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Trends in Molecular Medicine

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https://www.readbyqxmd.com/read/28899755/nad-in-aging-molecular-mechanisms-and-translational-implications
#1
REVIEW
Evandro F Fang, Sofie Lautrup, Yujun Hou, Tyler G Demarest, Deborah L Croteau, Mark P Mattson, Vilhelm A Bohr
The coenzyme NAD(+) is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD(+) levels is important for cells with high energy demands and for proficient neuronal function. NAD(+) depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD(+) decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD(+) levels might retard aspects of aging and forestall some age-related diseases...
September 9, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28899754/on-the-whereabouts-of-hiv-1-cellular-entry-and-its-fusion-ports
#2
REVIEW
G Maria Jakobsdottir, Maro Iliopoulou, Rory Nolan, Luis Alvarez, Alex A Compton, Sergi Padilla-Parra
HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus-cell fusion in vitro may contribute to the development of future therapeutic interventions...
September 9, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28890135/targeted-immune-interventions-for-an-hiv-1-cure
#3
REVIEW
Matthieu Perreau, Riddhima Banga, Giuseppe Pantaleo
Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure...
September 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28890134/modifiers-of-grn-associated-frontotemporal-lobar-degeneration
#4
REVIEW
Eline Wauters, Sara Van Mossevelde, Julie Van der Zee, Marc Cruts, Christine Van Broeckhoven
Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials...
September 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28887051/precision-oncology-the-road-ahead
#5
REVIEW
Daniela Senft, Mark D M Leiserson, Eytan Ruppin, Ze'ev A Ronai
Current efforts in precision oncology largely focus on the benefit of genomics-guided therapy. Yet, advances in sequencing techniques provide an unprecedented view of the complex genetic and nongenetic heterogeneity within individual tumors. Herein, we outline the benefits of integrating genomic and transcriptomic analyses for advanced precision oncology. We summarize relevant computational approaches to detect novel drivers and genetic vulnerabilities, suitable for therapeutic exploration. Clinically relevant platforms to functionally test predicted drugs/drug combinations for individual patients are reviewed...
September 5, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28887050/genome-engineering-for-personalized-arthritis-therapeutics
#6
REVIEW
Shaunak S Adkar, Jonathan M Brunger, Vincent P Willard, Chia-Lung Wu, Charles A Gersbach, Farshid Guilak
Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis...
September 5, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28870601/lung-alveolar-repair-not-all-cells-are-equal
#7
Charlotte H Dean, Clare M Lloyd
The lungs are capable of repair but the extent to which this occurs varies widely. Recent data indicate that, following injury, different progenitor cell populations can arise, depending on the molecular environment. In turn, these result in either normal or aberrant alveolar repair. Thus, a key question in lung regenerative medicine is how to maintain a 'Goldilocks zone' of repair.
September 1, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28867556/neoantigen-vaccines-pass-the-immunogenicity-test
#8
Gerald P Linette, Beatriz M Carreno
Neoantigens arising from tumor-specific genomic alterations constitute authentic non-self antigens and represent a new class of targets for cancer immunotherapy. Recent reports on various vaccine platforms targeting neoantigens suggest a basis for precision therapies customized to each patient's tumor mutational profile.
August 31, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28822631/clinical-evaluation-of-ebola-virus-disease-therapeutics
#9
REVIEW
Guodong Liu, Gary Wong, Shuo Su, Yuhai Bi, Frank Plummer, George F Gao, Gary Kobinger, Xiangguo Qiu
Ebola virus disease (EVD) was first described over 40 years ago, but no treatment has been approved for humans. The 2013-2016 EVD outbreak in West Africa has expedited the clinical evaluation of several candidate therapeutics that act through different mechanisms, but with mixed results. Nevertheless, these studies are important because the accumulation of clinical data and valuable experience in conducting efficacy trials under emergency circumstances will lead to better implementation of similar studies in the future...
August 16, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28811172/current-options-for-cell-therapy-in-spinal-cord-injury
#10
REVIEW
Irma Vismara, Simonetta Papa, Filippo Rossi, Gianluigi Forloni, Pietro Veglianese
Spinal cord injury (SCI) is a complex pathology that evolves after primary acute mechanical injury, causing further damage to the spinal cord tissue that exacerbates clinical outcomes. Based on encouraging results from preclinical experiments, some cell treatments being translated into clinical practice demonstrate promising and effective improvement in sensory/motor function. Combinatorial treatments of cell and drug/biological factors have been demonstrated to be more effective than cell treatments alone...
August 12, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28811171/molecular-sensors-of-blood-flow-in-endothelial-cells
#11
REVIEW
Sara Baratchi, Khashayar Khoshmanesh, Owen L Woodman, Simon Potocnik, Karlheinz Peter, Peter McIntyre
Mechanical stress from blood flow has a significant effect on endothelial physiology, with a key role in initiating vasoregulatory signals. Disturbances in blood flow, such as in regions of disease-associated stenosis, arterial branch points, and sharp turns, can induce proatherogenic phenotypes in endothelial cells. The disruption of vascular homeostasis as a result of endothelial dysfunction may contribute to early and late stages of atherosclerosis, the underlying cause of coronary artery disease. In-depth knowledge of the mechanobiology of endothelial cells is essential to identifying mechanosensory complexes involved in the pathogenesis of atherosclerosis...
