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Phenotypic heterogeneity

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https://www.readbyqxmd.com/read/29053742/are-current-chronic-fatigue-syndrome-criteria-diagnosing-different-disease-phenotypes
#1
Laura Maclachlan, Stuart Watson, Peter Gallagher, Andreas Finkelmeyer, Leonard A Jason, Madison Sunnquist, Julia L Newton
IMPORTANCE: Chronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ)...
2017: PloS One
https://www.readbyqxmd.com/read/29052866/runx-mediated-growth-arrest-and-senescence-are-attenuated-by-diverse-mechanisms-in-cells-expressing-runx1-fusion-oncoproteins
#2
Gail Anderson, Nancy Mackay, Kathryn Gilroy, Jodie Hay, Gillian Borland, Alma McDonald, Margaret Bell, Siti Ayuni Hassanudin, Ewan Cameron, James C Neil, Anna Kilbey
RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs...
October 20, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29052317/defective-ciliogenesis-in-inpp5e-related-joubert-syndrome
#3
Isabel Hardee, Ariane Soldatos, Mariska Davids, Thierry Vilboux, Camilo Toro, Karen L David, Carlos R Ferreira, Michele Nehrebecky, Joseph Snow, Audrey Thurm, Theo Heller, Ellen F Macnamara, Meral Gunay-Aygun, Wadih M Zein, William A Gahl, May Christine V Malicdan
Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium...
October 20, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29051922/hidden-heritability-due-to-heterogeneity-across-seven-populations
#4
Felix C Tropf, S Hong Lee, Renske M Verweij, Gert Stulp, Peter J van der Most, Ronald de Vlaming, Andrew Bakshi, Daniel A Briley, Charles Rahal, Robert Hellpap, Anastasia Nyman, Tõnu Esko, Andres Metspalu, Sarah E Medland, Nicholas G Martin, Nicola Barban, Harold Snieder, Matthew R Robinson, Melinda C Mills
Meta-analyses of genome-wide association studies (GWAS), which dominate genetic discovery are based on data from diverse historical time periods and populations. Genetic scores derived from GWAS explain only a fraction of the heritability estimates obtained from whole-genome studies on single populations, known as the 'hidden heritability' puzzle. Using seven sampling populations (N=35,062), we test whether hidden heritability is attributed to heterogeneity across sampling populations and time, showing that estimates are substantially smaller from across compared to within populations...
October 2017: Nature Human Behaviour
https://www.readbyqxmd.com/read/29051534/surface-marker-profiling-of-sh-sy5y-cells-enables-small-molecule-screens-identifying-bmp4-as-a-modulator-of-neuroblastoma-differentiation
#5
Fraua Christina Ferlemann, Vishal Menon, Alexandra Larisa Condurat, Jochen Rößler, Jan Pruszak
Neuroblastoma is the most common extra-cranial solid tumor in children. Its broad spectrum of clinical outcomes reflects the underlying inherent cellular heterogeneity. As current treatments often do not lead to tumor eradication, there is a need to better define therapy-resistant neuroblastoma and to identify new modulatory molecules. To this end, we performed the first comprehensive flow cytometric characterization of surface molecule expression in neuroblastoma cell lines. Exploiting an established clustering algorithm (SPADE) for unbiased visualization of cellular subsets, we conducted a multiwell screen for small molecule modulators of neuroblastoma phenotype...
October 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29051276/precision-medicine-in-airway-diseases-moving-to-clinical-practice
#6
Alvar Agustí, Mona Bafadhel, Richard Beasley, Elisabeth H Bel, Rosa Faner, Peter G Gibson, Renaud Louis, Vanessa M McDonald, Peter J Sterk, Mike Thomas, Claus Vogelmeier, Ian D Pavord
On February 21, 2017, a European Respiratory Society research seminar held in Barcelona discussed how to best apply precision medicine to chronic airway diseases such as asthma and chronic obstructive pulmonary disease. It is now clear that both are complex and heterogeneous diseases, that often overlap and that both require individualised assessment and treatment. This paper summarises the presentations and discussions that took place during the seminar. Specifically, we discussed the need for a new taxonomy of human diseases, the role of different players in this scenario (exposome, genes, endotypes, phenotypes, biomarkers and treatable traits) and a number of unanswered key questions in the field...
