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Cold Spring Harbor Perspectives in Medicine

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https://www.readbyqxmd.com/read/28062559/atrx-and-daxx-mechanisms-and-mutations
#1
Michael A Dyer, Zulekha A Qadeer, David Valle-Garcia, Emily Bernstein
Recent genome sequencing efforts in a variety of cancers have revealed mutations and/or structural alterations in ATRX and DAXX, which together encode a complex that deposits histone variant H3.3 into repetitive heterochromatin. These regions include retrotransposons, pericentric heterochromatin, and telomeres, the latter of which show deregulation in ATRX/DAXX-mutant tumors. Interestingly, ATRX and DAXX mutations are often found in pediatric tumors, suggesting a particular developmental context in which these mutations drive disease...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28062558/biological-spectrum-of-amyotrophic-lateral-sclerosis-prions
#2
Magdalini Polymenidou, Don W Cleveland
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28062557/fosfomycin-mechanism-and-resistance
#3
Lynn L Silver
Fosfomycin, a natural product antibiotic, has been in use for >20 years in Spain, Germany, France, Japan, Brazil, and South Africa for urinary tract infections (UTIs) and other indications and was registered in the United States for the oral treatment of uncomplicated UTIs because of Enterococcus faecalis and Escherichia coli in 1996. It has a broad spectrum, is bactericidal, has very low toxicity, and acts as a time-dependent inhibitor of the MurA enzyme, which catalyzes the first committed step of peptidoglycan synthesis...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28062556/the-cellular-origin-and-evolution-of-breast-cancer
#4
Mei Zhang, Adrian V Lee, Jeffrey M Rosen
In this review, we will discuss how the cell of origin may modulate breast cancer intratumoral heterogeneity (ITH) as well as the role of ITH in the evolution of cancer. The clonal evolution and the cancer stem cell (CSC) models, as well as a model that integrates clonal evolution with a CSC hierarchy, have all been proposed to explain the development of ITH. The extent of ITH correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. A unique subtype of breast cancer, the claudin-low subtype that is highly resistant to chemotherapy and most closely resembles mammary epithelial stem cells, will be discussed...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28062555/antibody-therapeutics-targeting-a%C3%AE-and-tau
#5
Gilbert Gallardo, David M Holtzman
The astonishing findings that active and passive immunization against amyloid-β (Aβ) in mouse models of Alzheimer's disease (AD) dramatically decreased amyloid burden led to a rapid initiation of human clinical trials with much enthusiasm. However, methodological issues and adverse effects relating to these clinical trials arose, challenging the effectiveness and safety of these reagents. Efforts are now underway to develop safer immunotherapeutic approaches toward Aβ and the treatment of individuals at risk for AD before or in the earliest stages of cognitive decline with new hopes...
January 6, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003281/dnmt3a-in-leukemia
#6
Lorenzo Brunetti, Michael C Gundry, Margaret A Goodell
DNA methylation is an epigenetic process involved in development, aging, and cancer. Although the advent of new molecular techniques has enhanced our knowledge of how DNA methylation alters chromatin and subsequently affects gene expression, a direct link between epigenetic marks and tumorigenesis has not been established. DNMT3A is a de novo DNA methyltransferase that has recently gained relevance because of its frequent mutation in a large variety of immature and mature hematologic neoplasms. DNMT3A mutations are early events during cancer development and seem to confer poor prognosis to acute myeloid leukemia (AML) patients making this gene an attractive target for new therapies...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003280/malaria-modeling-in-the-era-of-eradication
#7
Thomas A Smith, Nakul Chitnis, Melissa Penny, Marcel Tanner
Mathematical models provide the essential basis of rational research and development strategies in malaria, informing the choice of which technologies to target, which deployment strategies to consider, and which populations to focus on. The Internet and remote sensing technologies also enable assembly of ever more relevant field data. Together with supercomputing technology, this has made available timely descriptions of the geography of malaria transmission and disease across the world and made it possible for policy and planning to be informed by detailed simulations of the potential impact of intervention programs...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003279/structural-biology-of-prp-prions
#8
Gerald Stubbs, Jan Stöhr
Prion diseases are characterized by the deposition of amyloids, misfolded conformers of the prion protein. The misfolded conformation is self-replicating, by a mechanism solely enciphered in the conformation of the protein. Because of low solubility and heterogeneous aggregate sizes, the detailed atomic structure of the infectious isoform is still unknown. Progress has, however, been made, and has allowed insights into the structural and disease-related mechanisms of prions. Many structural models have been proposed, and a number of them support a consensus trimeric β-helical model, significantly more complex than simple amyloid models...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003278/clinical-spectrum-of-amyotrophic-lateral-sclerosis-als
#9
Leslie I Grad, Guy A Rouleau, John Ravits, Neil R Cashman
Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003277/genetics-of-%C3%AE-amyloid-precursor-protein-in-alzheimer-s-disease
#10
Julia Tcw, Alison M Goate
Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Aβ is generated by proteolytic processing of the β-amyloid precursor protein (APP). Most individuals with Down syndrome (DS) have three copies of APP, leading to elevated APP expression, increased Aβ deposition, and characteristic AD neuropathology. Sequencing of APP in familial early-onset AD identified missense mutations that cause AD, while a recently discovered coding variant, APP A673T, reduces the risk for AD...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003276/lesion-directed-therapies-and-monitoring-tumor-evolution-using-liquid-biopsies
#11
Mariangela Russo, Alberto Bardelli
Precision oncology relies on targeted drugs, such as kinase inhibitors, that are presently administered based on molecular profiles obtained from surgical or bioptic tissue samples. The inherent ability of human tumors to molecularly evolve in response to drug pressures represents a daunting diagnostic challenge. Circulating free DNA (cfDNA) released from primary and metastatic lesions can be used to draw molecular maps that can be continuously updated to match each tumor's evolution. We will present evidence that liquid biopsies can effectively interrogate how targeted therapies drive lesion-specific drug-resistance mechanisms...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28003275/tp53-mutations-in-hypodiploid-acute-lymphoblastic-leukemia
#12
Evan Q Comeaux, Charles G Mullighan
Acute lymphoblastic leukemia (ALL) is an aggressive neoplasm of B- or T-lymphoid progenitors and is the commonest childhood tumor. ALL comprises multiple subtypes characterized by distinct genetic alterations, with stereotyped patterns of aneuploidy present in many cases. Although alterations of TP53 are common in many tumors, they are infrequent in ALL, with the exception of two ALL subtypes associated with poor outcome: relapsed disease and ALL with hypodiploidy. TP53 alterations are present in almost all cases of ALL with low hypodiploidy and are associated with alterations of the lymphoid transcription factor IKZF2 and the tumor-suppressor gene loci CDKN2A and CDKN2B...
