Abstract：
:While preclinical studies have reported improvement of behavioral deficits in the Ts65Dn mouse model of Down syndrome (DS), translation to human clinical trials to improve cognition in individuals with DS has had a poor success record. Timing of the intervention, choice of animal models, strategy for drug selection, and lack of translational endpoints between animals and humans contributed to prior failures of human clinical trials. Here, we focus on in vitro cell models from humans with DS to identify the molecular mechanisms underlying the brain phenotype associated with DS. We emphasize the importance of using these cell models to screen for therapeutic molecules, followed by validating them in the most suitable animal models prior to initiating human clinical trials.
journal_name
Trends Mol Medjournal_title
Trends in molecular medicineauthors
Lee SE,Duran-Martinez M,Khantsis S,Bianchi DW,Guedj Fdoi
10.1016/j.molmed.2019.10.001subject
Has Abstractpub_date
2020-02-01 00:00:00pages
150-169issue
2eissn
1471-4914issn
1471-499Xpii
S1471-4914(19)30242-4journal_volume
26pub_type
杂志文章abstract：:Transport into the endoplasmic reticulum (ER) is the crucial step in the biosynthesis of most secretory proteins and many membrane proteins. The products of the SIL1, SEC62 and SEC63 genes act in concert with the SEC61 complex and the molecular chaperones BiP and GRP170 to transport proteins into the ER. Interestingly...
journal_title：Trends in molecular medicine
pub_type： 杂志文章
doi：10.1016/j.molmed.2006.10.004
更新日期：2006-12-01 00:00:00
abstract：:Hypoxia-inducible factor 1 (HIF-1) controls oxygen delivery (via angiogenesis) and metabolic adaptation to hypoxia (via glycolysis). HIF-1 consists of a constitutively expressed HIF-1 beta subunit and an oxygen- and growth-factor-regulated HIF-1 alpha subunit. In xenografts, tumor growth and angiogenesis are correlate...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/s1471-4914(02)02317-1
更新日期：2002-01-01 00:00:00
abstract：:Alterations in histone lysine methylation and other epigenetic regulators of gene expression contribute to changes in brain transcriptomes in mood and psychosis spectrum disorders, including depression and schizophrenia. Genetic association studies and animal models implicate multiple lysine methyltransferases and dem...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2011.02.003
更新日期：2011-07-01 00:00:00
abstract：:The efficacy of drugs administered by traditional routes is limited by numerous biological barriers that preclude reaching the intended site of action. Further, full body systemic exposure leads to dose-limiting, off-target side effects. Topical formulations may provide more efficacious drug and nucleic acid delivery ...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2020.12.001
更新日期：2021-01-04 00:00:00
abstract：:Prior to zygotic genome activation, early mammalian development relies on maternal-effect genes to orchestrate the oocyte-to-embryo transition. Recently, a subcortical maternal complex (SCMC) was identified to be essential for mouse preimplantation development. The SCMC integrates multiple proteins encoded by maternal...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2017.09.004
更新日期：2017-11-01 00:00:00
abstract：:Accumulating evidence supports the important role for epigenetic changes in modulating clinical parameters of complex disorders, including neurodegenerative disease. Several conditions, including fragile X syndrome and Huntington's disease are caused by trinucleotide repeat (TNR) expansions in or near specific genes. ...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2013.07.007
更新日期：2013-11-01 00:00:00
abstract：:Despite concerted international efforts, mortality from neonatal infections remains unacceptably high in some areas of the world, particularly for premature infants. Recent developments in flow cytometry and next-generation sequencing technologies have led to major discoveries over the past few years, providing a more...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2016.02.001
更新日期：2016-04-01 00:00:00
abstract：:The identification of functionally relevant polymorphisms of peptidylarginine deiminase 4, an enzyme that catalyzes the post-translational citrullination of proteins, as a rheumatoid arthritis gene is one of the most convincing success stories of complex disease gene mapping to date. In addition to an extensive single...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2003.08.007
更新日期：2003-10-01 00:00:00
abstract：:cAMP-dependent protein kinase A (PKA) signaling has a key role in memory processes and has been identified as a potential therapeutic target for memory disorders. The activation of PKA signaling is crucial for the consolidation of long-term memories dependent on the hippocampus and/or the amygdala, By contrast, initia...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2005.01.006
更新日期：2005-03-01 00:00:00
abstract：:Immune checkpoint inhibitors (ICIs) have revolutionised cancer immunotherapy but their success is wholly dependent on amplifying an existing immune response directed against the tumour. A recent study by Tsuchiya et al. suggests how the properties of induced pluripotent stem cells (iPSCs) may be exploited for the targ...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2019.09.001
更新日期：2019-11-01 00:00:00
abstract：:Betulinic acid (BA) derivatives are low molecular weight organic compounds synthesized from a plant-derived natural product. Several BA derivatives are potent and highly selective inhibitors of HIV-1. Depending on the specific side-chain modification, these compounds function by inhibiting HIV fusion or, as recently d...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2004.11.001
更新日期：2005-01-01 00:00:00
abstract：:Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-β (Aβ) plaques, their clearance may be clinically more efficacious than removing Aβ when cognitive defic...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2015.03.003
更新日期：2015-06-01 00:00:00
abstract：:Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the g...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2010.10.010
更新日期：2011-02-01 00:00:00
abstract：:The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain. Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exp...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2020.07.002
更新日期：2020-10-01 00:00:00
abstract：:The surfaces of all vertebrate cells are decorated with a dense and complex array of sugar chains, which are mostly attached to proteins and lipids. Most soluble secreted proteins are also similarly decorated with such glycans. Sialic acids are a diverse family of sugar units with a nine-carbon backbone that are typic...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2008.06.002
更新日期：2008-08-01 00:00:00
abstract：:Medical diagnosis and phenotyping increasingly incorporate information from complex biological samples. This has promoted the development and clinical application of non-invasive metabolomics in exhaled air (breathomics). In respiratory medicine, expired volatile organic compounds (VOCs) are associated with inflammato...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2015.08.001
更新日期：2015-10-01 00:00:00
abstract：:In a meticulous study, Humbert, Durr, and colleagues showed evidence for aberrant neurodevelopment in both Huntington's disease (HD) and mouse models of HD. We consider the implications of prenatal pathological changes for the onset and progression of HD and their relatedness to current therapeutic plans. ...