October 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/29051230/iphemap-an-atlas-of-phenotype-to-genotype-relationships-of-human-ipsc-models-of-neurological%C3%A2-diseases
#7
Ethan W Hollingsworth, Jacob E Vaughn, Josh C Orack, Chelsea Skinner, Jamil Khouri, Sofia B Lizarraga, Mark E Hester, Fumihiro Watanabe, Kenneth S Kosik, Jaime Imitola
Disease modeling with induced pluripotent stem cells (iPSCs) is creating an abundance of phenotypic information that has become difficult to follow and interpret. Here, we report a systematic analysis of research practices and reporting bias in neurological disease models from 93 published articles. We find heterogeneity in current research practices and a reporting bias toward certain diseases. Moreover, we identified 663 CNS cell-derived phenotypes from 243 patients and 214 controls, which varied by mutation type and developmental stage in vitro We clustered these phenotypes into a taxonomy and characterized these phenotype-genotype relationships to generate a phenogenetic map that revealed novel correlations among previously unrelated genes...
October 19, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29050567/biological-phenotypes-of-heart-failure-with-preserved-ejection-fraction
#8
REVIEW
Gavin A Lewis, Erik B Schelbert, Simon G Williams, Colin Cunnington, Fozia Ahmed, Theresa A McDonagh, Christopher A Miller
Heart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, which result in the heterogeneous phenotypes that are evident clinically, and which have potentially confounded previous HFpEF trials. A greater understanding of the in vivo human processes involved, and in particular, which are the causes and which are the downstream effects, may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on the underlying biology. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotype...
October 24, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/29050382/distinct-18f-av-1451-tau-pet-retention-patterns-in-early-and-late-onset-alzheimer-s-disease
#9
Michael Schöll, Rik Ossenkoppele, Olof Strandberg, Sebastian Palmqvist, Jonas Jögi, Tomas Ohlsson, Ruben Smith, Oskar Hansson
Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns...
September 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29050228/mutation-landscape-and-intra-tumor-heterogeneity-of-two-manecs-of-the-esophagus-revealed-by-multi-region-sequencing
#10
Wenqing Yuan, Zhen Liu, Wanjun Lei, Li Sun, Haijun Yang, Yu Wang, Shweta Ramdas, Xiao Dong, Ruiping Xu, Hong Cai, Jun Z Li, Yang Ke
Mixed adenoneuroendocrine carcinoma (MANEC) in the esophagus is an infrequent but highly malignant cancer with few known genomic alterations. We conducted whole-exome sequencing and whole-genome SNP genotyping for 4-6 tumor subregions and 5-6 adjacent normal tissue sites and 1-3 lymph node metastases in two esophageal MANECs to detect somatic mutations and copy number alterations, and to explore their spatial heterogeneity and underlying clonal structure. TP53 mutation, RB1 deletion or LOH, and PIK3CA, PTEN, KRAS, SOX2, DVL3, TP63 amplification appeared in all regions in both tumors...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050118/-gene-mutation-and-clinical-phenotype-analysis-of-patients-with-noonan-syndrome-and-hypertrophic-cardiomyopathy
#11
X H Liu, W W Ding, L Han, X R Liu, Y Y Xiao, J Yang, Y Mo
Objective: To analyze the gene mutations and clinical features of patients with Noonan syndrome and hypertrophic cardiomyopathy. Method: Determined the mutation domain in five cases diagnosed with Noonan syndrome and hypertrophic cardiomyopathy and identified the relationship between the mutant domain and hypertrophic cardiomyopathy by searching relevant articles in pubmed database. Result: Three mutant genes (PTPN11 gene in chromosome 12, RIT1 gene in chromosome 1 and RAF1 gene in chromosome 3) in five cases all had been reported to be related to hypertrophic cardiomyopathy...
