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https://www.readbyqxmd.com/read/29341164/patient-derived-organoid-models-help-define-personalized-management-of-gastrointestinal-cancer
#1
REVIEW
M R Aberle, R A Burkhart, H Tiriac, S W M Olde Damink, C H C Dejong, D A Tuveson, R M van Dam
BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models...
January 2018: British Journal of Surgery
https://www.readbyqxmd.com/read/29339448/development-of-intestinal-m-cells-and-follicle-associated-epithelium-is-regulated-by-traf6-mediated-nf-%C3%AE%C2%BAb-signaling
#2
Takashi Kanaya, Sayuri Sakakibara, Toshi Jinnohara, Masami Hachisuka, Naoko Tachibana, Shinya Hidano, Takashi Kobayashi, Shunsuke Kimura, Toshihiko Iwanaga, Tomoo Nakagawa, Tatsuro Katsuno, Naoya Kato, Taishin Akiyama, Toshiro Sato, Ifor R Williams, Hiroshi Ohno
M cells are located in the follicle-associated epithelium (FAE) that covers Peyer's patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell-associated molecules but is not sufficient to complete M cell differentiation...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29337182/human-pancreatic-tumor-organoids-reveal-loss-of-stem-cell-niche-factor-dependence-during-disease-progression
#3
Takashi Seino, Shintaro Kawasaki, Mariko Shimokawa, Hiroki Tamagawa, Kohta Toshimitsu, Masayuki Fujii, Yuki Ohta, Mami Matano, Kosaku Nanki, Kenta Kawasaki, Sirirat Takahashi, Shinya Sugimoto, Eisuke Iwasaki, Junichi Takagi, Takao Itoi, Minoru Kitago, Yuko Kitagawa, Takanori Kanai, Toshiro Sato
Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin...
January 10, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29334242/development-and-disease-in-a-dish-the-epigenetics-of-neurodevelopmental-disorders
#4
Emily Ma Lewis, Kristen L Kroll
Human neurodevelopmental disorders (NDDs) involve mutations in hundreds of individual genes, with over-representation in genes encoding proteins that alter chromatin structure to modulate gene expression. Here, we highlight efforts to model these NDDs through in vitro differentiation of patient-specific induced pluripotent stem cells into neurons. We discuss how epigenetic regulation controls normal cortical development, how mutations in several classes of epigenetic regulators contribute to NDDs, and approaches for modeling cortical development and function using both directed differentiation and formation of cerebral organoids...
January 15, 2018: Epigenomics
https://www.readbyqxmd.com/read/29330203/personalized-rna-medicine-for-pancreatic-cancer
#5
Maud-Emmanuelle Gilles, Liangliang Hao, Ling Huang, Rajesha Rupaimoole, Pedro P Lopez-Casas, Emilia Pulver, Jong Cheol Jeong, Senthil K Muthuswamy, Manuel Hidalgo, Sangeeta N Bhatia, Frank J Slack
PURPOSE: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.  Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29329541/a-role-for-endothelial-nitric-oxide-synthase-in-intestinal-stem-cell-proliferation-and-mesenchymal-colorectal-cancer
#6
Jon Peñarando, Laura M López-Sánchez, Rafael Mena, Silvia Guil-Luna, Francisco Conde, Vanessa Hernández, Marta Toledano, Victoria Gudiño, Michela Raponi, Caroline Billard, Carlos Villar, César Díaz, José Gómez-Barbadillo, Juan De la Haba-Rodríguez, Kevin Myant, Enrique Aranda, Antonio Rodríguez-Ariza
BACKGROUND: Nitric oxide (NO) has been highlighted as an important agent in cancer-related events. Although the inducible nitric oxide synthase (iNOS) isoform has received most attention, recent studies in the literature indicate that the endothelial isoenzyme (eNOS) can also modulate different tumor processes including resistance, angiogenesis, invasion, and metastasis. However, the role of eNOS in cancer stem cell (CSC) biology and mesenchymal tumors is unknown. RESULTS: Here, we show that eNOS was significantly upregulated in VilCre ERT2 Apc fl/+ and VilCre ERT2 Apc fl/fl mouse intestinal tissue, with intense immunostaining in hyperproliferative crypts...
January 10, 2018: BMC Biology
https://www.readbyqxmd.com/read/29328793/novel-molecular-and-phenotypic-insights-into-congenital-lung-malformations
#7
Daniel T Swarr, William H Peranteau, Jennifer Pogoriler, David B Frank, N Scott Adzick, Holly L Hedrick, Mike Morley, Su Zhou, Edward E Morrisey
RATIONALE: Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects as they are often surgically resected. OBJECTIVES: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS: Clinical data, and lung tissue for DNA, RNA, and histology were obtained from 58 infants undergoing surgical resection of a congenital lung lesion...
