bluuebunny/crossref_metadata_2025 huggingface dataset:
Is a Dissective Virtual Reality Model an Effective Learning Tool?
Authors: Aggarwal Akanksha , Birk Sapriya Kaur , Hass Katrina , Gill Jaskaran Singh , Mitchell Josh , Fenesi Barb , Wainman Bruce
Published: June 2021

Three‐dimensional (3D) visualization technology such as virtual reality (VR) has the ability to illustrate and replicate physical dissection, and its novelty has captured the interest of many educational institutions. Unfortunately, the testing of 3D technology lags behind development, and most research is confined to case studies. This study's objective is to (1) analyze the short‐term and long‐term efficacy of VR dissection technology compared to an interactive, physical dissective model, and (2) determine if other factors, such as spatial ability, impacts the effectiveness of learning anatomy from VR models. Based on previous research in our lab, static physical models have been shown to be superior to VR models when learning anatomy. Thus, the physical dissection model is hypothesized to perform better in teaching anatomy. The interactive, physical model consists of a 3D‐printed bony pelvis and fabric perineal structures to effectively display the dissections. The physical model was scanned to produce an identical VR replica which is displayed on an HTC Vive. This crossover study will use undergraduate McMaster University students (n=52) with no formal anatomy education. Participants will be asked to learn anatomical structures from both physical and VR models, and be tested on the knowledge from each model in two separate tests. After 48 hours, they will be tested to determine if either model exhibits better long‐term retention. Tests will include nominal, functional, and spatial questions to assess recognition, critical thinking, and spatial awareness. Preliminary data (n=13) suggests that there is no statistically significant difference between either models when learning anatomy during short‐term testing (p=0.24) and long‐term testing (p=0.054). On short‐term retention tests, participants are receiving an average score of 7(3) and 6(2) out of 15 when learning from the VR and physical models, respectively. During long‐term testing, participants are achieving an average score of 7(3) and 5(2) out of 15 when also learning from the VR and physical models, respectively. Data collection is underway and expected to yield complete results by January 2019. Data from additional participants will further elucidate the impact of VR and physical dissection models on student learning. These results could help guide and improve the development of future anatomy education programs.

Support or Funding Information

This project was self‐funded.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exploring pain mechanisms, drug effects and sex dimorphism with proteomics
Authors: Svensson Camilla Ingegerd
Published: June 2021

This presentation will give examples of how examining global peptide and protein expression profiles can aid in advancing our understanding of pain mechanisms and effects of pharmacological intervention. Furthermore, the importance of being aware of and understanding the limitations of different extraction methods for peptidomic and proteomics analysis will be highlighted. High‐mobility group box‐1 protein (HMGB1) has emerged as a danger‐associated molecular pattern molecule protein with important roles in various diseases and injury states. Spinal delivery of disulfide HMGB1, which is an endogenous toll like receptor 4 (TLR4) ligand, leads to an increase of factors associated with microglia reactivity in both male and female mice. Interestingly, intrathecal administration of minocycline, frequently used as a microglia inhibitor, attenuated disulfide HMGB1‐induced mechanical hypersensitivity in male but not in female mice. In order to advance our understanding of how HGMB1 induces pain as well as the basis for the sex‐dependent minocycline effect, we examined the global spinal peptide and protein expression profile using LC‐MS/MS. Using a 2×2 factorial design we found that male and females subjected to disulfide HMGB1 show a differential regulation of spinal protein expression. In addition, upon treatment with minocycline there was a striking difference in expression and a statistically significant interaction between gender and the injection effect of minocycline. Thus, the importance of mapping sex‐associated differences in pain mechanisms will be discussed, as well as opportunities and challenges using global protein expression analysis as a basis for such work.

Support or Funding Information

Swedish Research Council (2013–8373), Knut and Alice Wallenberg Foundation, William K. Bowes Foundation, European Union Seventh Framework Programe (FP7/2007–2013) under grant agreement No. 602919 (GLORIA) and European Union Horizon 2020 research and innovation program under the Marie Sklodowska‐Curie grant agreement No. 642720 (BonePain).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Metformin Activates Neural Stem and Progenitor Cells in the Spinal Cord and Improves Functional Outcomes Following Injury
Authors: Gilbert Emily A.B. , Morshead Cindi M
Published: June 2021