October 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29049843/metabolic-strategies-of-melanoma-cells-mechanisms-interactions-with-the-tumor-microenvironment-and-therapeutic-implications
#12
REVIEW
Grant M Fischer, Y N Vashisht Gopal, Jennifer L McQuade, Weiyi Peng, Ralph J DeBerardinis, Michael A Davies
Melanomas are metabolically heterogeneous, and they are able to adapt in order to utilize a variety of fuels that facilitate tumor progression and metastasis. The significance of metabolism in melanoma is supported by growing evidence of impact on the efficacy of contemporary therapies for this disease. There is also data to support that the metabolic phenotypes of melanoma cells depend upon contributions from both intrinsic oncogenic pathways and extrinsic factors in the tumor microenvironment. This review summarizes current understanding of the metabolic processes that promote cutaneous melanoma tumorigenesis and progression, the regulation of cancer cell metabolism by the tumor microenvironment, and the impact of metabolic pathways on targeted and immune therapies...
October 19, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29049371/combining-epidemiology-with-basic-biology-of-sand-flies-parasites-and-hosts-to-inform-leishmaniasis-transmission-dynamics-and-control
#13
REVIEW
Orin Courtenay, Nathan C Peters, Matthew E Rogers, Caryn Bern
Quantitation of the nonlinear heterogeneities in Leishmania parasites, sand fly vectors, and mammalian host relationships provides insights to better understand leishmanial transmission epidemiology towards improving its control. The parasite manipulates the sand fly via production of promastigote secretory gel (PSG), leading to the "blocked sand fly" phenotype, persistent feeding attempts, and feeding on multiple hosts. PSG is injected into the mammalian host with the parasite and promotes the establishment of infection...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29048949/discovering-pediatric-asthma-phenotypes-based-on-response-to-controller-medication-using-machine-learning
#14
Mindy K Ross, Jinsung Yoon, Auke van der Schaar, Mihaela van der Schaar
RATIONALE: Pediatric asthma has variable underlying inflammation and symptom control. Approaches to address this heterogeneity such as clustering methods to find phenotypes and predicting outcomes have been investigated. However, clustering based upon the relationship between treatment and clinical outcome has not been performed. Also, machine learning approaches for long-term outcome prediction in pediatric asthma have not been studied in depth. OBJECTIVES: Our objectives were to use our novel machine learning algorithm, Predictor Pursuit (PP) to discover pediatric asthma phenotypes based on treatment response to different asthma controller medications, to predict outcomes of children with asthma over time, and to identify the most indicative features of asthma control for the discovered pediatric phenotypes...
October 19, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/29048610/evidence-of-lateral-transmission-of-aggressive-features-between-different-types-of-breast-cancer-cells
#15
Nancy Adriana Espinoza-Sánchez, Eduardo Vadillo, Juan Carlos Balandrán, Alberto Monroy-García, Rosana Pelayo, Ezequiel M Fuentes-Pananá
Breast cancer (BrC) is a major public health problem worldwide. The intra-tumoral heterogeneity and tumor cell plasticity importantly contribute to disease progression and treatment failure. However, the dynamic interactions between different tumor clones, as well as their contribution to tumor aggressiveness are still poorly understood. In this study, we provide evidence of a lateral transmission of aggressive features between aggressive and non-aggressive tumor cells, consisting of gain of expression of cancer stem cell markers, increased expression of CXCL12 receptors CXCR4 and CXCR7 and increased invasiveness in response to CXCL12, which correlated with high levels of secretion of pro-inflammatory mediators G-CSF, GM-CSF, MCP-1, IL-8 and metalloproteinases 1 and 2 by the aggressive cells...
