scholarly journals High-resolution mapping of cancer cell networks using co-functional interactions

2018 ◽  
Author(s):  
Evan A. Boyle ◽  
Jonathan K. Pritchard ◽  
William J. Greenleaf
Keyword(s):  
Cancer Cell ◽  
New Technologies ◽  
Protein Complexes ◽  
Cell Types ◽  
Genetic Interactions ◽  
Model Systems ◽  
Detection Approach ◽  
Crispr Screen ◽  
Resolution Mapping ◽  
Cell Networks

AbstractPowerful new technologies for perturbing genetic elements have expanded the study of genetic interactions in model systems ranging from yeast to human cell lines. However, technical artifacts can confound signal across genetic screens and limit the immense potential of parallel screening approaches. To address this problem, we devised a novel PCA-based method for eliminating these artifacts and bolstering sensitivity and specificity for detection of genetic interactions. Applying this strategy to a set of >300 whole genome CRISPR screens, we report ~1 million pairs of correlated “co-functional” genes that provide finer-scale information about cell compartments, biological pathways, and protein complexes than traditional gene sets. Lastly, we employed a gene community detection approach to implicate core genes for cancer growth and compress signal from functionally related genes in the same community into a single score. This work establishes new algorithms for probing cancer cell networks and motivates the acquisition of further CRISPR screen data across diverse genotypes and cell types to further resolve the complexity of cell signaling processes.

scholarly journals Stable transgenesis in Astyanax mexicanus using the Tol2 transposase system

2019 ◽  
Author(s):  
Bethany A. Stahl ◽  
Robert Peuß ◽  
Brittnee McDole ◽  
Alexander Kenzior ◽  
James B. Jaggard ◽  
...  
Keyword(s):  
New Technologies ◽  
Genetic Model ◽  
Model Organism ◽  
Cell Types ◽  
Model Systems ◽  
Transgenic Zebrafish ◽  
Specific Cell ◽  
Astyanax Mexicanus ◽  
Fish Model ◽  
Transgenic Lines

AbstractAstyanax mexicanus is a well-established and widely used fish model system for evolutionary and developmental biology research. These fish exist as surface forms that inhabit rivers and 30 different populations of cavefish. The establishment of A. mexicanus as an emergent model organism for understanding the evolutionary basis of development and behavior has been accelerated by an increasing availability of genomic approaches to identify genotype-phenotype associations. Despite important progress in the deployment of new technologies, deep mechanistic insights into A. mexicanus evolution and development have been limited by a lack of transgenic lines commonly used in genetic model systems. Here, we expand the toolkit of transgenesis by characterizing two novel stable transgenic lines that were generated using the highly efficient Tol2 system, commonly used to generate transgenic zebrafish. A stable transgenic line consisting of the zebrafish ubiquitin promoter fused to eGFP expressed eGFP ubiquitously throughout development in a surface population of Astyanax. To define specific cell-types, we injected fish with a Cntnap2-mCherry construct that labels lateral line mechanosensory neurons in zebrafish. Strikingly, both constructs appear to label the predicted cell types, suggesting many genetic tools and defined promoter regions in zebrafish are directly transferrable to cavefish. The lines provide proof-of-principle for the application of Tol2 transgenic technology in A. mexicanus. Expansion on these initial transgenic lines will provide a platform to address broadly important problems in the quest to bridge the genotype to phenotype gap.