Across mammals, spinal cord injuries (SCI) result in devastating functional deficits with minimal treatment options. Neural stem and progenitor cells (NSPCs) exist within the spinal cord and are located in the periventricular region lining the central canal. Although normally relatively quiescent and non‐neurogenic, these NSPCs are activated in response to injury, however their response is not sufficient to support functional recovery. Enhancing the response of resident NSPCs is an innovative approach to improve structural and functional outcomes following SCI. The FDA‐approved drug metformin (MET) has demonstrated efficacy in promoting neural repair in the injured brain where it expands the size of the NSPC pool and promotes both oligogenesis and neurogenesis from NSPCs. Here, we seek to determine whether MET can influence NSPCs within the spinal cord prior to and following SCI. Using the in vitro colony‐forming assay (neurosphere assay) we examined the size of the neural stem cell (NSC) pool in the spinal cord following 7 days of in vivo MET treatment. Females, but not males, demonstrated a three‐fold increase in the size of the NSC pool in response to MET treatment. Conversely, the differentiation profile of male and female‐derived NSPCs was not sex dependent in the presence of MET. Our results show that MET exposure led to an increase in oligogenesis across both males and females, with no change in neurogenesis. Next, we evaluated whether MET administration would improve functional outcomes following SCI using a dorsal column lesion in the thoracic spinal cord. MET was delivered to animals immediately post‐SCI and treatment resulted in a significantly reduced impairment at 7 days post‐injury (DPI) on a skilled walking task, compared to vehicle‐treated SCI mice. Strikingly, MET‐treated mice recovered to baseline by 14 DPI. Our data reveals that MET has differential effects on spinal cord NSPCs across males and females and that MET administration reduces the severity of SCI and results in improves functional outcomes post‐injury. Taken together, our results support MET as a viable therapeutic strategy for enhancing neural repair and improving recovery following SCI.

Support or Funding Information

American Association of Anatomists

Ontario Institute for Regeneration Medicine

Krembil Foundation

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anatomy Nights—A Public Engagement Format Bringing Experts to the Public
Authors: Sanders Kat , Philp Janet
Published: June 2021

Anatomy Nights is a public engagement event created, organised, and hosted by anatomists that highlight the amazing architecture of our bodies. The public's appetite for anatomy is growing. However, the involvement of experienced and expert anatomists in many popular events is limited and it is time we got involved. In 2018, we held two sold‐out Anatomy Nights across five locations around the UK, reaching an audience of over 400 people. Each event focused on a specific organ: the heart on Valentine's Day, and the brain in the week around Halloween.

Anatomy Nights brings the fundamental practice of dissection into the public sphere and gives audiences a chance to hear from anatomy experts in casual spaces such as bars and pubs. There is a general structure followed at each location. The event starts with a talk on the organ of focus, covering the basics of where is it, what does it look like, and what does it do? This is followed by a dissection of the organ (acquired from a butcher or similar source), and after a short break it all wraps up with a Q&A session.

The aim of the event is to increase the publics' knowledge about their own bodies. As the audience come in, we ask them to complete a pre‐talk questionnaire that establishes the baseline knowledge. The data from these questionnaires give us an insight into the standard level of anatomy that the public knows and the common misconceptions that they hold (e.g. location of the heart often thought to be left and lower than actuality). After the dissection, the questionnaire is repeated. Everything in the questionnaire is covered in the talk, so we can see from the responses what particular anatomical knowledge the audience now know, and what topics people still struggle with.

The organisation of Anatomy Nights is achieved at two levels. A core team arrange dates and themes, promotional material, presentation material, ticketing and supports the local teams. Each location then organises what they need on the ground (venue, the organ for dissection, AV equipment, volunteers to assist, etc.)

Past events have been hosted by both seasoned and novice science communicators. A key benefit of the shared platform is that we are building a public engagement community in anatomy with a common goal: to ensure that the public has greater access to anatomy knowledge from reliable and expert sources; the anatomists themselves. We aim to encourage more anatomists to step out of the lab and host their own Anatomy Nights events around the globe, with the support of a growing Anatomy Nights community that brings the anatomist directly to the public.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Learning Styles and Evidence‐Based Approaches to Education
Authors: Newton Phil
Published: June 2021

The basic idea behind the use of ‘Learning Styles' classifications is to diagnose learners into one or more of a handful of ‘styles' (e.g. Visual, Auditory, Converger) and then teach students according to their supposed style. This idea has been repeatedly tested and does not improve learning, according to current experimental evidence. Continued use of a teaching method that is not evidence‐based is potentially associated with negative effects on learning, particularly where learners are compartmentalized into a small number of ‘styles'. Despite this lack of evidence, survey and literature review research I will present here demonstrates that belief in the use of Learning Styles appears to be widespread amongst teaching staff in Higher Education (58%). This may be in part due to the continued publication of research papers that are based on the premise that matching teaching to Learning Styles is an effective approach. However the percentage of respondents who reported actually using Learning Styles in the last year (33%) was lower. Far more reported using a number of techniques that are demonstrably evidence‐based. As a group, participants agreed with all the posited weaknesses and negative consequences of Learning Styles theory. However, a substantial number of participants (32%) stated that they planned to continue using Learning Styles despite being presented with the lack of an evidence base to support them, suggesting that a ‘debunking’ approach to belief in Learning Styles may not be an effective way to promote evidence‐based approaches education. Qualitative comments revealed a number of potential reasons why belief in Learning Styles persists.