August 12, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28803703/viral-hijacking-of-formins-in-neurodevelopmental-pathologies
#12
REVIEW
Karen Racicot, Sarah VanOeveren, Art Alberts
The 2015 Zika virus (ZIKV) outbreak caused global concern when it was determined to cause microcephaly, hearing loss, and other neurodevelopmental manifestations upon fetal exposure. Significant progress has been made in our understanding of the interactions between ZIKV and the pregnant host, but there is still a critical need to understand how ZIKV and other neurotropic viruses affect fetal neurodevelopment. Diaphanous-related formins (Diaphs) have recently been identified as microcephaly-associated proteins in humans and mice...
August 10, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28797787/t-cell-exhaustion-an-epigenetically-imprinted-phenotypic-and-functional-makeover
#13
Francesca Alfei, Dietmar Zehn
A recent article in Cell demonstrates that the absence of a single DNA methyltransferase, Dnmt3a, prevents cytotoxic T cells from acquiring the hypofunctional or exhausted phenotype typically seen in chronic viral infections and tumors. Upon establishing a causal relationship between exhaustion-associated epigenetic changes and reduced CD8(+) T cell function, the authors provided mechanistic evidence that exhaustion constitutes a specific differentiation program.
August 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28789830/sphingosine-kinase-1-a-potential-therapeutic-target-in-pulmonary-arterial-hypertension
#14
REVIEW
Nigel J Pyne, Susan Pyne
Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion, more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting their effectiveness in PAH...
August 5, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28774478/putting-glioblastoma-in-its-place-irf3-inhibits-invasion
#15
Siobhan S Pattwell, Eric C Holland
With an unsurpassed capacity for invasion into normal brain tissue, glioblastoma multiforme is the most lethal primary brain tumor. New research suggests that altering a subset of extracellular matrix factors, including interferon regulatory factor (IRF)3 and casein kinase (CK)2, may decrease the migratory potential of these aggressive tumors.
July 31, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28739207/obstructive-sleep-apnea-and-hallmarks-of-aging
#16
REVIEW
Laetitia S Gaspar, Ana Rita Álvaro, Joaquim Moita, Cláudia Cavadas
Obstructive sleep apnea (OSA) is one of the most common sleep disorders. Since aging is a risk factor for OSA development, it is expected that its prevalence will increase with the current increase in life span. In recent years, several studies have shown that OSA potentially contributes to functional decline, mainly prompted by chronic intermittent hypoxia and sleep fragmentation. Here, we propose that OSA might anticipate/aggravate aging by inducing cellular and molecular impairments that characterize the aging process, such as stem cell exhaustion, telomere attrition and epigenetic changes...
July 21, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28732688/molecular-pathophysiology-of-gout
#17
REVIEW
Jyaysi Desai, Stefanie Steiger, Hans-Joachim Anders
Three contradictory clinical presentations of gout have puzzled clinicians and basic scientists for some time: first, the crescendo of sterile inflammation in acute gouty arthritis; second, its spontaneous resolution, despite monosodium urate (MSU) crystal persistence in the synovium; and third, immune anergy to MSU crystal masses observed in tophaceous or visceral gout. Here, we provide an update on the molecular pathophysiology of these gout manifestations, namely, how MSU crystals can trigger the auto-amplification loop of necroinflammation underlying the crescendo of acute gouty arthritis...
July 18, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28732687/selective-therapeutic-intervention-a-challenge-against-off-target-effects
#18
Filip Rázga, Veronika Némethová
Despite the massive global spend on biology-driven drug discovery, tackling the issue of side effects and adverse events resulting from drug promiscuity represents a persistent challenge. Although delivering authentic medical innovations today is more complex than ever, minimization of off-target effects should be a priority.
July 18, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28716624/recent-advances-in-mitochondrial-aminoacyl-trna-synthetases-and-disease
#19
REVIEW
Marie Sissler, Ligia Elena González-Serrano, Eric Westhof
Dysfunctions in mitochondria - the powerhouses of the cell - lead to several human pathologies. Because mitochondria integrate nuclear and mitochondrial genetic systems, they are richly intertwined with cellular activities. The nucleus-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key components of the mitochondrial translation apparatus. Mutations in these enzymes predominantly affect the central nervous system (CNS) but also target other organs. Comparable mutations in mt-aaRSs can lead to vastly diverse diseases, occurring at different stages in life, and within different tissues; this represents a confounding issue...
July 14, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28697885/neutralizing-the-threat-pan-ebolavirus-antibodies-close-the-loop
#20
Chad E Mire, Thomas W Geisbert
The glycoprotein (GP) of ebolaviruses participates in a critical membrane fusion process to establish infection of a cell and therefore, represents an important target of both vaccines and antivirals. The latest reports on pan-ebolavirus monoclonal antibodies in small animal models may offer promising outcomes and insight into how best to target the GP in vaccine and antiviral discovery.
July 8, 2017: Trends in Molecular Medicine
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