Mass Spectrometry for Proteomics and Recent Developments in ESI, MALDI and other Ionization Methodologies

2019 ◽  
Vol 16 (4) ◽  
pp. 267-276
Author(s):  
Qurat ul Ain Farooq ◽  
Noor ul Haq ◽  
Abdul Aziz ◽  
Sara Aimen ◽  
Muhammad Inam ul Haq
Keyword(s):  
Mass Spectrometry ◽  
Electrospray Ionization ◽  
New Technologies ◽  
Protein Complexes ◽  
Imaging Techniques ◽  
Desorption Electrospray Ionization ◽  
High Throughput Analysis ◽  
Enhanced Sensitivity ◽  
Recent Developments ◽  
The Way

Background: Mass spectrometry is a tool used in analytical chemistry to identify components in a chemical compound and it is of tremendous importance in the field of biology for high throughput analysis of biomolecules, among which protein is of great interest. Objective: Advancement in proteomics based on mass spectrometry has led the way to quantify multiple protein complexes, and proteins interactions with DNA/RNA or other chemical compounds which is a breakthrough in the field of bioinformatics. Methods: Many new technologies have been introduced in electrospray ionization (ESI) and Matrixassisted Laser Desorption/Ionization (MALDI) techniques which have enhanced sensitivity, resolution and many other key features for the characterization of proteins. Results: The advent of ambient mass spectrometry and its different versions like Desorption Electrospray Ionization (DESI), DART and ELDI has brought a huge revolution in proteomics research. Different imaging techniques are also introduced in MS to map proteins and other significant biomolecules. These drastic developments have paved the way to analyze large proteins of >200kDa easily. Conclusion: Here, we discuss the recent advancement in mass spectrometry, which is of great importance and it could lead us to further deep analysis of the molecules from different perspectives and further advancement in these techniques will enable us to find better ways for prediction of molecules and their behavioral properties.

Role of inflammation in the development of colorectal cancer

2020 ◽  
Vol 20 ◽  
Author(s):  
Sridhar Muthusami ◽  
R. Ileng Kumaran ◽  
Kokelavani Nampalli Babu ◽  
Sneha Krishnamoorthy ◽  
Akash Guruswamy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chronic Inflammation ◽  
Interleukin 1 ◽  
Cell Types ◽  
Model Systems ◽  
Cytokine Gene Expression ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Proinflammatory Molecules

: Chronic inflammation can lead to the development of many diseases including cancer. Inflammatory bowel disease (IBD) that includes both ulcerative colitis (UC) and Crohn's disease (CD) are risk factors for the development of colorectal cancer (CRC). Many cytokines produced primarily by the gut immune cells either during or in response to localized inflammation in the colon and rectum are known to stimulate the complex interactions between the different cell types in the gut environment resulting in acute inflammation. Subsequently, chronic inflammation together with genetic and epigenetic changes has been shown to lead to the development and progression of CRC. Various cell types present in the colon such as enterocytes, Paneth cells, goblet cells and macrophages express receptors for inflammatory cytokines and respond to tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6 and other cytokines. Among the several cytokines produced, TNF-α and IL-1β are the key proinflammatory molecules that play critical roles in the development of CRC. The current review is intended to consolidate the published findings to focus on the role of proinflammatory cytokines, namely TNF-α and IL-1β, on inflammation (and the altered immune response) in the gut, to better understand the development of CRC in IBD, using various experimental model systems, preclinical and clinical studies. Moreover, this review also highlights the current therapeutic strategies available (monotherapy and combination therapy), to alleviate the symptoms or treat inflammationassociated CRC by using monoclonal antibodies or aptamers to block proinflammatory molecules, inhibitors of tyrosine kinases in inflammatory signaling cascade, competitive inhibitors of proinflammatory molecules, and the nucleic acid drugs like small activating RNAs (saRNAs) or microRNA (miRNA) mimics to activate tumor suppressor or repress oncogene/proinflammatory cytokine gene expression.

scholarly journals Inhibition of MMP2-PEX by a novel ester of dihydroxy cinnamic and linoleic acid from the seagrass Cymodocea serrulata

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
V. S. Christina ◽  
R. Lakshmi Sundaram ◽  
V. Sivamurugan ◽  
D. Thirumal Kumar ◽  
C. D. Mohanapriya ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Md Simulations ◽  
Cell Types ◽  
Structural Details ◽  
M Phase ◽  
Ft Ir ◽  
Target Binding ◽  
Cymodocea Serrulata