Support or Funding Information

N/A

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
This is your brain on education – how an understanding of the human brain can give us insights into best approaches to teaching and learning
Authors: Krebs Claudia
Published: June 2021

The human brain defines who we are, how we perceive and process the world around us, how we interact with each other and our environment. The human brain has the unique ability for interpretation, imagination, and creativity. The implications of these functions are profound for how we learn and an understanding of how the brain processes and responds to information can lead to new approaches in education.

The cortex plays a huge role in all of our cognitive processes – extensive work has been done to map the cortex and areas that are important for learning. From a more generalist perspective, while the temporal cortex is important for the recognition of people, objects, and patterns, the prefrontal cortex is the site of our reasoning and our imagination. The question for educators is how do we motivate and engage students to learn? How do we capture their attention? Subcortical structures such as the limbic system are important for affective‐motivational processing and memory formation, the basal ganglia integrate the sum of our cortical activity into one cortical – cognitive and behavioral – output. Finally, the cerebellum helps automate processes in our brains. Together, these are some of the neuroanatomical substrates and networks that need to be engaged for an effective approach to education. Learning requires a multi‐faceted approach and each aspect of learning will engage neural networks that will process, interpret, remember and forget the information or situation we are presented with. Mindful pedagogical planning can engage the brain on both a cognitive‐procedural level as well as an affective‐motivational level, which leads to better learning outcomes: we remember what we care about. The human brain is not a static organ and the neuroplasticity that occurs during learning can give us insights into what constitutes a truly transformative learning experience.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
De novo Lipogenesis in Adipocytes Results in the Production of Structurally Novel Signaling Lipids with Beneficial Metabolic and Anti‐inflammatory Effects
Authors: Kahn Barbara B.
Published: June 2021

Increased de novo lipogenesis in adipose tissue is associated with enhanced insulin sensitivity in humans and rodents. Mice overexpressing the Glut4 glucose transporter in adipose tissue have elevated adipose tissue lipogenesis and increased glucose tolerance in spite of obesity and elevated circulating fatty acids. Untargeted lipidomic analysis of adipose tissue from these mice revealed marked elevation of a structurally novel class of lipids, branched Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs). More than 25 FAHFA family members, which are distinguished by different acyl chain composition, have been identified in mammalian tissues and plants. Levels of some family members such as Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are highly regulated in altered nutritional and metabolic states. PAHSA levels are reduced in serum and subcutaneous adipose tissue of insulin‐resistant humans and serum PAHSA levels correlate very strongly with insulin sensitivity in humans. Chronic PAHSA treatment improves glucose tolerance and insulin sensitivity in insulin‐resistant mice. PAHSAs also have anti‐inflammatory effects in states such as obesity, colitis and auto‐immune Type 1 diabetes in mice. Many effects of PAHSA are mediated through G‐protein coupled receptors. Thus, PAHSAs exert multiple beneficial metabolic and anti‐inflammatory effects in diabetes and immune‐mediated diseases. The pathways that regulate these lipids provide new opportunities for disease prevention and treatment.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Modification of mRNA by snoRNA‐guided 2′‐O‐methylation
Authors: Holley Christopher , Elliot Brittany , Ho Hsiang‐Ting
Published: June 2021

Post‐transcriptional modifications of messenger RNA (mRNA) are emerging as an important layer of regulatory control over gene expression. Base modifications, especially N6‐methyladenosine (m6A), influence mRNA splicing, stability, and translation by altering base‐pair interactions and recruiting or inhibiting RNA‐binding proteins. While there is evidence that internal ribose modification by 2′‐O‐methylation (Nm) also occurs on mRNA, questions have been raised regarding its detection, and no biological role has been validated for this modification in cells or tissues. Here we show that internal 2′‐O‐methylation of mRNA serves as a new mechanism of genetic regulatory control, with the ability to influence mRNA abundance and protein levels, both in vitro and in vivo. Using genetic models, we show that this requires: (1) small nucleolar RNAs (snoRNAs), and (2) the snoRNA‐guided 2′‐O‐methylase (fibrillarin, Fbl). Since there are hundreds of box C/D snoRNAs (SNORDs) that can guide Nm modifications, snoRNA‐guided modification of mRNA could be a widespread mechanism of post‐transcriptional gene regulation. Overall, these findings show that SNORDs guide 2′‐O‐methylation of mRNA, and that Nm can provide a significant post‐transcriptional regulatory mechanism to regulate physiologic gene expression in vivo.

Support or Funding Information

The following funding sources supported this work: NIH K08HL114889, R03HL135475, and Duke Heart Center Junior Faculty Development Award to C.L.H., AHA 14POST20380015 and NIH T32HL7101‐42 to B.A.E., and AHA 16POST27540007 to H.H.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Single Cell Genomics: When Stochasticity Meets Precision
Authors: Xie Sunney , Chen Chongyi , Xing Dong , Tan Longzhi , Chapman Alec , Lee David
Published: June 2021

DNA exists as single molecules in individual cells. Genomic variations such as copy‐number variations (CNVs) and single nucleotide variations (SNVs) in a single cell occur in a stochastic way, necessitating single‐cell and single‐molecule measurements to be identified. However, existing single‐cell whole genome amplification (WGA) methods are limited by low accuracy of CNV and SNV detection. We have developed transposase‐based methods for single‐cell WGA, which have superseded previous methods.