September 19, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/29047204/influence-of-cell-distribution-and-diabetes-status-on-the-association-between-mitochondrial-dna-copy-number-and-aging-phenotypes-in-the-inchianti-study
#16
Ann Zenobia Moore, Jun Ding, Marcus A Tuke, Andrew R Wood, Stefania Bandinelli, Timothy M Frayling, Luigi Ferrucci
Mitochondrial DNA copy number (mtDNA-CN) estimated in whole blood is a novel marker of mitochondrial mass and function that can be used in large population-based studies. Analyses that attempt to relate mtDNA-CN to specific aging phenotypes may be confounded by differences in the distribution of blood cell types across samples. Also, low or high mtDNA-CN may have a different meaning given the presence of diseases associated with mitochondrial damage. We evaluated the impact of blood cell type distribution and diabetes status on the association between mtDNA-CN and aging phenotypes, namely chronologic age, interleukin-6, hemoglobin, and all-cause mortality, among 672 participants of the InCHIANTI study...
October 19, 2017: Aging Cell
https://www.readbyqxmd.com/read/29046784/the-role-of-gene-variants-in-the-pathogenesis-of-neurodegenerative-disorders-as-revealed-by-next-generation-sequencing-studies-a-review
#17
REVIEW
Shirley Yin-Yu Pang, Kay-Cheong Teo, Jacob Shujui Hsu, Richard Shek-Kwan Chang, Miaoxin Li, Pak-Chung Sham, Shu-Leong Ho
The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms. It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder. The advent of next generation sequencing (NGS) has allowed for a system-wide, unbiased approach to identify all gene variants in the genome simultaneously. With the plethora of new genes being identified, genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia (SCA), hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth disease (CMT) has become widely accepted...
2017: Translational Neurodegeneration
https://www.readbyqxmd.com/read/29046687/how-do-plants-and-phytohormones-accomplish-heterophylly-leaf-phenotypic-plasticity-in-response-to-environmental-cues
#18
REVIEW
Hokuto Nakayama, Neelima R Sinha, Seisuke Kimura
Plant species are known to respond to variations in environmental conditions. Many plant species have the ability to alter their leaf morphology in response to such changes. This phenomenon is termed heterophylly and is widespread among land plants. In some cases, heterophylly is thought to be an adaptive mechanism that allows plants to optimally respond to environmental heterogeneity. Recently, many research studies have investigated the occurrence of heterophylly in a wide variety of plants. Several studies have suggested that heterophylly in plants is regulated by phytohormones...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29045840/clonal-heterogeneity-influences-the-fate-of-new-adaptive-mutations
#19
Ignacio Vázquez-García, Francisco Salinas, Jing Li, Andrej Fischer, Benjamin Barré, Johan Hallin, Anders Bergström, Elisa Alonso-Perez, Jonas Warringer, Ville Mustonen, Gianni Liti
The joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood but essential to designing successful antimicrobial or cancer therapies. To address this, we evolve genetically diverse populations of budding yeast, S. cerevisiae, consisting of diploid cells with unique haplotype combinations. We study the asexual evolution of these populations under selective inhibition with chemotherapeutic drugs by time-resolved whole-genome sequencing and phenotyping. All populations undergo clonal expansions driven by de novo mutations but remain genetically and phenotypically diverse...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045754/genomic-studies-of-local-adaptation-in-natural-plant-populations
#20
Victoria L Sork
Local adaptation arises as a result of selection by the local environment favoring phenotypes that enhance fitness. Geographic patterns of phenotypic variation are in part due to this selective process. Classically, the genetic basis of those phenotypes has been studied in plant populations using a quantitative genetic approach in which plants from different source populations are grown in common environments, in reciprocal transplant experiments, or in studies across a wide geographic and environmentally heterogeneous area...
October 14, 2017: Journal of Heredity
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