bluuebunny/crossref_metadata_2025_split huggingface dataset:
C/EBPɑ is crucial determinant of epithelial homeostasis by preventing epithelial‐to‐mesenchymal transition
Authors: Coffer Paul , Lourenco Ana‐Rita , Frederiks Cindy , Seinstra Danielle , Margarido Andreia , Roukens Guy , van Rheenen Jacco 
Published: June 2021

Extracellular signals such as transforming growth factor beta (TGF‐β) have been shown to influence both tumor initiation and metastasis. TGF‐β has been demonstrated to induce epithelial‐to‐mesenchymal transition (EMT) in cancers of epithelial origin by promoting molecular and phenotypical changes resulting in pro‐metastatic characteristics. Using global RNA‐sequencing analysis, we identified CCAAT/enhancer binding protein alpha (C/EBPα) as one of most TGF‐β‐mediated downregulated transcription factors in human mammary epithelial cells. Here, we show that upon TGF‐β pathway activation, SMAD3 binding to the CEBPA locus is enriched while SMAD3‐knockdown cells fail to repress CEBPA expression. Constitutive C/EBPα expression impaired TGF‐β‐driven EMT by inhibiting the expression of known EMT factors including N‐cadherin, MMP‐2 or ZEB1, and by maintaining E‐cadherin expression. Conversely, depletion of C/EBPα expression alone was sufficient to induce mesenchymal‐like morphology and molecular features. Moreover, cells that had undergone TGF‐β‐induced EMT reverted to an epithelial‐like state upon C/EBPα re‐expression. TGF‐β‐mediated disruption of epithelial spheroids architecture could also be rescued by the introduction of C/EBPα. By using an established mouse model of breast cancer EMT‐driven metastasis, we show that mice injected with tumor organoids constitutively expressing C/EBPα display a dramatic reduction of metastatic lesions in their lungs compared to controls. Taken together, these results show that C/EBPα is required for maintaining epithelial homeostasis by repressing the expression of key mesenchymal markers, thus preventing EMT‐mediated tumorigenesis. These data suggest that C/EBPα is an epithelial “gatekeeper” whose expression is required to prevent unwarranted mesenchymal transition, thereby supporting an important role for EMT in mediating breast cancer metastasis.Support or Funding InformationThis work was supported by a grant from the Dutch Cancer Foundation (KWF).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Clinically‐Oriented Verbal Laboratory Assessments in the Gross Anatomy Pre‐Clerkship Medical Curriculum that are Designed to Assess Multiple Competencies
Authors: Martin Charys M. 
Published: June 2021

One of the fundamental principles of a competency‐based medical education curriculum is the integration of the assessment with the curriculum. Assessment needs to be designed to drive learning and similarly learning should drive assessment. Canadian medical schools follow the framework outlined by the Royal College of Physicians and Surgeons of Canada that a competent physician embodies the competencies of all seven CanMeds Roles: Medical Expert, Communicator, Collaborator, Leader, Health Advocate, Scholar, and Professional. All assessments within an integrated competency‐based medical education curriculum should assess more than medical expert. As such, at the Schulich School of Medicine and Dentistry at Western University, we re‐structured traditional bell‐ringer exams into verbal assessments with both individual and group components. Our goal in offering verbal assessments in a group setting was threefold: 1) students would be assessed in three CanMeds Roles: medical expert, collaborator, and communicator; 2) students would be able to receive immediate formative feedback on their knowledge level which in turn would promote mastery of the material; and 3) the verbal assessment would allow us to better assess the application of anatomical knowledge within a clinical context. This talk focusses on the effectiveness and limitations of this new model of assessment. In addition, the process and resources required for the in‐laboratory verbal assessments will be outlined and future directions will be explored.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Integrated Self‐Study Medical Histology Modules: Innovative Approach
Authors: Hussein Inaya Hajj 
Published: June 2021

