Integrating fMRI and SNP data for biomarker identification for schizophrenia with a sparse representation based variable selection method

BACKGROUND: In recent years, both single-nucleotide polymorphism (SNP) array and functional magnetic resonance imaging (fMRI) have been widely used for the study of schizophrenia (SCZ). In addition, a few studies have been reported integrating both SNPs data and fMRI data for comprehensive analysis. METHODS: In this study, a novel sparse representation based variable selection (SRVS) method has been proposed and tested on a simulation data set to demonstrate its multi-resolution properties. Then the SRVS method was applied to an integrative analysis of two different SCZ data sets, a Single-nucleotide polymorphism (SNP) data set and a functional resonance imaging (fMRI) data set, including 92 cases and 116 controls. Biomarkers for the disease were identified and validated with a multivariate classification approach followed by a leave one out (LOO) cross-validation. Then we compared the results with that of a previously reported sparse representation based feature selection method. RESULTS: Results showed that biomarkers from our proposed SRVS method gave significantly higher classification accuracy in discriminating SCZ patients from healthy controls than that of the previous reported sparse representation method. Furthermore, using biomarkers from both data sets led to better classification accuracy than using single type of biomarkers, which suggests the advantage of integrative analysis of different types of data. CONCLUSIONS: The proposed SRVS algorithm is effective in identifying significant biomarkers for complicated disease as SCZ. Integrating different types of data (e.g. SNP and fMRI data) may identify complementary biomarkers benefitting the diagnosis accuracy of the disease

Program and Proceedings: The Nebraska Academy of Sciences 1880-2010

PROGRAM FRIDAY, APRIL 23, 2010 REGISTRATION FOR ACADEMY, Lobby of Lecture wing, Olin Hall Aeronautics and Space Science, Session A, Olin 249 Aeronautics and Space Science, Session B, Olin 224 Chemistry and Physics, Section A, Chemistry, Olin A Collegiate Academy, Biology Session A, Olin B Collegiate Academy, Chemistry and Physics, Session A, Olin 324 Biological and Medical Sciences, Session A, Olin 112 Biological and Medical Sciences, Session B, Smith Callen Conference Center Chemistry and Physics, Section B, Physics, Planetarium History and Philosophy of Science, Olin 325 Junior Academy, Judges Check-In, Olin 219 Junior Academy, Senior High REGISTRATION, Olin Hall Lobby NWU Health and Sciences Graduate School Fair, Olin and Smith Curtiss Halls Junior Academy, Senior High Competition, Olin 124, Olin 131 Aeronautics and Space Science, Poster Session, Olin 249 Teaching of Science and Math, Olin 325 MAIBEN MEMORIAL LECTURE, OLIN B Dr. Mark Greip, Vice-Chair, Department of Chemistry, University of Nebraska-Lincoln LUNCH, PATIO ROOM, STORY STUDENT CENTER (pay and carry tray through cafeteria line, or pay at NAS registration desk) Aeronautics Group, Conestoga Room Anthropology, Olin 111 Biological and Medical Sciences, Session C, Olin 112 Biological and Medical Sciences, Session D, Smith Callen Conference Center Chemistry and Physics, Section A, Chemistry, Olin A Chemistry and Physics, Section B, Physics, Planetarium Collegiate Academy, Biology Session A, Olin B Collegiate Academy, Biology Session B, Olin 249 Collegiate Academy, Chemistry and Physics, Session A, Olin 324 Junior Academy, Judges Check-In, Olin 219 Junior Academy, Junior High REGISTRATION, Olin Hall Lobby Junior Academy, Senior High Competition, (Final), Olin 110 Earth Science, Olin 224 Junior Academy, Junior High Competition, Olin 124, Olin 131 NJAS Board/Teacher Meeting, Olin 219 Junior Academy, General Awards Presentations, Smith Callen Conference Center BUSINESS MEETING, OLIN B SOCIAL HOUR for Members, Spouses, and Guests First United Methodist Church, 2723 N 50th Street, Lincoln, NE ANNUAL BANQUET and Presentation of Awards and Scholarships First United Methodist Church, 2723 N 50th Street, Lincoln, N

Exploring the Mechanobiology of Pancreatic Cancer using Tumour Microenvironment Models.