With the improved genome coverage of our new WGA method, we have also developed a high‐resolution single‐cell chromatin conformation capture method, which allows for the first 3D genome map of a human diploid cell.

Gene expression is also stochastic due to the fact that the DNA exists as single‐molecules in individual cells. The correlations among different mRNAs in a single‐cell are masked within the stochastic gene expression noise. We have developed a method for single‐cell transcriptome with improved detection efficiency and accuracy, revealing intrinsic correlations among all detected mRNAs in a single‐cell. For a particular human cell type, we uncovered ~120 transcriptionally correlated modules (TCMs) from the gene expression data of ~700 individual cells under a steady state condition. We found that the TCMs are cell type dependent.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Penta‐O‐Galloyl‐β‐D‐Glucose (PGG) Anti‐Proliferative and Pro‐Apoptotic Effect through Up‐Regulation of Tumor Necrosis Factor and its Receptors in Triple Negative Breast Cancer Cells
Authors: Mendonca Patricia , Alghamdy Sumaiah , Messeha Samia S , Soliman Karam F.
Published: June 2021

1,2,3,4,6‐Penta‐O‐Galloyl‐β‐D‐Glucose (PGG) is a naturally occurring polyphenolic compound found in many medicinal plants such as Rhus chinensis Mill and Paeonia suffruticosa. PGG potential in chemoprevention has been reported in many cancer studies including lung, prostate, breast, liver, and sarcoma. In mechanistic studies, PGG modulated apoptosis, angiogenesis, metastasis, and signaling pathways. In the present study, we investigated PGG anti‐proliferative and pro‐apoptotic effects in MDA‐MB‐231 (Caucasian) and MDA‐MB‐468 (African American) triple‐negative breast cancer (TNBC) cells; recognized as the most aggressive type of breast cancer with poor prognosis. The results showed that PGG inhibited cell viability of both cell lines in a dose‐dependent manner. Notably, PGG was 5‐fold more potent in African American cells (IC50 35.7 μM) compared to MDA‐MB‐231(IC50 176.1 μM). PGG anti‐proliferative effect was similar to Taxol in concentrations of 50 and 25 μM in MDA‐MB‐231 and MDA‐MB‐468, respectively, demonstrating more effectiveness in African American cells compared to Caucasians. Results obtained from Annexin V/PI flow cytometry showed that PGG treatment induced 42.3% of apoptosis in Caucasian, and 62% in African American breast cancer cells in the concentration of 100 μM. Subsequently, the expression of several genes associated with apoptosis regulation was detected by RT‐PCR assay to explore underlying apoptosis mechanisms. PGG increased mRNA expression of apoptosis genes in 5‐fold or more in both cell lines, inducing the expression of 12 genes in MDA‐MB‐231, versus 5 genes in MDA‐MB‐468 cells. Remarkably, the highest increase was seen in Tumor Necrosis Factor (TNF) expression which presented a 154.6‐fold increase in African American cells, compared to 14.6‐fold in MDA‐MB‐231. TNF Receptor Superfamily Member 10a (TNFRSF10A) expression was also increased in both cell lines; however, TNF Receptor Superfamily Member 9 (TNFRSF9) expression was induced exclusively in MDA‐MB‐231 cells. TNF‐induced apoptosis is known to be mediated through activation of type I receptors, the death domain of which recruits many different signaling proteins, which together are considered part of an apoptotic cascade. Therefore the results suggest that PGG could be a potential inducer of apoptosis in TNBC cells in Caucasian and African American women, by inducing expression of TNF and its receptors and thus offering a promising approach for cancer therapy.

Support or Funding Information

This research was supported by grants received from NIH NIMHD G12‐MD007582 and P20 MD 0006738

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Interleukin‐1 Alpha and EGFR Expression on Recurrence and Survival Outcomes in Oral Squamous Cell Carcinoma
Authors: Gibson‐Corley Katherine N. , Rajan Anand , Ofori‐Amanfo Georgina , Eyck Patrick Ten , Espinosa‐Cotton Madelyn , Sperry Steven , Simons Andrean L.
Published: June 2021