For the past seven years, at Oakland University William Beaumont School of Medicine (OUWB), increased emphasis is being placed to implement integrated medical curricula, especially those focusing on students' critical thinking and active participation in a clinically relevant approach. Consequently, the teaching of anatomical sciences, in particular Histology, suffered from a reduction in the teaching hours. In this regard, innovative strategies for teaching and assessment were encouraged to assure reaching the acquired competencies.Along this line, a histology module for each organ‐system was developed and interactive strategies were designed to promote student‐centered and active learning, teamwork and peer teaching as well as self and peer assessment. Students displayed considerable initiative in exploring the histological features of tissues, identifying the changes in various pathological states and recognizing the relationship to clinical manifestations. Such a well‐structured approach, with students working in small groups, enhanced active participation, critical thinking, and self‐directed learning in a clinical context. Different types of formative assessments were adopted in order to meet the expectations and challenges associated with acquiring the set of competencies in the integrated curricular. The study modules were designed for students to use modern and interactive technology for self and peer assessment. This peer teaching and peer assessment approach helped students identify areas of weakness and deficiencies, thus allowing for timely interventions to adjust and compensate for lacunes and provided a positive environment and a stimulus for improvement.In this era of periodic revisions of the medical curricula, assessment in a timely manner is getting a considerable importance in orienting such revisions. It is a key feature and a fundamental component to monitor and evaluate, at various levels, the rate of success as well as the direction of amendments to make. In this respect, this renewed approach to self and peer assessment is considered effective in enhancing life‐long learning skills and attitudes. It also can minimize the potential adverse impact of decreasing teaching hours in anatomical sciences, while ensuring that learning remains both meaningful and interesting. However, it takes more efforts from teachers and students.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Origin Recognition Complex: where it all begins
Authors: Joshua‐Tor Leemor , Tocilj Ante , On Kenneth , Yuan Zuanning , Sun Jingchuan , Li Huilin , Stillman Bruce 
Published: June 2021

Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. I will present the structure of the active form of human ORC determined by X‐ray crystallography and cryo‐electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double‐layered shallow corkscrew, with the AAA+ and AAA+‐like domains forming one layer, and the winged‐helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA‐binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier‐Gorlin Syndrome mutations.Support or Funding InformationHoward Hughes Medical InstituteNational Institutes of HealthThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Quantifying Two Dimensional (2D) and Three Dimensional (3D) Anatomical Learning Using a Neuroeducational Approach
Authors: Anderson Sarah J. , Jamniczky Heather , Krigolson Olav , Hecker Kent 
Published: June 2021

BackgroundAdvances in computer visualization enabling both 2D and 3D representation have generated tools to aid perception of spatial relationships and provide a new forum for instructional design. To date, studies examining the effectiveness of these educational tools have been comparative, using performance measurement as proxy variables for learning. A key knowledge gap in the field of health professional education is the lack of understanding of how the brain processes and learns from spatially presented content.ObjectiveTo use a reinforcement‐based learning activity to assess learning with 2D and 3D (stereoscopic) anatomical representations by comparing event‐related brain potentials (ERPs) as measured by electroencephalography (EEG).MethodsMean ERP waveforms of two ERP components, N250 (related to object perception) and reward positivity (related to learners responding to positive feedback), were compared as novice participants (n = 61) learned to identify and localize neuroanatomical structures. Participants learned from 2D, 3D or a combination of 2D and 3D models.ResultsN250 is significantly greater when participants view 3D versus 2D represented anatomical images. Behavioural learning curves and reward positivity did not differ based on model type used during initial learning. However, interleaved learning incorporating 2D and 3D models provided an advantage in retention and transfer activities represented by decreased reward positivity.ConclusionDespite the lack of difference in behavioural‐based learning efficiency outcomes for 2D versus 3D models, neural measures reveal new insights. Greater object recognition was noted for participants learning from 3D models and interleaved training using both 2D and 3D model types provides advantages for memory retention. These new insights should be kept in mind as educators are designing learning activities in the anatomical sciences. Validation of quantitative neurophysiological variables that measure learning will enable a direct measure of knowledge acquisition that can be used to strategically assess and optimize new forms of teaching, learning, and evaluation.Support or Funding InformationThis research was supported by University of Calgary grants (competitive) awarded to the authors including: Teaching and Learning Grant; University Research Grants Committee (URGC) Seed Grant; and the Data and Technology Fund. SA would like to acknowledge scholarship funding provided by: Social Sciences and Humanities Research Council (SSHRC) Doctoral Fellowship; Alberta Innovates Health Solutions (AIHS) Graduate Studentship, and the Queen Elizabeth II Graduate Doctoral Scholarship.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vinculin in Neutrophil Adhesion, Motility and Trafficking
Authors: Wilson Zachary , Harman Michael , Hazlett Lauren , Odzer Jamie , Witt Hadley , Franck Christian , Reichner Jonathan , Lefort Craig 
Published: June 2021

