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Phenotypic heterogeneity

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https://www.readbyqxmd.com/read/29444439/differential-effector-engagement-by-oncogenic-kras
#1
Tina L Yuan, Arnaud Amzallag, Rachel Bagni, Ming Yi, Shervin Afghani, William Burgan, Nicole Fer, Leslie A Strathern, Katie Powell, Brian Smith, Andrew M Waters, David Drubin, Ty Thomson, Rosy Liao, Patricia Greninger, Giovanna T Stein, Ellen Murchie, Eliane Cortez, Regina K Egan, Lauren Procter, Matthew Bess, Kwong Tai Cheng, Chih-Shia Lee, Liam Changwoo Lee, Christof Fellmann, Robert Stephens, Ji Luo, Scott W Lowe, Cyril H Benes, Frank McCormick
KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention...
February 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29444207/the-functional-network-signature-of-heterogeneity-in-freezing-of-gait
#2
Kaylena A Ehgoetz Martens, Julie M Hall, Matthew J Georgiades, Moran Gilat, Courtney C Walton, Elie Matar, Simon J G Lewis, James M Shine
Freezing of gait is a complex, heterogeneous, and highly variable phenomenon whose pathophysiology and neural signature remains enigmatic. Evidence suggests that freezing is associated with impairments across cognitive, motor and affective domains; however, most research to date has focused on investigating one axis of freezing of gait in isolation. This has led to inconsistent findings and a range of different pathophysiological models of freezing of gait, due in large part to the tendency for studies to investigate freezing of gait as a homogeneous entity...
February 9, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29444168/identifying-genetic-risk-loci-for-diabetic-complications-and-showing-evidence-for-heterogeneity-of-type-1-diabetes-based-on-complications-risk
#3
Nandita Mukhopadhyay, Janelle A Noble, Manika Govil, Mary L Marazita, David A Greenberg
There is a growing body of evidence suggesting that type 1 diabetes (T1D) is a genetically heterogeneous disease. However, the extent of this heterogeneity, and what observations may distinguish different forms, is unclear. One indicator may be T1D-related microvascular complications (MVCs), which are familial, but occur in some families, and not others. We tested the hypothesis that T1D plus MVC is genetically distinct from T1D without MCV. We studied 415 families (2,462 individuals, 896 with T1D) using genome-wide linkage analysis, comparing families with and without MVC...
2018: PloS One
https://www.readbyqxmd.com/read/29442327/zic2-in-holoprosencephaly
#4
Kristen S Barratt, Ruth M Arkell
The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29441650/incidence-prevalence-and-clinical-correlates-of-antidepressant-emergent-mania-in-bipolar-depression-a-systematic-review-and-meta-analysis
#5
REVIEW
Michele Fornaro, Annalisa Anastasia, Stefano Novello, Andrea Fusco, Marco Solmi, Francesco Monaco, Nicola Veronese, Domenico De Berardis, Andrea de Bartolomeis
BACKGROUND: Treatment-emergent mania (TEM) represents a common phenomenon inconsistently reported across primary studies, warranting further assessment. METHODS: A systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were conducted. Major electronic databases were searched from inception to May 2017 to assess the incidence and prevalence rates and clinical features associated with manic switch among bipolar depressed patients receiving antidepressants, using meta-regression and subgroup analysis...
February 14, 2018: Bipolar Disorders
https://www.readbyqxmd.com/read/29441485/clinical-spectrum-of-c9orf72-expansion-in-a-cohort-of-huntington-s-disease-phenocopies
#6
Joana Martins, Joana Damásio, Alexandre Mendes, Nuno Vila-Chã, José E Alves, Cristina Ramos, Sara Cavaco, João Silva, Isabel Alonso, Marina Magalhães
The expansion in the C9orf72 gene has been recently reported as a genetic cause of Huntington's disease (HD) phenocopies. We aim to assess the frequency of the C9orf72 gene expansion in a Portuguese HD phenocopies cohort. Twenty HD phenotype-like patients without diagnosis were identified in our institutional database. C9orf72 gene expansion was detected using repeat-primed PCR. Clinical files were reviewed to characterize the phenotype of expansion-positive cases. One patient (5%) was positive for the C9orf72 expansion...
February 13, 2018: Neurological Sciences
https://www.readbyqxmd.com/read/29441299/livedo-racemosa-reticulated-ulcerations-panniculitis-and-violaceous-plaques-in-a-46-year-old-woman
#7
Alfredo Agulló, Brian Hinds, Mónica Larrea, Ignacio Yanguas
Clinically amyopathic dermatomyositis (CADM) is a subset of dermatomyositis (DM) that has conventional cutaneous manifestations of DM, but paradoxically, little or no muscle involvement. In 2005, a novel antibody was described in association with CADM - anti-melanoma differentiation-associated gene 5 (anti-MDA5). Patients with this serologic marker have a characteristic mucocutaneous phenotype consisting of skin ulceration among other signs. We describe the case of a 46-year-old woman with CADM, elevated anti-MDA5 autoantibodies, and unusual clinical features (livedo racemosa, florid acral edema) among the classical phenotype of MDA5 DM (arthralgias, ulcerations, panniculitis) and classical DM lesions (Gottron papules, heliotrope rash)...