Interleukin‐1 alpha (IL‐1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas (HNSCCs). Although IL‐1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL‐1α expression in patient outcomes are poorly understood. This study is aimed at investigating the clinical relevance of nuclear and cytoplasmic immunohistochemical IL‐1α expression in oral squamous cell carcinomas (OSCCs). Tissue microarrays (TMAs) containing 146 OSCCs were analyzed for IL‐1α and EGFR expression by immunohistochemistry. Nuclear and cytoplasmic IL‐1α and EGFR expression scores were correlated with clinicopathological parameters and patient outcomes. IL‐1α expression was observed in the nuclear and/or cytoplasm compartments in 98% of evaluable tumors and 78% of tumors expressed IL‐1α in both compartments. Tumors with combined high nuclear and moderate cytoplasmic IL‐1α expression showed a trend toward worse disease‐free and overall survival compared to tumors with other nuclear/cytoplasmic IL‐1α expression profiles. EGFR expression was observed in 62% of tumors. A combined EGFR‐negative and high nuclear IL‐1α expression profile was associated with a low risk of tumor recurrence and favorable overall survival compared to all other EGFR/IL‐1α expression profiles. IL‐1α in combination with EGFR expression may be a strong indicator of risk of recurrence in OSCC and warrants further study as a tissue biomarker for predicting patient outcomes.

Support or Funding Information

This work was supported by the Department of Pathology, and National Institutes of Health (NIH) grants R01DE024550, and CTSA UL1TR002537 administered through the Institute for Clinical and Translational Science (ICTS) at the University of Iowa.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Performance of preoperative plasma tumor markers HE4 and CA125 in predicting ovarian cancer mortality in women with epithelial ovarian cancer
Authors: Furrer Daniela , Grégoire Jean , Turcotte Stéphane , Plante Marie , Bachvarov Dimcho , Trudel Dominique , Têtu Bernard , Douville Pierre , Bairati Isabelle
Published: June 2021

Objective

Clinical utility of new biomarkers often requires the identification of their optimal threshold. This external validation study was conducted to assess the performance of the preoperative plasma tumor markers HE4 and CA125 optimal cut‐offs to predict cancer mortality in women with epithelial ovarian cancer (EOC).

Methods

Participating women had upfront debulking surgery in the University Hospital of Quebec City (Canada) between 1988 and 2013. A total of 136 women participated in the training cohort (cohort 1) and 177 in the validation cohort (cohort 2). Preoperative plasma HE4 and CA125 levels were measured by Elecsys®. Optimal thresholds were identified in the cohort 1 using time‐dependent receiver operating characteristic (ROC) curves. Multivariate Cox models were used to validate the biomarkers using their optimal cut‐offs in the cohort 2. The likelihood ratio (LR) test was done to test the prognostic value of each biomarker.

Results

The Areas Under the Curves (AUC) for HE4 and CA125 were respectively 64.2 (95% CI: 54.7–73.6) and 63.1 (95%CI: 53.6–72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA125. Only HE4 (≥277 pmol/L) was significantly associated with EOC mortality (adjusted hazard ratio: 1.80; 95% CI: 1.03–3.15). In addition, HE4 added prediction for death over the standard prognostic markers (p‐value for LR‐test: 0.03).

Conclusions

Preoperative HE4 is a promising prognostic biomarker and performs better in predicting EOC mortality than CA125. This prognostic information provided by this optimal HE4 cut‐off, before surgery, could be useful for clinicians to better plan treatment strategies.

Support or Funding Information

This study was partly funded by the “Banque de tissus et de données du Réseau de recherche sur le cancer, Fonds de Recherche du Québec‐Santé », which is affiliated with the Canadian Tumor Repository Network. We thank Roche Diagnostics (Laval, Canada) for providing the HE4 and CA125 kits and the funds for the dosages and the statistical analyses.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Grey Parrot Anatomy Project—A study for science
Authors: Echols Scott Scott
Published: June 2021

The Grey Parrot Anatomy Project is a collaborative effort to define the anatomy of one bird (Psittacus erithacus erithacus), utilize and develop new imaging technology that can potentially be used on any species including humans, collaborate with multiple scientific disciplines and share the data. This presentation will highlight the Project, demonstrate some of the new technology developed and show how the information is being utilized to better understand anatomy and diagnose and treat disease in multiple species. The Project has been funded by private donations and has been centered at the University of Utah. Many collaborators at other institutions and clinical practices have contributed to and/or benefited from the Project. In addition to being informative, this presentation is an invitation to collaborate.

Support or Funding Information

Private donations

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Personalized 3D Craniofacial Morphometrics
Authors: Cevidanes Lucia H , Bianchi Jonas , de Oliveira Ruellas Antonio Carlos , Yatabe Ioshida Marilia S , Paniagua Beatriz , Goncalves Joao R , Prieto Juan Carlos
Published: June 2021

This presentation will review current state of the art in 3D image analysis including 3D superimpositions relative to the cranial base and different regional superimpositions, the development of open source and commercial tools for 3D analysis, how this technology has increased clinical research collaborations from centers all around the globe, some insight on how to incorporate artificial intelligence for big data analysis and progress towards personalized facial morphometry assessments. Clinical applications of 3D image registration and superimposition have contributed to better understanding growth changes and clinical outcomes. The use of 3D dental and craniofacial imaging in dentistry requires validated image analysis methods for improved diagnosis, treatment planning, navigation and assessment of treatment response. Advanced 3D facial morphometry utilizes shape correspondence to train a neural network for shape variation analyses.