PhD Thesis.The dismal prognosis and treatment options for pancreatic ductal adenocarcinoma (PDAC) have seen little advances over the past decades, making PDAC one of the most lethal malignancies to date. Hydrogel-based in vitro modelling of this cancer and its tumour microenvironment (TME) is a promising avenue to bridge the gap between laboratory and clinical data. Current collagen gel-based approaches are limited by varying batch composition, little tuneability and limited mechanical properties, which preclude the accurate recapitulation of key PDAC features, such as matrix stiffness, desmoplasia and drug resistance. In this study, gelatin methacryloyl (GelMA)-based hydrogels were used for the three-dimensional (3D) multicellular culture of PDAC and stromal cells (myeloid cells and patient-derived fibroblasts). The hydrogel’s mechanical properties, architecture and matrix protein expression of embedded cells were characterised and benchmarked against collagen gels and native human tissues. Mechanical testing of fresh human tissues was performed to inform the physical properties of the model. PDAC tissues were significantly stiffer (7.4 ± 0.6 kPa, p<0.0001) than normal adjacent tissues (2.2 ± 0.2 kPa), prompting the modelling of these observed biomechanics with the use of GelMA-based hydrogels. Immunofluorescence, flow cytometry, metabolic activity and DNA quantification analyses confirmed the suitability of GelMA hydrogels for 3D PDAC research by showing high viability of embedded cells, spheroid formation ability, expression of cancer-associated markers and proliferation. The simultaneous 3D co-culture of PDAC and stromal cells led to matrix stiffening, increased cell proliferation and increased in vivo tumorigenicity via a stiffness-dependant upregulation of IL-6, IL-8, STAT3 and downregulation of ERK. Transcriptomic analyses revealed that 3D GelMA cultures had signatures that correlated with those of cells grown in collagen gels, as well as primary tumour organoids cultured in Matrigel, while showing an upregulation in mechano-transduction pathways. Treatment with the mechano-modulating inhibitor fasudil led to increased chemotherapy efficiency via relaxation of matrix stiffness, downregulation of pro-survival and matrix gene signatures, and reduced IL-6 and IL-8 secretion. These findings demonstrated that GelMA-based hydrogels are a modular and informative 3D cell culture platform for the investigation of functional, transcriptional and mechanical aspects of the pancreatic TME. The tuneable physical properties of GelMA allowed me to uncover the increased biomechanical functions and to assess treatment responses of PDAC and stromal cells in matrices of physiologically relevant stiffness, which could not be assessed, to this extent, in commonly-used collagen matrices

Psr1p interacts with SUN/sad1p and EB1/mal3p to establish the bipolar spindle

Regular Abstracts - Sunday Poster Presentations: no. 382During mitosis, interpolar microtubules from two spindle pole bodies (SPBs) interdigitate to create an antiparallel microtubule array for accommodating numerous regulatory proteins. Among these proteins, the kinesin-5 cut7p/Eg5 is the key player responsible for sliding apart antiparallel microtubules and thus helps in establishing the bipolar spindle. At the onset of mitosis, two SPBs are adjacent to one another with most microtubules running nearly parallel toward the nuclear envelope, creating an unfavorable microtubule configuration for the kinesin-5 kinesins. Therefore, how the cell organizes the antiparallel microtubule array in the first place at mitotic onset remains enigmatic. Here, we show that a novel protein psrp1p localizes to the SPB and plays a key role in organizing the antiparallel microtubule array. The absence of psr1+ leads to a transient monopolar spindle and massive chromosome loss. Further functional characterization demonstrates that psr1p is recruited to the SPB through interaction with the conserved SUN protein sad1p and that psr1p physically interacts with the conserved microtubule plus tip protein mal3p/EB1. These results suggest a model that psr1p serves as a linking protein between sad1p/SUN and mal3p/EB1 to allow microtubule plus ends to be coupled to the SPBs for organization of an antiparallel microtubule array. Thus, we conclude that psr1p is involved in organizing the antiparallel microtubule array in the first place at mitosis onset by interaction with SUN/sad1p and EB1/mal3p, thereby establishing the bipolar spindle.postprin

Removal of antagonistic spindle forces can rescue metaphase spindle length and reduce chromosome segregation defects