January 2018: Indian Dermatology Online Journal
https://www.readbyqxmd.com/read/29441128/chromosomal-microarray-analysis-in-the-genetic-evaluation-of-279-patients-with-syndromic-obesity
#8
Carla Sustek D'Angelo, Monica Castro Varela, Claudia Irene Emílio de Castro, Paulo Alberto Otto, Ana Beatriz Alvarez Perez, Charles Marques Lourenço, Chong Ae Kim, Debora Romeo Bertola, Fernando Kok, Luis Garcia-Alonso, Celia Priszkulnik Koiffmann
Background: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study...
2018: Molecular Cytogenetics
https://www.readbyqxmd.com/read/29439669/a-novel-mir-375-hoxb3-cdca3-dnmt3b-regulatory-circuitry-contributes-to-leukemogenesis-in-acute-myeloid-leukemia
#9
Laixi Bi, Bin Zhou, Haiying Li, Licai He, Chunjing Wang, Zhonggai Wang, Liqing Zhu, Mengqian Chen, Shenmeng Gao
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies due to sophisticated genetic mutations and epigenetic dysregulation. MicroRNAs (miRNAs), a class of small non-coding RNAs, are important regulators of gene expression in all biological processes, including leukemogenesis. Recently, miR-375 has been reported to be a suppressive miRNA in multiple types of cancers, but its underlying anti-leukemia activity in AML is largely unknown. METHODS: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure the expression of miR-375 and HOXB3 in leukemic cells and normal controls...
February 13, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29438283/new-insights-into-the-tumor-microenvironment-utilizing-protein-array-technology
#10
REVIEW
Wei Huang, Shuhong Luo, Rob Burgess, Yu-Hua Yi, Gordon F Huang, Ruo-Pan Huang
The tumor microenvironment (TME) is a considerably heterogeneous niche, which is created by tumor cells, the surrounding tumor stroma, blood vessels, infiltrating immune cells, and a variety of associated stromal cells. Intercellular communication within this niche is driven by soluble proteins synthesized by local tumor and stromal cells and include chemokines, growth factors, interferons, interleukins, and angiogenic factors. The interaction of tumor cells with their microenvironment is essential for tumorigenesis, tumor progression, growth, and metastasis, and resistance to drug therapy...
February 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29438113/morphologic-and-immunohistochemical-appraisal-of-primary-gastric-carcinomas
#11
Gunes Guner, Aynur Isik, Erdem Karabulut, Gokhan Gedikoglu, Cenk Sokmensuer, Aytekin Akyol
Gastric carcinoma management requires adjustments answering their genetic and morphologic heterogeneity. We aim to assess the expression and significance of a myriad of biomarkers (p53, MLH1, MSH2, PMS2, MSH6, Epstein-Barr encoding region-RNA, c-erbB2, E-cadherin, CEA, chromogranin, Ki-67, CDX2, presenilin-1, cathepsin E, MUC5AC, cyclin-dependent kinase 1) in 117 gastric carcinomas, which we have morphologically subclassified with a simple algorithm. Immunohistochemical stains were applied to 3 tissue microarrays of primary gastric carcinomas (n=117) obtained from resection specimens of untreated patients...
February 12, 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29437708/expression-of-adipocyte-macrophage-fatty-acid-binding-protein-in-tumor-associated-macrophages-promotes-breast-cancer-progression
#12
Jiaqing Hao, Fei Yan, Yuwen Zhang, Ashley Triplett, Ying Zhang, Debra A Schultz, Yanwen Sun, Jun Zeng, Kevin A T Silverstein, Qi Zheng, David A Bernlohr, Margot P Cleary, Nejat K Egilmez, Edward Sauter, Shujun Liu, Jill Suttles, Bing Li
Tumor associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically-relevant markers for pro-tumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid binding protein (A-FABP) in TAM promotes breast cancer progression. While upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis...
February 6, 2018: Cancer Research
https://www.readbyqxmd.com/read/29437585/mr-phewas-exploring-the-causal-effect-of-sua-level-on-multiple-disease-outcomes-by-using-genetic-instruments-in-uk-biobank
#13
Xue Li, Xiangrui Meng, Athina Spiliopoulou, Maria Timofeeva, Wei-Qi Wei, Aliya Gifford, Xia Shen, Yazhou He, Tim Varley, Paul McKeigue, Ioanna Tzoulaki, Alan F Wright, Peter Joshi, Joshua C Denny, Harry Campbell, Evropi Theodoratou
OBJECTIVES: We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank. METHODS: We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelian randomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS...