Support or Funding Information

NIDCR R01 DE024450 and R21 DE025306

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Doxorubicin in myocardial lysophosphatidic acid signaling
Authors: Miriyala Sumitra , Sharma Sudha , Bhattarai Susmita , Leon Anthony , Panchatcharam Manikandan
Published: June 2021

Generation of reactive oxygen species has been implicated in the toxicity of nearly 50% of the current FDA approved cancer therapeutic drugs. Mitochondrial respiration is a major source of reactive oxygen species production and that the presence of the mitochondrial antioxidant enzyme, manganese superoxide dismutase, is essential for the survival of all aerobic life. Our studies of animals using the prototype redox‐active anticancer drug, doxorubicin, indicate that overexpression of manganese superoxide dismutase protects the heart against doxorubicin‐induced cardiac injury and reduction of manganese superoxide dismutase by heterozygous knockout mice increases cardiac injury after exposure to doxorubicin. While the bioactive glycerophospholipid lysophosphatidic acid rises by seven‐fold over control subjects, suggesting lysophosphatidic acid may contribute to the doxorubicin‐induced cardiac toxicity. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase‐3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that doxorubicin‐induced cardiac injury enhances myocardial autotaxin levels and decreases myocardial LPP3 expression, and this is associated with increased serum lysophosphatidic acid levels. Reactive oxygen species production arises as a burst of superoxide from mitochondria following doxorubicin‐induced cardiac injury. The redox‐sensitive transcription factor NFAT (a nuclear factor of activated T‐cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of cardiac injury through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that doxorubicin‐induced cardiac injury alters autotaxin and LPP3 expression through mitochondrial superoxide production to drive lysophosphatidic acid signaling and cardiomyocyte dysfunction. The following interrelated specific aims are designed to provide step‐wise and in‐depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of myocardial superoxide production in autotaxin expression and lysophosphatidic acid production in doxorubicin‐induced cardiac injury. Specific aim 2 will determine the role of mitochondrial superoxide production in LPP3 depletion and lysophosphatidic acid regulation in doxorubicin‐induced cardiac injury. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect in doxorubicin‐induced cardiac injury models.

Support or Funding Information

AAA‐ FGAP Fellow grant funded by the American Association of Anatomists.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeting Epithelial Expressed Sialyl Lewis A Improves Intestinal Mucosal Wound Healing and Protects Against Colitis
Authors: Kelm Matthias , Quiros Miguel , Cummings Richard D. , Nusrat Asma , Parkos Charles A. , Brazil Jennifer C.
Published: June 2021

Dysregulated healing of mucosal wounds is a hallmark of many pathological conditions including inflammatory bowel disease (IBD). Mucosal wound healing involves a complex interplay between epithelial cells and infiltrating immune cells that trigger cell signaling events and epithelial cell migration, proliferation and differentiation that are necessary for mucosal homeostasis. Specific alterations in surface glycosylation have been reported in intestinal epithelial cells following injury, and we have shown that targeting the inflammation induced epithelial glycan sialyl Lewis A (sLea) with a specific mAb termed GM35 results in inhibition of neutrophil (PMN) trafficking in the inflamed intestine. Despite this observation, the role of glycans in intestinal wound healing has not been examined. Here we report that, in addition to inhibiting PMN transepithelial migration, targeting epithelial expressed sLea increases intestinal epithelial wound healing and recovery from barrier disruption in vitro. We report that these protective effects are mediated through deactivation of Akt (a kinase previously shown to destabilize epithelial adherens junctions) downstream of sLea engagement. Furthermore, wound bed injection of GM35 directly into biopsy‐induced colonic wounds resulted in a significant increase in mucosal wound healing in vivo. Finally, administration of GM35 to C57BL/6J mice followed by induction of colitis with dextran sodium sulfate resulted in reduced disease activity as assessed clinically and histologically, compared to mice treated with an isotype control mAb. Given our observations of robust upregulation of epithelial sLea during intestinal inflammation in mice and humans, these data suggest that targeting sLea may represent a promising new target for regulating intestinal trafficking of PMNs. In addition, targeting of this glycan may also provide an additional therapeutic strategy for improved recovery of epithelial barrier function and restitution of intestinal homeostasis following inflammation or injury.

