scholarly journals Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1909
Author(s):  
Joachim T. Siaw ◽  
Jonatan L. Gabre ◽  
Ezgi Uçkun ◽  
Marc Vigny ◽  
Wancun Zhang ◽  
...  
Keyword(s):  
Genome Engineering ◽  
Neuroblastoma Cells ◽  
Gene Signature ◽  
Additional Insight ◽  
Downstream Target ◽  
Anaplastic Lymphoma ◽  
Extracellular Matrix Components ◽  
Transforming Gene ◽  
Insight Into

Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.

scholarly journals Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

2018 ◽  
Vol 11 (557) ◽  
pp. eaap9752 ◽  
Author(s):  
Kristina B. Emdal ◽  
Anna-Kathrine Pedersen ◽  
Dorte B. Bekker-Jensen ◽  
Alicia Lundby ◽  
Shana Claeys ◽  
...  
Keyword(s):  
Cell Survival ◽  
Kinase Inhibitors ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Adaptor Protein ◽  
Therapy Resistance ◽  
Oncogenic Signaling ◽  
Downstream Target ◽  
Anaplastic Lymphoma ◽  
Signaling Axis

Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry–based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI–sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor protein that links ALK to neuroblastoma cell survival through the Akt-FoxO3 signaling axis.

scholarly journals NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

2019 ◽  
Vol 11 (11) ◽  
pp. 994-1005 ◽  
Author(s):  
Ran Wei ◽  
Xuguang Liu ◽  
Courtney Voss ◽  
Wentao Qin ◽  
Lina Dagnino ◽  
...  
Keyword(s):  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Anaplastic Lymphoma Kinase ◽  
Degradation Pathway ◽  
Anaplastic Lymphoma ◽  
Mechanistic Insight ◽  
Evolutionarily Conserved ◽  
Specific Manner ◽  
Insight Into

Abstract NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation.

scholarly journals The Evaluation of the Role of the Office for Protection of Competition of the Czech Republic in Regulating Public Procurement

2016 ◽  
Vol 9 (1) ◽  
pp. 97-116 ◽  
Author(s):  
Michal Plaček ◽  
František Ochrana ◽  
Martin Schmidt ◽  
Milan Půček
Keyword(s):  
Public Procurement ◽  
Theoretical Background ◽  
Effective Control ◽  
Input Process ◽  
Additional Insight ◽  
The Czech Republic ◽  
Process Output ◽  
And Behavior ◽  
Insight Into

AbstractOur study offers additional insight into the Office for Protection of Competition. It examines the Office for Protection of Competition in terms of an input-process-output model, defines the inputs needed for its activities and examines the outputs of its control activities. It also identifies external factors (in the environment) that affect the performance and behavior of the Office for Protection of Competition and have an impact on inspection activities. The theoretical background as well as assumptions are then subjected to empirical scrutiny. Theoretical conclusions and recommendations for more effective control of public contracts are drawn from the conclusions which are established.

scholarly journals PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum

Development ◽  
1996 ◽  
Vol 122 (3) ◽  
pp. 983-995 ◽  
Author(s):  
M.F. Offield ◽  
T.L. Jetton ◽  
P.A. Labosky ◽  
M. Ray ◽  
R.W. Stein ◽  
...  
Keyword(s):  
Homeobox Gene ◽  
Lacz Reporter ◽  
Additional Insight ◽  
Pancreatic Progenitors ◽  
Proliferation And Differentiation ◽  
Endodermal Differentiation ◽  
Neomycin Resistance ◽  
Beta Galactosidase ◽  
Insight Into