February 6, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29437559/dna-methylation-mapping-identifies-gene-regulatory-effects-in-patients-with-systemic-lupus-erythematosus
#14
Juliana Imgenberg-Kreuz, Jonas Carlsson Almlöf, Dag Leonard, Andrei Alexsson, Gunnel Nordmark, Maija-Leena Eloranta, Solbritt Rantapää-Dahlqvist, Anders A Bengtsson, Andreas Jönsen, Leonid Padyukov, Iva Gunnarsson, Elisabet Svenungsson, Christopher Sjöwall, Lars Rönnblom, Ann-Christine Syvänen, Johanna K Sandling
OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals. METHODS: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome...
February 1, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29437493/identification-of-five-novel-variants-in-chinese-oculocutaneous-albinism-by-targeted-next-generation-sequencing
#15
Biyuan Qiu, Tao Ma, Chunyan Peng, Xiaoqin Zheng, Jiyun Yang
BACKGROUND: The diagnosis of oculocutaneous albinism (OCA) is established using clinical signs and symptoms. OCA is, however, a highly genetically heterogeneous disease with mutations identified in at least nineteen unique genes, many of which produce overlapping phenotypic traits. Thus, differentiating genetic OCA subtypes for diagnoses and genetic counseling is challenging, based on clinical presentation alone, and would benefit from a comprehensive molecular diagnostic. AIM: To develop and validate a more comprehensive, targeted, next-generation-sequencing-based diagnostic for the identification of OCA-causing variants...
February 13, 2018: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29437235/exome-sequencing-reveals-three-homozygous-missense-variants-in-snrpa-in-two-sisters-with-syndromic-intellectual-disability
#16
M M Rangel-Sosa, L E Figuera-Villanueva, I A González-Ramos, Y X Pérez-Páramo, L A Martínez-Jacobo, L Arnaud-López, J A Nastasi-Catanese, A M Rivas-Estilla, K A Galán-Huerta, A Rojas-Martínez, R Ortiz-López, C Córdova-Fletes
Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in two female siblings with three homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing...
February 13, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29437007/blood-eosinophils-as-biomarkers-to-drive-treatment-choices-in-asthma-and-copd
#17
Francesco Patalano, Konstantinos Kostikas, Caterina Brindicci
Both asthma and COPD are complex, heterogeneous conditions comprising a wide range of phenotypes, some of which are refractory to currently available treatments. Elucidation of these phenotypes and identification of biomarkers with which to recognize them and guide appropriate treatment remains a priority. This review describes the utility of blood eosinophils as a surrogate biomarker of eosinophilic airway inflammation, a common feature of specific asthma and COPD phenotypes. The role of blood eosinophils in airway disease is described, as is their relevance in reflecting airway eosinophilia...
February 12, 2018: Current Drug Targets
https://www.readbyqxmd.com/read/29436242/prediction-in-obstructive-sleep-apnoea-diagnosis-comorbidity-risk-and-treatment-outcomes
#18
Kate Sutherland, Fernanda R Almeida, Philip de Chazal, Peter A Cistulli
Obstructive sleep apnoea (OSA) is common disorder, under-diagnosed, and can be difficult to treat adequately across the lifespan. OSA is a heterogeneous disorder with different risk factors, clinical presentations, pathophysiology and morbidity. Prediction has an important role in OSA recognition and management, embodied in screening methods to circumvent the need for diagnosis by overnight sleep studies and prediction of treatment efficacy and adherence. Other opportunities exist in predicting susceptibility to comorbidity and health outcomes...
February 13, 2018: Expert Review of Respiratory Medicine
https://www.readbyqxmd.com/read/29434605/mhc-intratumoral-heterogeneity-may-predict-cancer-progression-and-response-to-immunotherapy
#19
Irene Romero, Cristina Garrido, Ignacio Algarra, Virginia Chamorro, Antonia Collado, Federico Garrido, Angel M Garcia-Lora
An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-γ treatment...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29434354/single-cell-gene-expression-reveals-a-landscape-of-regulatory-t-cell-phenotypes-shaped-by-the-tcr
#20
David Zemmour, Rapolas Zilionis, Evgeny Kiner, Allon M Klein, Diane Mathis, Christophe Benoist
CD4+ T regulatory cells (Treg) are central to immune homeostasis, their phenotypic heterogeneity reflecting the diverse environments and target cells that they regulate. To understand this heterogeneity, we combined single-cell RNA-seq, activation reporter and T cell receptor (TCR) analysis to profile thousands of Treg or conventional CD4+FoxP3- T cells (Tconv) from mouse lymphoid organs and human blood. Treg and Tconv pools showed areas of overlap, as resting 'furtive' Tregs with overall similarity to Tconvs or as a convergence of activated states...
February 12, 2018: Nature Immunology
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