Support or Funding Information

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 410855404), a senior Research Award from the Crohn's and Colitis Foundation (CCF) and R01 awards from the NIH (DK072564 and DK079392).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endogenous DNA damage as a driver of senescence and aging
Authors: Niedernhofer Laura J
Published: June 2021

Aging is defined as a loss of tissue homeostasis and resilience in the face of stress and is attributed to stochastic damage that occurs over time. However, in measuring the various types of cellular damage it is impossible to determine what damage caused aging and what is a consequence of it. Genetic depletion of the DNA repair enzyme in mice or cells leads to the accelerated accumulation of spontaneous endogenous DNA damage, which cannot be repaired. With this as an initiating event, we found that deletion of ERCC1‐XPF in primary fibroblasts causes a rapid acceleration of senescence. In vivo, depletion of ERCC1‐XPF also causes accelerated accumulation of senescent cells in numerous tissues including lung, heart, pancreas, liver, spleen, skin and brain. There is accelerated onset of age‐related pathology and spontaneous onset of multiple age‐related diseases including cerebral atrophy, chronic kidney disease, loss of vision and hearing, osteoporosis and disc degeneration. We also discovered increased production of reactive oxygen species and evidence of oxidative damage to multiple types of macromolecules in cells. Furthermore, in ERCC1‐XPF deficient mice we see loss of stem cell function, mitochondrial dysfunction, epigenetic changes, alterations in autophagy and stress responses. In all cases, changes seen in ERCC1‐XPF‐deficient mice were recapitulated in aged wild‐type mice. Finally, tissue‐specific deletion of ERCC1‐XPF is enough to cause rapid onset of age‐related disease such as cardiomyopathy, diabetes and dementia. These data establish endogenous DNA damage as a driver of aging. Furthermore, the response to DNA damage impacts all pillars of aging.

Support or Funding Information

NIA P01 AG043376, NIA U19 AG056278, The Glenn Foundation

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acetyl‐CoA metabolism and the response to dietary sugar
Authors: Wellen Kathryn
Published: June 2021

Acetyl‐CoA is a central metabolite at the interface of metabolism, signaling, and epigenetics due to its functions in energetics, lipid metabolism, and as the acetyl group donor for lysine acetylation. Generation of the nuclear‐cytoplasmic pools of acetyl‐CoA that are needed for lipid synthesis and histone acetylation occurs largely from the export of citrate from mitochondria and cleavage by ATP‐citrate lyase (ACLY). Sugar consumption has increased dramatically in the United States and around the world in recent decades. ACLY levels increase in response to carbohydrate consumption in adipose tissue and in liver, and we hypothesized that ACLY in these tissues might be important for both the metabolic and transcriptional responses to carbohydrate consumption. In this presentation, I will discuss new findings using genetic models in which Acly is deleted from adipocytes or from the liver. Our data point to unexpected and distinct roles for ACLY in gene regulation and in lipid metabolism in response to dietary sugar.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Capsaicin and natural capsaicin‐like compounds suppress metastasis in lung adenocarcinoma
Authors: Friedman Jamie R , Richbart Stephen D , Merritt Justin C , Brown Kathleen C , Denning Krista L , Brown Linda G , Egleton Richard D , Dasgupta Piyali
Published: June 2021

Lung adenocarcinoma (LAC) accounts for the majority of all non‐small cell lung cancer (NSCLC) cases. A substantial proportion of LAC patients present with local and distant metastasis at the time of their diagnosis. One of the earliest events of the metastatic process is the invasion of malignant cells through the surrounding extracellular basement membrane into the blood and lymph. The long‐term goal of our laboratory is to identify nutrition‐based agents which will suppress the growth and progression of human LACs. Capsaicin is the pungent ingredient of chili peppers. Published reports have revealed that capsaicin inhibits the invasion and metastasis of several types of human cancers including melanoma, prostate cancer, and cholangiosarcoma. However, the clinical application of capsaicin as an anti‐cancer drug is limited by its unpleasant side‐effect profile. This led us to compare the anti‐metastatic activity of capsaicin with natural non‐pungent capsaicin‐like compounds, namely capsiate and capsiconiate. The structure and bioactivity of capsaicin closely resembles capsiate. There are no published reports involving the biological activity of capsiconiate. We measured the anti‐invasive activity of these compounds by two independent invasion assays, namely the Boyden chamber assay and spherical invasion assay. We found that capsaicin and capsiate displayed anti‐invasive activity in three human LAC cell lines. In contrast, capsiconiate did not suppress the invasion of any LAC cell lines. Furthermore, we tested the anti‐metastatic activity of capsaicin in a syngeneic mouse model of metastasis. We observed that the daily dietary administration of capsaicin in AIN‐76A diet (with 5% lipid level) robustly decreased the area metastatic foci (in the lung) relative to vehicle‐treated mice. We investigated the signaling pathway underlying the anti‐metastatic activity of capsaicin. Our results show that capsaicin directly interacts with Src and inhibits Src activation to suppress the metastasis of LAC. The results of our studies may foster the development of novel anti‐metastatic therapies for human LAC.

