate insensibility does not support the use of this shot placement when upper cervical or brain shot placement is an option. It is reasonable to achieve sufficient accuracy to target the brain or upper cervical vertebrae of deer under field conditions and meet standards of euthanasia while accomplishing management objectives.
Journal Article