It has been proposed that the Xenopus homeobox gene, XlHbox8, is involved in endodermal differentiation during pancreatic and duodenal development (Wright, C.V.E., Schnegelsberg, P. and De Robertis, E.M. (1988). Development 105, 787–794). To test this hypothesis directly, gene targeting was used to make two different null mutations in the mouse XlHbox8 homolog, pdx-1. In the first, the second pdx-1 exon, including the homeobox, was replaced by a neomycin resistance cassette. In the second, a lacZ reporter was fused in-frame with the N terminus of PDX-1, replacing most of the homeodomain. Neonatal pdx-1 −/− mice are apancreatic, in confirmation of previous reports (Jonsson, J., Carlsson, L., Edlund, T. and Edlund, H. (1994). Nature 371, 606–609). However, the pancreatic buds do form in homozygous mutants, and the dorsal bud undergoes limited proliferation and outgrowth to form a small, irregularly branched, ductular tree. This outgrowth does not contain insulin or amylase-positive cells, but glucagon-expressing cells are found. The rostral duodenum shows a local absence of the normal columnar epithelial lining, villi, and Brunner's glands, which are replaced by a GLUT2-positive cuboidal epithelium resembling the bile duct lining. Just distal of the abnormal epithelium, the numbers of enteroendocrine cells in the villi are greatly reduced. The PDX-1/beta-galactosidase fusion allele is expressed in pancreatic and duodenal cells in the absence of functional PDX-1, with expression continuing into perinatal stages with similar boundaries and expression levels. These results offer additional insight into the role of pdx-1 in the determination and differentiation of the posterior foregut, particularly regarding the proliferation and differentiation of the pancreatic progenitors.

scholarly journals THE EFFECT OF SELF-CONGRUITY AND CELEBRITY ENDORSEMENT ON BRAND LOYALTY WITH BRAND ATTITUDE AS A MEDIATION VARIABLES

2021 ◽  
Vol 19 (1) ◽  
pp. 156-165
Author(s):  
Kardina Yudha Parwati ◽  
◽  
Fatchur Rohman ◽  
Astrid Puspaningrum ◽  
◽  
...  
Keyword(s):  
Brand Loyalty ◽  
Brand Attitude ◽  
Consumer Loyalty ◽  
Celebrity Endorsement ◽  
Additional Insight ◽  
Research Contribution ◽  
The Relationship ◽  
Insight Into

This research is conducted to analyze the effect of cognition and affection factors on consumer loyalty, the object used in this research is the consumer of local fashion product Cotton Ink. The main purpose of this research is to analyze and describe the relationship between self-congruity, celebrity endorsement, brand attitude, and brand loyalty. Besides, this research analyzes the role of brand attitude as the mediating variable of the relationship between self-congruity and celebrity endorsement toward brand loyalty. This research contribution is giving additional insight into the relationship between variables on the Cognition-Affect-Behavior Paradigms.

The Role of Arts and Humanities in undergraduate Medical Curricula

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
E. Sukhanova
Keyword(s):  
Medical Students ◽  
Human Condition ◽  
Human Beings ◽  
Additional Insight ◽  
Arts And Humanities ◽  
The Social ◽  
Interpretive Skills ◽  
Insight Into ◽  
Specific Learning

This paper will explore possible ways of integrating humanities disciplines in medical education.In today's world, medical students have to learn to understand the social and cultural environment in which medicine is practiced. The humanities have long since have been the principal site of diversity in the academy. Now they can help medical students come to terms with diversity that is the context ot today's medicine.Studies in arts and humanities help recognize the limitations of purely biotechnical approach to patient care, in complex and paradigm-changing ways. Such studies also pave the way for understanding how social assumptions and values play out in healthcare policies. In sum, the humanities provide an additional insight into the human condition, allowing students “to consider human beings in their totality,” in the words of Jean Delay, a pioneer of psychopharmacology who also maintained a literary career throughout his life.Furthermore, humanities contribute to the development of complex interpretive skills, embracing affective aspects of intelligence as much as they embrace conventional rationalist forms of inquiry such as logic, analysis, deconstruction and critique. There is some evidence that medical students who have an additional background in the humanities are less vulnerable to burnout while studying and go on to perform better in important areas of practice. Approaches to developing specific learning outcomes and curricular guidelines will be discussed.

scholarly journals Quantitative Phosphoproteomics Reveals System-Wide Phosphorylation Network Altered by Spry in Mouse Mammary Stromal Fibroblasts

2019 ◽  
Vol 20 (21) ◽  
pp. 5400 ◽  
Author(s):  
Tiezhu Shi ◽  
Linli Yao ◽  
Ying Han ◽  
Piliang Hao ◽  
Pengfei Lu
Keyword(s):  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Normal Development ◽  
Underlying Mechanism ◽  
Phosphorylation Sites ◽  
Additional Insight ◽  
Stromal Fibroblasts ◽  
Rtk Signaling ◽  
Insight Into