Support or Funding Information

Funding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02) and a NASA Undergraduate Fellowship to NAN.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Endothelial RhoA in Melanoma and Lung Cancer Trans‐endothelial Migration and Metastasis
Authors: Sajib Md Sanaullah , Zahra Fatema Tuz , Park Jee Hyun , Tullar Paul , Srivastava Sanjay K. , Bickel Ulrich , Mikelis Constantinos M
Published: June 2021

Vascular permeability, regulated by the balanced control of endothelial monolayer integrity, is altered in cancer. We have previously shown that activation of RhoA, a small GTPase, modulates actin cytoskeleton dynamics in endothelial cells, thus regulating the barrier function of the blood vessels. The barrier function is a limiting factor during metastasis, as the cancer cells need to cross the endothelial monolayer twice, during intravasation and extravasation. In this study, we explored the role of endothelial RhoA during the transmigration and metastatic dissemination of melanoma and lung carcinoma cells. We used a highly reproducible and quantifiable transwell‐based model to study trans‐endothelial migration in vitro, where fluorescently‐labelled cancer cells transmigrate through an endothelial monolayer. RhoA and its downstream signaling molecule Rho‐associated protein kinase (ROCK) were blocked by both pharmacological and knockdown approaches. Syngeneic murine melanoma (B16‐F10) and lung carcinoma (LLC‐LL3) cell lines were selected and tested in trans‐endothelial cell migration in vitro and experimental metastasis in vivo. Experimental metastasis experiments were performed through intravenous and intra‐cardiac administration in endothelial‐specific RhoA deficient mice or in the presence of clinically‐relevant ROCK inhibitors. Conditioned medium from both melanoma and cancer cells significantly increased in RhoA activation in primary endothelial cells. In vitro, blockade of endothelial RhoA‐ROCK pathway by either C3 toxin or the ROCK inhibitors decreased the trans‐endothelial migration of both cancer types and knock‐down of RhoA by siRNA in endothelial cells had similar effect. In vivo, decreased number of lung metastases was observed in mice deficient of endothelial RhoA in both intravenous and intra‐cardiac models, when compared to their littermate controls. Furthermore, treatment with a ROCK inhibitor, Fasudil, decreased the metastatic burden in the lungs without any visible toxicity. Taken together, these findings highlight the importance of endothelial RhoA as a target for melanoma and lung cancer metastasis.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mast Cell‐Derived Histamine Promotes Large Cholangiocyte Damage via H2 Histamine Receptor Signaling
Authors: Kennedy Lindsey , Hargrove Laura , Demieville Jennifer , Meadows Vik , Reinhart Evan , Virani Shohaib , Alpini Gianfranco , Glaser Shannon , Francis Heather
Published: June 2021

The biliary tree contains both small and large ducts, that are surrounded by small and large cholangiocytes, respectively. Large cholangiocytes are more susceptible to damage, and proliferate following bile duct ligation (BDL). Further, we have shown that large cholangiocytes undergo senescence following cholestatic injury. Mast cells (MCs) infiltrate the liver following BDL, reside near large ducts, and secrete histamine that promotes biliary proliferation via cAMP/ERK signaling. Histamine signals through four histamine receptors (HRs), and H2HR is expressed by large cholangiocytes. The aim of our study was to identify the mechanism by which MC‐derived histamine promotes large cholangiocyte damage.

12 wk old male wild‐type (WT) and KitW‐sh (MC‐deficient) mice were subjected to sham or BDL for 1 wk and selected WT and KitW‐sh mice received one tail vein injection of cultured MCs 3 days prior to sacrifice. Large ductal mass was measured by CK‐19 staining and semi‐quantification, and qPCR for PCNA is isolated large cholangiocytes. Large cholangiocyte senescence was shown by immunofluorescence (IF) for p16 and p21 (co‐stained with CK‐19) in liver sections, and qPCR in isolated large cholangiocytes. In large ducts, we evaluated H2HR expression and cAMP and pERK, expression by IF. In vitro, MCs were treated with control or the l‐histidine decarboxylase (HDC) inhibitor (3 mM, a‐methyl‐dl‐histidine (a‐Me)) for 48 hrs. Supernatants from treated MCs were placed on cultured large cholangiocytes and evaluated for: (i) proliferation; (ii) senescence; (iii) H2HR expression; (iv) cAMP expression and activity; and (v) pERK expression .

BDL WT mice had increased large (but not small) ductal mass, which was reversed in BDL KitW‐sh mice. MC injection into WT and KitW‐sh mice increased large duct mass. Similarly, large cholangiocyte senescence increased following MC injections and in BDL WT mice, but was reduced in BDL KitW‐sh mice. MC injection and BDL WT mice had enhanced large cholangiocyte H2HR/cAMP/pERK expression; however, this was decreased in BDL KitW‐sh mice. In vitro, large cholangiocytes treated with MC supernatants had increased (i) proliferation, (ii) senescence, and (iii) H2HR/cAMP/pERK signaling. However, these parameters were reduced in large cholangiocytes treated with supernatants from MCs treated with a‐Me.

During cholestatic liver injury, MCs primarily induce large cholangiocyte damage and MC‐derived histamine promotes large cholangiocyte proliferation and senescence via H2HR/cAMP/pERK signaling. Inhibition of MC‐derived histamine or large cholangiocyte H2HR signaling may be therapeutic for patients with large ductal damage.

Support or Funding Information

VA Merit and NIH NIDDK R01

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.