Neutrophils are innate immune effector cells that migrate from the blood to resolve bacterial and fungal infections. Understanding how neutrophils migrate is critical for regulating excessive inflammation and subsequent collateral injury. β2 integrins are essential to classical neutrophil recruitment from the blood, and the activation of β2 integrins has been well defined in previous studies. Adhesion stabilization of neutrophils on the endothelial surface as they crawl into a favorable position for transmigration is not as well defined. Neutrophils do not make mature focal adhesions, but do express the focal adhesion protein vinculin. Vinculin associates with integrins by binding to talin‐1 and stabilizes integrin adhesions by recruiting various actin‐associated proteins or by associating with actin directly. This study characterizes the role of vinculin in neutrophil β2 integrin‐dependent adhesion, motility and anti‐bacterial function. Intrinsic activation of β2 integrins is unaffected by vinculin knockout after CXCL1 activation. Vinculin knockout attenuates neutrophil adhesion, spreading, and motility on glass coated with β2 integrin ligand, ICAM‐1, and activating CXCL1. Vinculin knockout also reduces neutrophil spreading in response to ICAM‐1/CXCL1 on polyacrylamide gels of high stiffness but not lower stiffness. Vinculin knockout reduces traction stresses of neutrophils and the actin stiffening response after stimulation. Unlike static conditions, vinculin knockout does not affect neutrophil motility under flow conditions. Vinculin knockout attenuates respiratory burst, but does not affect phagocytosis. In mixed chimeric mice given intraperitoneal thioglycollate, we find comparable migration of vinculin‐knockout and vinculin‐sufficient neutrophils into the peritoneum. Altogether, while vinculin enhances neutrophil β2 integrin adhesion strength, vinculin knockout does not affect neutrophil motility and trafficking under physiological conditions.Support or Funding InformationAmerican Heart Association (12SDG12080281), Scientist Development Grant CLDepartment of Surgery, Rhode Island HospitalThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
STAT3 signaling mediates FAK inhibitor response and resistance in pancreatic cancer
Authors: Jiang Hong , Knolhoff Brett L. , Krisnawan Varintra , DeNardo David 
Published: June 2021

Pancreatic cancer is not responsive to targeted therapy. This may be due to the presence of a uniquely fibrotic and immunosuppressive tumor microenvironment present in pancreatic ductal adenocarcinoma (PDAC). Critical obstacles to targeted therapy in PDAC tumors include the dense desmoplastic stroma that acts as a physical barrier to drug delivery and the high numbers of tumor‐associated immunosuppressive cells. In our previous study, we identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive tumor microenvironment (TME). FAK inhibition (VS‐4718) significantly limited tumor progression, and prolonged mice survival. Herein, we observed that STAT3 signaling was constantly activated in non‐responsive and recurrent tumors, suggesting STAT3 signaling pathway regulates FAK inhibitor (FAKi) response and resistance. Furthermore, gene enrichment analysis showed that TGF‐b signaling was significantly downregulated upon FAK inhibition, suggesting a negative feed back regulation of STAT3 by TGF‐ b signaling. We proposed that overcoming STAT3 reactivation upon FAK inhibition would enhance pancreatic cancer sensitive to FAK inhibitor. Accordingly, we found that combined STAT3 inhibition (Stattic) with FAK inhibition significantly prolonged the survival in the p48‐Cre/LSL‐KrasG12D/p53Flox/ Flox (KPPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of immunosuppressive myeloid cells and increased tumor cell death. Together, our data indicate that STAT3 inhibition sensitizes PADC to FAKi and overcomes FAKi resistance.Support or Funding InformationThis work was supported by Lustgarten Foundation, an AACR/PANCAN Award, NCI awards R01‐CA177670, R01‐CA203890 and R21‐CA182701This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Non‐enzymatic Functions of Aldolase A Induce Oct4 Activation to Promote Lung Cancer Stemness
Authors: Chang Yu‐Chan , Hsiao Michael 
Published: June 2021

ALDOA is involved in glycolysis process. The enzyme can exert its function to catalyze Fructose 1, 6‐bisphosphate to glyceraldehyde 3‐phosphate and dihydroxyacetone phosphate. In recent year, several reports focusing on exploring the non‐enzymatic role of ALDOA to control proliferation and/or enhance metastasis ability in cancer. However, its roles in cancer stemness remain unclear. Therefore, we established the ALDOA‐based transcriptomics and proteomics database to explore its functional roles in lung cancer. Through Genespring software to normalization, we have selected candidate targets for prediction potential upstream regulator and pathway by Ingenuity Pathway Analysis (IPA) that may be mediated the induction of lung cancer stemness. Our preliminary results showed that stemness‐related transcription factor Oct4 was activated in ALDOA overexpressed cell. Furthermore, we designed several specific mutant forms of ALDOA to block its enzymatic activity or wild‐type ALDOA expression. We observed ALDOA still induced significant in vitro sphere formations and in vivo tumorigenicity. Knockdown of these molecules of Oct4 downstream could significantly decrease stemness ability in lung cancer. In addition, the established ALDOA transcriptomics database in our study identified the candidate drug that significantly suppressed Oct4 activation‐induced axis signaling and suppressed ALDOA induced invasion in vitro and metastasis in vivo. Combined All evidences, our study reveals novel ALDOA functional roles in inducing cancer stemness through activating Oct4 transcriptomic responses. These findings provided a new therapeutic strategy to modulate the Oct4 activation and downstream signalling to combat lung cancers stemness.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of differential phosphorylation of JAM‐A in regulating epithelial barrier function
Authors: Fan Shuling , Weight Caroline , Hilgarth Roland , Nusrat Asma , Parkos Charles 
Published: June 2021