AbstractMatrix metalloproteinases (MMPs) are pivotal for cancer cell migration and metastasis which are generally over-expressed in such cell types. Many drugs targeting MMPs do so by binding to the conserved catalytic domains and thus exhibit poor selectivity due to domain-similarities with other proteases. We report herein the binding of a novel compound [3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl 9Z, 12Z-octadeca-9, 12-dienoate; Mol. wt: 516.67 Da], (C1), isolated from a seagrass, Cymodocea serrulata to the unconserved hemopexin-like (PEX) domain of MMP2 (− 9.258 kcal/mol). MD simulations for 25 ns, suggest stable ligand-target binding. In addition, C1 killed an ovarian cancer cell line, PA1 at IC50: 5.8 μM (lesser than Doxorubicin: 8.6 µM) and formed micronuclei, apoptotic bodies and nucleoplasmic bridges whilst causing DNA laddering, S and G2/M phase dual arrests and MMP disturbance, suggesting intrinsic apoptosis. The molecule increased mRNA transcripts of BAX and BAD and down-regulated cell survival genes, Bcl-xL, Bcl-2, MMP2 and MMP9. The chemical and structural details of C1 were deduced through FT-IR, GC–MS, ESI–MS, 1H and 13C NMR [both 1D and 2D] spectra.

scholarly journals X-ray and UV Radiation Damage of dsDNA/Protein Complexes

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3132
Author(s):  
Paweł Wityk ◽  
Dorota Kostrzewa-Nowak ◽  
Beata Krawczyk ◽  
Michał Michalik ◽  
Robert Nowak
Keyword(s):  
Dna Damage ◽  
Simple Model ◽  
Uv Radiation ◽  
Protein Complexes ◽  
Chemical Processes ◽  
Model Systems ◽  
Degradation Pathways ◽  
X Ray ◽  
Physico Chemical ◽  
Sensitization Process

Radiation and photodynamic therapies are used for cancer treatment by targeting DNA. However, efficiency is limited due to physico-chemical processes and the insensitivity of native nucleobases to damage. Thus, incorporation of radio- and photosensitizers into these therapies should increase both efficacy and the yield of DNA damage. To date, studies of sensitization processes have been performed on simple model systems, e.g., buffered solutions of dsDNA or sensitizers alone. To fully understand the sensitization processes and to be able to develop new efficient sensitizers in the future, well established model systems are necessary. In the cell environment, DNA tightly interacts with proteins and incorporating this interaction is necessary to fully understand the DNA sensitization process. In this work, we used dsDNA/protein complexes labeled with photo- and radiosensitizers and investigated degradation pathways using LC-MS and HPLC after X-ray or UV radiation.

Nanomaterials combine multiple therapeutic approaches for cancer cell multidrug resistance, ferroptotic cell death is promising in various cancers

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cell Death ◽  
Multidrug Resistance ◽  
Cancer Cell ◽  
High Efficiency ◽  
New Technologies ◽  
Multidrug Resistant ◽  
Therapeutic Approaches ◽  
Combination Strategies ◽  
New Strategy ◽  
Chemotherapy Patients

Cancer cell multidrug resistance (MDR) is one of the most significant barriers to chemotherapy patients' ability to treat malignant tumors.This review first discusses the basic processes of MDR and then details the newest usage of nanomaterials combining multiple therapeutic approaches (e.g. PDT, PTT, gas therapy, gene therapy, and CDT) with MDR chemotherapy. We also analyze the advantages and rationales of these combination systems and why they can reduce MDR cancer cells. Currently, together with various new treatment approaches, MDR-related chemotherapeutic research is gaining momentum in search of better therapeutic results. PDT, for example, has the ability to eliminate high-efficiency multidrug-resistant malignancies but has limited relevance to tumor treatment. In this perspective, SDT is a highly promising approach as it increases ROS production utilizing ultrasonic vibrations, allowing magnitude orders to reach deeper than light. PTT is also often criticized for NIR light's restricted penetration depth; thermomagnetic therapy, using magnetic fields to produce local tissue hyperthermia, can considerably alleviate this problem. However, current research on the possibilities of using these new technologies to fight MDR remains rather rare, and more combination strategies should be carefully investigated in the future. Moreover, ongoing discoveries of cell death pathways, highlighted by recent ferroptosis findings, present a new strategy for our battle against MDR and may revolutionize our knowledge of MDR formation. Ferroptotic cell death promises to treat MDR in various cancers. While most of this cutting-edge research is still in its infancy, we anticipate gaining a deeper understanding of the effectiveness of these revolutionary anti-MDR medicines in the near future.