December 21, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27940602/huntington-s-disease-mechanisms-of-pathogenesis-and-therapeutic-strategies
#13
Maria Jimenez-Sanchez, Floriana Licitra, Benjamin R Underwood, David C Rubinsztein
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract...
December 9, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27940601/binding-sites-for-amyloid-%C3%AE-oligomers-and-synaptic-toxicity
#14
Levi M Smith, Stephen M Strittmatter
In Alzheimer's disease (AD), insoluble and fibrillary amyloid-β (Aβ) peptide accumulates in plaques. However, soluble Aβ oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Aβ oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Aβ binding proteins, and one or more are likely to mediate Aβ oligomer toxicity in AD. Cellular prion protein (PrP(C)) is a high-affinity Aβ oligomer binding site, and a range of data delineates a signaling pathway leading from Aβ complexation with PrP(C) to neuronal impairment...
December 9, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27940600/the-prion-like-behavior-of-assembled-tau-in-transgenic-mice
#15
Florence Clavaguera, Markus Tolnay, Michel Goedert
Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system...
December 9, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27940599/interactions-between-microtubule-associated-protein-tau-mapt-and-small-molecules
#16
Jennifer N Rauch, Steven H Olson, Jason E Gestwicki
Tau aggregation is linked to multiple neurodegenerative disorders that are collectively termed tauopathies. Small molecules are powerful probes of the aggregation process, helping to reveal the key steps and serving as diagnostics and reporters. Moreover, some of these small molecules may have potential as therapeutics. This review details how small molecules and chemical biology have helped to elucidate the mechanisms of tau aggregation and how they are being used to detect and prevent tau aggregation. In addition, we comment on how new insights into tau prions are changing the approach to small molecule discovery...
December 9, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27920026/the-transcellular-propagation-and-intracellular-trafficking-of-%C3%AE-synuclein
#17
George K Tofaris, Michel Goedert, Maria Grazia Spillantini
Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27920025/biology-and-genetics-of-prp-prion-strains
#18
Sina Ghaemmaghami
Prion diseases are a group of fatal neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrP(C)) into a pathogenic conformation (PrP(Sc)). PrP(Sc) is capable of folding into multiple self-replicating prion strains that produce phenotypically distinct neurological disorders. Evidence suggests that the structural heterogeneity of PrP(Sc) is the molecular basis of strain-specific prion properties. The self-templating of PrP(Sc) typically ensures that prion strains breed true upon passage...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27920024/biology-and-pathobiology-of-tdp-43-and-emergent-therapeutic-strategies
#19
Lin Guo, James Shorter
Cytoplasmic TDP-43 mislocalization and aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is an RNA-binding protein (RBP) with a prion-like domain (PrLD) that promotes TDP-43 misfolding. PrLDs possess compositional similarity to canonical prion domains of various yeast proteins, including Sup35. Strikingly, disease-causing TDP-43 mutations reside almost exclusively in the PrLD and can enhance TDP-43 misfolding and toxicity. Another ∼70 human RBPs harbor PrLDs, including FUS, TAF15, EWSR1, hnRNPA1, and hnRNPA2, which have surfaced in the etiology of neurodegenerative diseases...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27881444/the-regulation-of-cellular-functions-by-the-p53-protein-cellular-senescence
#20
Crystal A Tonnessen-Murray, Guillermina Lozano, James G Jackson
Transformed cells have properties that allow them to survive and proliferate inappropriately. These characteristics often arise as a result of mutations caused by DNA damage. p53 suppresses transformation by removing the proliferative or survival capacity of cells with DNA damage or inappropriate cell-cycle progression. Cellular senescence, marked by morphological and gene expression changes, is a critical component of p53-mediated tumor suppression. In response to stress, p53 can facilitate an arrest and senescence program in cells exposed to stresses such as DNA damage and oncogene activation, preventing transformation...
November 23, 2016: Cold Spring Harbor Perspectives in Medicine
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