Junctional adhesion molecule‐A (JAM‐A) is an epithelial tight junction protein that has been shown to play an important role in regulating intestinal permeability through association with a scaffold signaling complex containing ZO‐2, Afadin and the small GTPase Rap2. A previous study identified serine phosphorylation of the cytoplasmic tail of JAM‐A (p‐S284) and implicated its role in stabilizing tight junctions in MDCK cells. Here, we report that the cytoplasmic tail of JAM‐A is tyrosine phosphorylated (p‐Y280) under inflammatory conditions associated with loss of barrier. While minimal Y280 phosphorylation was observed in model intestinal epithelial monolayers with assembled intercellular junctions, serine phosphorylation was robust. Conversely, exposure of epithelial cells to cytokines IL‐22 or IL‐17a resulted in time dependent increase in p‐Y280 that paralleled compromised epithelial barrier function assessed by measurement of transepithelial resistance to passive ion flow or paracellular flux of 4kDa dextran. Consistent with these in‐vitro findings, in normal colonic mucosa, there was prominent serine phosphorylation but no tyrosine phosphorylation of JAM‐A. However, the opposite was observed in colonic mucosa of individuals with ulcerative colitis and in mice with experimentally induced colitis (DSS) where serine phosphorylation was lost and tyrosine phosphorylation was robust. Coimmunoprecipitation and knockdown experiments identified a role of Src kinase Yes‐1 in mediating tyrosine phosphorylation of JAM‐A. Consistent with these findings, treatment of epithelial monolayers with the Src kinase inhibitor PP2 was able to partially rescue the barrier defect associated with cytokine exposure and tyrosine phosphorylation of JAM‐A (p‐Y280). Analysis of protein interactions with JAM‐A under conditions of tyrosine phosphorylation revealed loss of tight junction‐associated p‐JAM‐A Y280 and scaffold proteins ZO‐2 and active Rap2 in parallel with compromise in the epithelial barrier function. These results suggest that JAM‐A mediated regulation of intestinal epithelial permeability is dependent on a delicate balance between serine and tyrosine phosphorylation events that are altered during inflammation resulting in a leaky barrier.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Birth Defects of the Craniofacial Skeleton and the Potential for Prevention
Authors: Trainor Paul 
Published: June 2021

Craniofacial anomalies account for approximately one‐third of all birth defects, and common anomalies such as cleft palate, craniosynostosis, and mandibulofacial dysostosis can occur in isolation or as part of one of nearly 700 distinct syndromes. Most of the bone, cartilage and connective tissue of the head and face is derived from a stem cell and progenitor cell population called neural crest cells. Congenital craniofacial anomalies are therefore typically associated with defects in neural crest cell development. Understanding the etiology and pathogenesis of craniofacial birth defects is dependent upon knowledge of the mechanisms that govern neural crest cell formation, migration, survival and differentiation. Recently, we discovered that ribosome biogenesis, the process of making ribosomes which are essential for protein translation in all cells, plays an essential role in neural crest cell proliferation and survival during craniofacial development. Ribosome biogenesis commences with transcription of rDNA by RNA Polymerases I and III, and this event is considered a rate‐limiting step in ribosome biogenesis. Mutations in genes that encode subunits of RNA Polymerase I, or its associated factors, lead to deficiencies in ribosome biogenesis, which results in neural crest cell apoptosis, and consequently congenital craniofacial disorders such as Treacher Collins syndrome, and Acrofacial Dysostosis ‐ Cincinnati type. Inhibition of neural crest cell death is capable of ameliorating and in some cases completely preventing craniofacial malformations in mouse and zebrafish models of these syndromes. Through investigating fundamental mechanisms that regulate neural crest cell biology, our work is facilitating the development of therapeutic approaches to prevent the pathogenesis of congenital craniofacial birth defects.Support or Funding InformationStowers Institute for Medical ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.