January 12, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29327488/isolation-of-human-photoreceptor-precursors-via-a-cell-surface-marker-panel-from-stem-cell-derived-retinal-organoids-and-fetal-retinae
#8
Jörn Lakowski, Emily Welby, Dimitri Budinger, Fabiana Di Marco, Valentina Di Foggia, James W B Bainbridge, Kyle Wallace, David M Gamm, Robin R Ali, Jane C Sowden
Loss of photoreceptor cells due to retinal degeneration is one of the main causes of blindness in the developed world. Although there is currently no effective treatment, cell replacement therapy using stem-cell-derived photoreceptor cells may be a feasible future treatment option. In order to ensure safety and efficacy of this approach, robust cell isolation and purification protocols must be developed. To this end, we previously developed a biomarker panel for the isolation of mouse photoreceptor precursors from the developing mouse retina and mouse embryonic stem cell cultures...
January 12, 2018: Stem Cells
https://www.readbyqxmd.com/read/29325707/successful-creation-of-pancreatic-cancer-organoids-by-means-of-eus-guided-fine-needle-biopsy-for-personalized-cancer-treatment
#9
Herve Tiriac, Juan Carlos Bucobo, Demetrios Tzimas, Suman Grewel, Joseph F Lacomb, Leahana M Rowehl, Satish Nagula, Maoxin Wu, Joseph Kim, Aaron Sasson, Shivakumar Vignesh, Laura Martello, Maria Munoz-Sagastibelza, Jonathan Somma, David A Tuveson, Ellen Li, Jonathan M Buscaglia
BACKGROUND AND AIMS: Pancreatic cancer organoids are tumor models of individualized human pancreatic ductal adenocarcinoma (PDA), created from surgical specimens and used for personalized treatment strategies. Unfortunately the vast majority of patients with PDA are not operative candidates. Creation of human PDA organoids at the time of initial tumor diagnosis is therefore critical. Our aim was to assess the feasibility of creating human PDA organoids by EUS fine-needle biopsy (EUS-FNB) in patients with PDA...
January 8, 2018: Gastrointestinal Endoscopy
https://www.readbyqxmd.com/read/29323154/effects-of-metformin-on-colorectal-cancer-stem-cells-depend-on-alterations-in-glutamine-metabolism
#10
Jae Hyun Kim, Kyoung Jin Lee, Yoojeong Seo, Ji-Hee Kwon, Jae Pil Yoon, Jo Yeon Kang, Hyun Jung Lee, Soo Jung Park, Sung Pil Hong, Jae Hee Cheon, Won Ho Kim, Tae Ii Kim
Metformin has been known to suppress cancer stem cells (CSCs) in some cancers. However, the differential effects of metformin on CSCs and their mechanisms have not been reported. Herein, metformin induced pAMPK activation and pS6 suppression in metformin-sensitive (HT29) cells, but not in metformin-resistant (SW620) cells. The oxygen consumption rate was higher in HT29 cells than in SW620 cells and showed a prominent decrease after metformin treatment in HT29 cells. In glutamine-depleted medium, but not in low-glucose medium, SW620 cells became sensitive to the CSC-suppressing effect of metformin...
January 11, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29322407/modelling-intestinal-carcinogenesis-using-in-vitro-organoid-cultures
#11
Thierry Jardé, Genevieve Kerr, Reyhan Akhtar, Helen E Abud
Mouse models of intestinal carcinogenesis are very powerful for studying the impact of specific mutations on tumour initiation and progression. Mutations can be studied both singularly and in combination using conditional alleles that can be induced in a temporal manner. The steps in intestinal carcinogenesis are complex and can be challenging to image in live animals at a cellular level. The ability to culture intestinal epithelial tissue in three-dimensional organoids in vitro provides an accessible system that can be genetically manipulated and easily visualised to assess specific biological impacts in living tissue...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29322086/engineered-livers-for-infectious-diseases
#12
REVIEW
Nil Gural, Liliana Mancio-Silva, Jiang He, Sangeeta N Bhatia
Engineered liver systems come in a variety of platform models, from 2-dimensional cocultures of primary human hepatocytes and stem cell-derived progeny, to 3-dimensional organoids and humanized mice. Because of the species-specificity of many human hepatropic pathogens, these engineered systems have been essential tools for biologic discovery and therapeutic agent development in the context of liver-dependent infectious diseases. Although improvement of existing models is always beneficial, and the addition of a robust immune component is a particular need, at present, considerable progress has been made using this combination of research platforms...
2018: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29321049/human-liver-organoids-generated-with-single-donor-derived-multiple-cells-rescue-mice-from-acute-liver-failure
#13
Yun-Zhong Nie, Yun-Wen Zheng, Miyuki Ogawa, Etsuko Miyagi, Hideki Taniguchi
BACKGROUND: Acute liver failure (ALF) is a life-threatening disease with a high mortality rate. However, there are limited treatments or devices available for ALF therapy. Here, we aimed to develop a new strategy for ALF treatment by transplanting functional liver organoids (LOs) generated from single donor-derived human induced pluripotent stem cell (hiPSC) endoderm, endothelial cells (ECs), and mesenchymal cells (MCs). METHODS: First, we isolated ECs and MCs from a single donor umbilical cord (UC) through enzyme digestion and characterized the UC-ECs and UC-MCs by flow cytometry...