journal_title：Trends in molecular medicine
pub_type： 评论,杂志文章
doi：10.1016/j.molmed.2020.08.004
更新日期：2020-10-01 00:00:00
abstract：:What biological factors account for resilience to pain or to behavioral stress? Here, we discuss examples of cellular and molecular mechanisms within disparate parts of the nervous system as contributors to such resilience. In some especially well-studied humans, it is possible to identify particular neuronal cell typ...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2020.03.007
更新日期：2020-10-01 00:00:00
abstract：:In recent years there have been major advances in the knowledge of the genetic alterations that drive cancer susceptibility and progression. However, the molecular links between these alteration levels (i.e., germline for susceptibility and somatic for progression) remain mostly unknown. Here, the potential of integra...
journal_title：Trends in molecular medicine
pub_type： 杂志文章
doi：10.1016/j.molmed.2014.05.004
更新日期：2014-08-01 00:00:00
abstract：:For decades it has been assumed that T cells reject tumors essentially by direct killing. However, solid tumors are composed of malignant cells and a variety of different nonmalignant cells, referred to as tumor stroma. Stromal cells, such as endothelial cells, fibroblasts and inflammatory cells, often support tumor g...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2005.03.002
更新日期：2005-05-01 00:00:00
abstract：:BAX is a formidable BCL-2 family protein that executes cellular suicide in response to physiologic and pathologic stress. A new article in Nature Chemical Biology (Garner et al.https://doi.org/10.1038/s41589-018-0223-0) reports small molecules that inhibit the conformational activation of BAX, informing a pharmacologi...
journal_title：Trends in molecular medicine
pub_type： 信件
doi：10.1016/j.molmed.2019.02.008
更新日期：2019-04-01 00:00:00
abstract：:Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-Eph...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2019.01.009
更新日期：2019-04-01 00:00:00
abstract：:Cancer cells meet their needs for energy and biomass production by consuming high levels of nutrients and rewiring metabolism to support macromolecular biosynthesis. Mitochondrial enzymes play central roles in anabolic growth, and acetylation may provide a key layer of regulation over mitochondrial metabolic pathways....
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2012.05.004
更新日期：2012-09-01 00:00:00
abstract：:Tumour classification has traditionally focused on differentiation and cellular morphology, and latterly on the application of genomic approaches. By combining chromatin immunoprecipitation with expression array, it has been possible to identify direct gene targets for transcription factors for nuclear hormone recepto...
journal_title：Trends in molecular medicine
pub_type： 临床试验,杂志文章
doi：10.1016/j.molmed.2008.09.002
更新日期：2008-11-01 00:00:00
abstract：:Accumulating evidence has revealed that immunogenic cell death triggered by particular chemotherapeutic agents plays a critical role in harnessing antitumor immunity to clinical responses. However, negative regulatory pathways exist which suppress the induction of effective immune responses by a broad spectrum of anti...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2013.06.001
更新日期：2013-09-01 00:00:00
abstract：:Although significant progress has been made in understanding autoimmunity, no immunotherapy to effectively halt immune-mediated destruction of β cells in type 1 diabetes (T1D) is currently available. For successful immunotherapy it will be necessary to identify novel drug targets as well as robust immunologic biomarke...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2018.08.005
更新日期：2018-11-01 00:00:00
abstract：:The Hedgehog (Hh) cascade controls cell proliferation, differentiation and patterning of tissues during embryogenesis but is largely suppressed in the adult. The Hh pathway can become reactivated in cancer. Here, we assimilate data from recent studies to understand how and when the Hh pathway is turned on to aid the n...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2010.05.003
更新日期：2010-08-01 00:00:00
abstract：:In his article, Szyf [1] has addressed the key challenges in and the controversies surrounding nongenetic inheritance. However, crucial findings that are important to counter two major criticisms held against transgenerational inheritance, especially in mammals--namely epigenetic memory survival across generations, an...
journal_title：Trends in molecular medicine
pub_type： 评论,信件
doi：10.1016/j.molmed.2015.02.010
更新日期：2015-05-01 00:00:00
abstract：:Phagocytosis is used not only for immune defense but may also be used to obtain nutrients, as observed when tumor cells feed upon neighboring cells during "tumor cell cannibalism". The TM9 protein TM9SF4, important in canonical phagocytosis, is involved in this cannibalism by metastatic cells and may represent a novel...
journal_title：Trends in molecular medicine
pub_type： 杂志文章
doi：10.1016/j.molmed.2011.09.001
更新日期：2012-01-01 00:00:00
abstract：:Keratinocytes and skin immune cells are actively metabolizing nutrients present in their microenvironment. This is particularly important in common chronic inflammatory skin diseases such as psoriasis and atopic dermatitis, characterized by hyperproliferation of keratinocytes and expansion of inflammatory cells, thus ...
journal_title：Trends in molecular medicine
pub_type： 杂志文章,评审
doi：10.1016/j.molmed.2020.04.004
更新日期：2020-11-01 00:00:00