Understanding the fundamental role of the stroma in normal development and cancer progression has been an emerging focus in recent years. The receptor tyrosine kinase (RTK) signaling pathway has been reported playing critical roles in regulating the normal and cancer microenvironment, but the underlying mechanism is still not very clear. By applying the quantitative phosphoproteomic analysis of Sprouty proteins (SPRYs), generic modulators of RTK signaling and deleted mouse mammary fibroblasts, we quantified a total of 11,215 unique phosphorylation sites. By contrast, 554 phosphorylation sites on 425 proteins had SPRY-responsive perturbations. Of these, 554 phosphosites, 362 sites on 277 proteins, were significantly increased, whereas 192 sites on 167 proteins were decreased. Among the regulated proteins, we identified 31 kinases, 7 phosphatases, and one phosphatase inhibitor that were not systematically characterized before. Furthermore, we reconstructed a phosphorylation network centered on RTK signaling regulated by SPRY. Collectively, this study uncovered a system-wide phosphorylation network regulated by SPRY, providing an additional insight into the complicated RTK signaling pathways involved in the mammary gland microenvironment.

THE ROLE OF SPATIO-TEMPORAL IMAGING CORRELATION (STIC) IN THE PRENATAL DIAGNOSIS OF CONGENITAL HEART DEFECTS

2014 ◽  
Vol 25 (1) ◽  
pp. 59-72
Author(s):  
JIMMY ESPINOZA
Keyword(s):  
Fetal Heart ◽  
Heart Defects ◽  
Beating Heart ◽  
Image Correlation ◽  
Additional Insight ◽  
Spatio Temporal ◽  
And Function ◽  
Anatomical Information ◽  
Insight Into

Spatio-temporal image correlation (STIC) is a feature of four-dimensional ultrasonography (4D US) that allows the acquisition of volume datasets akin to blocks of pathological specimens, where all the anatomical information is contained in the block and the information displayed depends on the level at which the block is cut. STIC has the additional advantages that these planes can be assessed in a virtual beating heart, and that rendering techniques can be used to gain additional insight into the structure and function of the fetal heart.

scholarly journals Wnt/β-Catenin Target Genes in Colon Cancer Metastasis: The Special Case of L1CAM

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3444
Author(s):  
Sanith Cheriyamundath ◽  
Avri Ben-Ze’ev
Keyword(s):  
Cell Adhesion ◽  
Wnt Signaling ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Metastatic Cancer ◽  
Gene Signature ◽  
Downstream Target ◽  
Normal Tissues ◽  
Fundamental Biological Process

Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.

Classification of Infant Vocalizations by Untrained Listeners

2019 ◽  
Vol 62 (9) ◽  
pp. 3265-3275
Author(s):  
Heather L. Ramsdell-Hudock ◽  
Anne S. Warlaumont ◽  
Lindsey E. Foss ◽  
Candice Perry
Keyword(s):  
Formal Education ◽  
Additional Insight ◽  
Listener Responses ◽  
Infant Vocalization ◽  
Early Infant ◽  
Infant Vocalizations ◽  
Audio Recordings ◽  
Speech And Language Development ◽  
Insight Into

Purpose To better enable communication among researchers, clinicians, and caregivers, we aimed to assess how untrained listeners classify early infant vocalization types in comparison to terms currently used by researchers and clinicians. Method Listeners were caregivers with no prior formal education in speech and language development. A 1st group of listeners reported on clinician/researcher-classified vowel, squeal, growl, raspberry, whisper, laugh, and cry vocalizations obtained from archived video/audio recordings of 10 infants from 4 through 12 months of age. A list of commonly used terms was generated based on listener responses and the standard research terminology. A 2nd group of listeners was presented with the same vocalizations and asked to select terms from the list that they thought best described the sounds. Results Classifications of the vocalizations by listeners largely overlapped with published categorical descriptors and yielded additional insight into alternate terms commonly used. The biggest discrepancies were found for the vowel category. Conclusion Prior research has shown that caregivers are accurate in identifying canonical babbling, a major prelinguistic vocalization milestone occurring at about 6–7 months of age. This indicates that caregivers are also well attuned to even earlier emerging vocalization types. This supports the value of continuing basic and clinical research on the vocal types infants produce in the 1st months of life and on their potential diagnostic utility, and may also help improve communication between speech-language pathologists and families.

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