January 10, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29317608/epigenetics-and-cerebral-organoids-promising-directions-in-autism-spectrum-disorders
#14
REVIEW
Sheena Louise Forsberg, Mirolyuba Ilieva, Tanja Maria Michel
Autism spectrum disorders (ASD) affect 1 in 68 children in the US according to the Centers for Disease Control and Prevention (CDC). It is characterized by impairments in social interactions and communication, restrictive and repetitive patterns of behaviors, and interests. Owing to disease complexity, only a limited number of treatment options are available mainly for children that alleviate but do not cure the debilitating symptoms. Studies confirm a genetic link, but environmental factors, such as medications, toxins, and maternal infection during pregnancy, as well as birth complications also play a role...
January 10, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29311338/faulty-neuronal-determination-and-cell-polarization-are-reverted-by-modulating-hd-early-phenotypes
#15
P Conforti, D Besusso, V D Bocchi, A Faedo, E Cesana, G Rossetti, V Ranzani, C N Svendsen, L M Thompson, M Toselli, G Biella, M Pagani, E Cattaneo
Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29311127/kras-in-organoids
#16
Derek Cheng, David Tuveson
Oncogenic Kras are genetic dependencies for the majority of pancreatic and colorectal adenocarcinomas; however, much remains to be understood regarding its tropism to these carcinomas. Recently developed organoid technology presents a more representative model culture system for pancreatic and colon epithelial tissues as well as better fostering the culture of nonimmortalized cells than two-dimensional culture. These advantages enable cancer researchers to directly compare tumor and normal tissue models to better study tumor initiation as well as therapeutic efficacy...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29311126/preclinical-models-of-prostate-cancer-patient-derived-xenografts-organoids-and-other-explant-models
#17
Gail P Risbridger, Roxanne Toivanen, Renea A Taylor
Prostate cancer remains a lethal disease. Preclinical cancer models that accurately represent the tumors of the patients they are intended to help are necessary to test potential therapeutic approaches and to better translate research discoveries. However, research in the prostate cancer field is hampered by the limited number of human cell lines and xenograft models, most of which do not recapitulate the human disease seen in the clinic today. This work reviews the recent advances in human patient-derived xenograft, organoid, and other explant models to address this need...
January 8, 2018: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29305721/paragangliomas-arise-through-an-autonomous-vasculo-angio-neurogenic-program-inhibited-by-imatinib
#18
Fabio Verginelli, Silvia Perconti, Simone Vespa, Francesca Schiavi, Sampath Chandra Prasat, Paola Lanuti, Alessandro Cama, Lorenzo Tramontana, Diana Liberata Esposito, Simone Guarnieri, Artenca Sheu, Mattia Russel Pantalone, Rosalba Florio, Annalisa Morgano, Cosmo Rossi, Giuseppina Bologna, Marco Marchisio, Andrea D'Argenio, Elisa Taschin, Rosa Visone, Giuseppe Opocher, Angelo Veronese, Carlo T Paties, Vinalogu K Rajasekhar, Cecilia Söderberg-Nauclér, Mario Sanna, Lavinia Vittoria Lotti, Renato Mariani-Costantini
Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts...
January 5, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29304256/dynamics-ultrastructure-and-gene-expression-of-human-in-vitro-organized-testis-cells-from-testicular-sperm-extraction-biopsies
#19
Kathrein von Kopylow, Wolfgang Schulze, Andrea Salzbrunn, Matthias Schaks, Elke Schäfer, Beate Roth, Stefan Schlatt, Andrej-Nikolai Spiess
STUDY QUESTION: Is it possible to induce in-vitro reorganization of primary human testis cells from testicular sperm extraction (TESE) biopsies, maintain their long-term cultivation in a 2D system and identify cellular compositions? SUMMARY ANSWER: In-vitro reorganization of primary human testis cells from TESE biopsies and their long-term cultivation on uncoated cell culture dishes is feasible and the cellular compositions can be uncovered through gene expression and microscopic analyses...
January 3, 2018: Molecular Human Reproduction
https://www.readbyqxmd.com/read/29303405/focal-adhesion-kinase-a-potential-therapeutic-target-for-pancreatic-cancer-and-malignant-pleural-mesothelioma
#20
Rajani Kanteti, Tamara Mirzapoiazova, Jacob J Riehm, Immanuel Dhanasingh, Bolot Mambetsariev, Jiale Wang, Prakash Kulkarni, Garima Kaushik, Parthasarathy Seshacharyulu, Moorthy P Ponnusamy, Hedy L Kindler, Mohd W Nasser, Surinder K Batra, Ravi Salgia
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines...
January 5, 2018: Cancer Biology & Therapy
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