Cold Spring Harbor perspectives in medicine
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Cold Spring Harb Perspect Med · Jan 2020
ReviewTargeting Immunophenotypic Markers on Leukemic Stem Cells: How Lessons from Current Approaches and Advances in the Leukemia Stem Cell (LSC) Model Can Inform Better Strategies for Treating Acute Myeloid Leukemia (AML).
Therapies targeting cell-surface antigens in acute myeloid leukemia (AML) have been tested over the past 20 years with limited improvement in overall survival. Recent advances in the understanding of AML pathogenesis support therapeutic targeting of leukemia stem cells as the most promising avenue toward a cure. ⋯ In addition, we explore limitations of current targeted strategies utilized in AML and describe the various immunophenotypic antigens that have been proposed as LSC-directed therapeutic targets. We draw lessons from current approaches as well as from the (pre)-LSC model to suggest criteria that immunophenotypic targets should meet for more specific and effective elimination of disease-initiating clones, highlighting in detail a few targets that we suggest fit these criteria most completely.
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Cold Spring Harb Perspect Med · Feb 2018
ReviewChronic Traumatic Encephalopathy: Is Latency in Symptom Onset Explained by Tau Propagation?
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive mild brain trauma. CTE, previously termed "dementia pugilistica," has been identified in American football, ice hockey, baseball, rugby and soccer players, boxers, wrestlers, and military personnel exposed to blast and other traumatic brain injuries. ⋯ The pathology of CTE is characterized by a progression from isolated focal perivascular hyperphosphorylated tau lesions in the cerebral cortex to a widespread tauopathy that involves diffuse cortical and medial temporal lobe regions. We hypothesize that the spread of tau from focal perivascular lesions to a widespread tauopathy occurs as a result of intraneuronal and intrasynaptic prion-like protein templating, as well as tau secretion and propagation along glymphatic and cerebrospinal fluid pathways.
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Cold Spring Harb Perspect Med · Nov 2017
ReviewExperimental Models of Inherited PrP Prion Diseases.
The inherited prion protein (PrP) prion disorders, which include familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia, constitute ∼10%-15% of all PrP prion disease cases in humans. Attempts to generate animal models of these disorders using transgenic mice expressing mutant PrP have produced variable results. ⋯ Furthermore, demonstrating the presence of protease-resistant PrP species and prion infectivity-two of the hallmarks of the PrP prion disorders-in the brains of spontaneously sick mice has proven particularly challenging. Here, we review the progress that has been made toward developing accurate mouse models of the inherited PrP prion disorders.
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Cold Spring Harb Perspect Med · Mar 2015
ReviewGene therapy for choroideremia using an adeno-associated viral (AAV) vector.
Choroideremia is an outer retinal degeneration with a characteristic clinical appearance that was first described in the nineteenth century. The disorder begins with reduction of night vision and gradually progresses to blindness by middle age. The appearance of the fundus in sufferers is recognizable by the characteristic pale color caused by the loss of the outer retina, retinal-pigmented epithelium, and choroidal vessels, leading to exposure of the underlying sclera. ⋯ Despite several decades of work to understand the exact pathogenesis, no established treatments currently exist to stop or even slow the progression of retinal degeneration in choroideremia. Encouragingly, several specific molecular and clinical features make choroideremia an ideal candidate for treatment with gene therapy. This work describes the considerations and challenges in the development of a new clinical trial using adeno-associated virus (AAV) encoding the CHM gene.
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Despite the availability of effective chemotherapy, tuberculosis (TB) killed 1.3 million people in 2012. Alongside HIV, it remains a top cause of death from an infectious disease. ⋯ Achieving these targets is the focus of national and international efforts in TB control, and showing whether or not they are achieved is of major importance to guide future and sustainable investments. This article provides a short overview of sources of data to estimate TB disease burden; presents estimates of TB incidence, prevalence, and mortality in 2012 and an assessment of progress toward the 2015 targets for reductions in these indicators based on trends since 1990 and projections up to 2015; analyzes trends in TB notifications and in the implementation of the Stop TB Strategy; and considers prospects for elimination of TB after 2015.