scholarly journals Pairwise genetic interactions modulate lipid plasma levels and cellular uptake

2020 ◽  
Author(s):  
Magdalena Zimon ◽  
Yunfeng Huang ◽  
Anthi Trasta ◽  
Jimmy Z. Liu ◽  
Chia-Yen Chen ◽  
...  
Keyword(s):  
Complex Traits ◽  
Drug Target ◽  
Human Genetics ◽  
Large Population ◽  
Genetic Interactions ◽  
Model Systems ◽  
Lipid Lowering ◽  
Gene Pairs ◽  
Population Sizes ◽  
The Uk

SUMMARYGenetic interactions (GIs), the joint impact of different genes or variants on a phenotype, are foundational to the genetic architecture of complex traits. However, identifying GIs through human genetics is challenging since it necessitates very large population sizes, while findings from model systems not always translate to humans. Here, we combined exome-sequencing and genotyping in the UK Biobank with combinatorial RNA-interference (coRNAi) screening to systematically test for pairwise GIs between 30 lipid GWAS genes. Gene-based protein-truncating variant (PTV) burden analyses from 240,970 exomes revealed additive GIs for APOB with PCSK9 and LPL, respectively. Both, genetics and coRNAi identified additive GIs for 12 additional gene pairs. Overlapping non-additive GIs were detected only for TOMM40 at the APOE locus with SORT1 and NCAN. Our study identifies distinct gene pairs that modulate both, plasma and cellular lipid levels via additive and non-additive effects and nominates drug target pairs for improved lipid-lowering combination therapies.

scholarly journals Mechanical Studies of the Third Dimension in Cancer: From 2D to 3D Model

2021 ◽  
Vol 22 (18) ◽  
pp. 10098
Author(s):  
Francesca Paradiso ◽  
Stefano Serpelloni ◽  
Lewis W. Francis ◽  
Francesca Taraballi
Keyword(s):  
Cell Fate ◽  
Cancer Cell ◽  
Cell Types ◽  
3D Models ◽  
Mechanical Tests ◽  
Research Approach ◽  
3D Scaffold ◽  
Multicellular Spheroids ◽  
Multiple Cell ◽  
Third Dimension

From the development of self-aggregating, scaffold-free multicellular spheroids to the inclusion of scaffold systems, 3D models have progressively increased in complexity to better mimic native tissues. The inclusion of a third dimension in cancer models allows researchers to zoom out from a significant but limited cancer cell research approach to a wider investigation of the tumor microenvironment. This model can include multiple cell types and many elements from the extracellular matrix (ECM), which provides mechanical support for the tissue, mediates cell-microenvironment interactions, and plays a key role in cancer cell invasion. Both biochemical and biophysical signals from the extracellular space strongly influence cell fate, the epigenetic landscape, and gene expression. Specifically, a detailed mechanistic understanding of tumor cell-ECM interactions, especially during cancer invasion, is lacking. In this review, we focus on the latest achievements in the study of ECM biomechanics and mechanosensing in cancer on 3D scaffold-based and scaffold-free models, focusing on each platform’s level of complexity, up-to-date mechanical tests performed, limitations, and potential for further improvements.

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