Regular Abstracts - Tuesday Poster Presentations: no. 1925Metaphase describes a phase of mitosis where chromosomes are attached and oriented on the bipolar spindle for subsequent segregation at anaphase. In diverse cell types, the metaphase spindle is maintained at a relatively constant length. Metaphase spindle length is proposed to be regulated by a balance of pushing and pulling forces generated by distinct sets of spindle microtubules and their interactions with motors and microtubule-associated proteins (MAPs). Spindle length appears important for chromosome segregation fidelity, as cells with shorter or longer than normal metaphase spindles, generated through deletion or inhibition of individual mitotic motors or MAPs, showed chromosome segregation defects. To test the force balance model of spindle length control and its effect on chromosome segregation, we applied fast microfluidic temperature-control with live-cell imaging to monitor the effect of switching off different combinations of antagonistic forces in the fission yeast metaphase spindle. We show that spindle midzone proteins kinesin-5 cut7p and microtubule bundler ase1p contribute to outward pushing forces, and spindle kinetochore proteins kinesin-8 klp5/6p and dam1p contribute to inward pulling forces. Removing these proteins individually led to aberrant metaphase spindle length and chromosome segregation defects. Removing these proteins in antagonistic combination rescued the defective spindle length and, in some combinations, also partially rescued chromosome segregation defects. Our results stress the importance of proper chromosome-to-microtubule attachment over spindle length regulation for proper chromosome segregation.postprin

2023 Medical Student Research Day Abstracts

Medical student research day is designed to highlight the breadth of research and scholarly activity that medical students have accomplished during their education at The GW School of Medicine and Health Sciences. All medical students are invited to present research regardless of the area of focus. Abstract submissions represent a broad range of research interests and disciplines, including basic and translational science, clinical research, health policy and public health research, and education-related research

Central Nervous System Tumors

Though the treatment of central nervous system (CNS) tumors has been challenging, new advances have helped us better understand the molecular and genetic makeup of many tumor types, and new chemotherapies and immunotherapies have extended survival in patients with aggressive primary CNS tumors. This book discusses pediatric and adult tumors of the CNS, the classification schemes used to categorize them, advances in surgical techniques, and several important genetic alterations found in these tumors. We hope this book contributes to the reader’s understanding of these tumors and provides the most up-to-date and cutting-edge discoveries in this exciting field

Decellularised Normal and Tumour Scaffolds for Cancer Organoid Cultures as a Model of Colorectal Peritoneal Metastases

Peritoneal metastasis (PM) is one of the most common routes of dissemination for colorectal cancer and remains a lethal disease. PM development is caused by a cross-talk between invading cancer cells and the rearrangement of the extracellular matrix (ECM). This interplay is governed by biochemical and biomechanical events that allow the development of a specific microenvironment: the so-called metastatic niche. ECM remodeling may be critical for PM spread. In fact, it has been demonstrated that ECMs are not only able to provide structural support to the exfoliated neoplastic cells, but also to trigger specific molecular pathways, paving the path for the seed of cancer cells, directly to their "pre-educated" soil. The mechanisms that determine the interactions within cancer cells and the ECM are still obscure and could be elucidated by an in vitro 3D-culture system that integrates all the elements involved in PM development. Cancer organoids have shown a profound impact in the field of oncology since they better reflect the main characteristics of the native organs compared to the traditional cell culture models. However, they still fail to represent the heterogeneity of the microenvironment. Methodologies have been recently established to remove cells from tissues and obtain matrices in which ECM and tissue architecture are maintained (dECM models), that could be used as the most representative scaffold on which implant 3D cultures. I aimed to obtain a 3D-model that closely recapitulates the microenvironment where the PM develops and includes d-ECM repopulated with PM-derived organoids (3D-dECM model). I removed the cellular component of ECMs derived from peritoneal cavity obtained from both PM samples and r matched normal peritoneum using detergents and enzymatic methods. dECMs analyses demonstrated that the procedure maintained the specific characteristics of their tissue of origin also in terms of distribution, localization, and architectural organization of ECM-related proteins. The obtained dECMs showed a different spatial rearrangement between normal and PM-derived peritoneum, suggesting that dECM scaffolds closely recapitulate the native PM microenvironment. Moreover, when I repopulated dECMs with PM-derived organoids I found that PM- and normal peritoneum-derived dECMs differentially regulated the localization and organization of the seeded organoids, which was the same as in the original tissue. The two 3D-ECM models presented different ability in supporting cell proliferation, where PM-derived 3D-dECMs showed a higher proliferation index and a major ability to maintain the stemness phenotype. PM- and normal peritoneum-derived 3D-dECMs differently modulated cell homeostasis and proliferation ratio. A gene expression analysis of organoids, grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. The impact of the ECM on the response to standard chemotherapy treatment for PM was also observed. This demonstrated the value of ex vivo 3D models obtained by combining patient-derived extracellular matrices depleted of cellular components and organoids to mimic the metastatic niche, which could provide tools to develop new therapeutic strategies in a biologically relevant context, to personalize treatments and increase their efficacy