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colorectal organoid

Xin Liu, Jessica K Lukowski, Colin Flinders, Rebecca Georgiadis, Seungil Kim, Shannon Mumenthaler, Amanda B Hummon
Immunotherapies are treatments that use a patient's immune system to combat disease. One important type of immunotherapy employed in cancer treatments is the delivery of monoclonal antibodies to block growth receptors. In this manuscript, we develop a methodology that enables accurate and simple evaluation of antibody-type drug delivery using MALDI-MSI. To overcome the mass range limitation that prevents the detection of large therapeutic antibodies, we used in situ reduction and alkylation to break disulfide bonds to generate smaller fragments...
November 27, 2018: Analytical Chemistry
Yuan Liu, Ye-Guang Chen
Colorectal cancer (CRC) is one of the most common cancers that have high occurrence and death in both males and females. As various factors have been found to contribute to CRC development, personalized therapies are critical for efficient treatment. To achieve this purpose, the establishment of patient-derived tumor models is critical for diagnosis and drug test. The establishment of three-dimensional (3D) organoid cultures and two-dimensional (2D) monolayer cultures of patient-derived epithelial tissues is a breakthrough for expanding living materials for later use...
November 22, 2018: Cells
Hua Xu, Jing Li, Hao Chen, Fayez K Ghishan
Background & Aims: Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+ /H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis-like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors...
2019: Cellular and Molecular Gastroenterology and Hepatology
Sang-Kyu Lee, Yong-Hee Cho, Pu-Hyeon Cha, Jeong-Soo Yoon, Eun Ji Ro, Woo-Jeong Jeong, Jieun Park, Hyuntae Kim, Tae Il Kim, Do Sik Min, Gyoonhee Han, Kang-Yell Choi
Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis...
November 20, 2018: Experimental & Molecular Medicine
Julio Aleman, Aleksander Skardal
Metastatic disease remains one of the primary reasons for cancer-related death, yet the majority of in vitro cancer models focus on the primary tumor sites. Here we describe a metastasis-on-a-chip device, that houses multiple bioengineered 3D organoids, established by a 3D photopatterning technique employing extracellular matrix-derived hydrogel biomaterials. Specifically, cancer cells begin in a colorectal cancer (CRC) organoid, which resides in a single microfluidic chamber connected to multiple downstream chambers in which liver, lung, and endothelial constructs are housed...
November 18, 2018: Biotechnology and Bioengineering
Kai-Yuan Chen, Tara Srinivasan, Christopher Lin, Kuei-Ling Tung, Ziyang Gao, David S Hsu, Steven M Lipkin, Xiling Shen
Organoids are three-dimensional cell cultures that mimic organ functions and structures. The organoid model has been developed as a versatile in vitro platform for stem cell biology and diseases modeling. Tumor organoids are shown to share ~ 90% of genetic mutations with biopsies from same patients. However, it's not clear whether tumor organoids recapitulate the cellular heterogeneity observed in patient tumors. Here, we used single-cell RNA-Seq to investigate the transcriptomics of tumor organoids derived from human colorectal tumors, and applied machine learning methods to unbiasedly cluster subtypes in tumor organoids...
July 2018: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
Alejandro Llanos-Chea, Robert J Citorik, Kourtney P Nickerson, Laura Ingano, Gloria Serena, Stefania Senger, Timothy K Lu, Alessio Fasano, Christina S Faherty
OBJECTIVE: Enteric bacterial pathogens cause diarrheal disease and mortality at significant rates throughout the world, particularly in children under the age of 5 years. Our ability to combat bacterial pathogens has been hindered antibiotic resistance, a lack of effective vaccines, and accurate models of infection. With the renewed interest in bacteriophage therapy, we sought to use a novel human intestinal model to investigate the efficacy of a newly isolated bacteriophage against Shigella flexneri...
November 8, 2018: Journal of Pediatric Gastroenterology and Nutrition
Fang Hua, Shuang Shang, Yu-Wei Yang, Hai-Zeng Zhang, Tian-Lei Xu, Jiao-Jiao Yu, Dan-Dan Zhou, Bing Cui, Ke Li, Xiao-Xi Lv, Xiao-Wei Zhang, Shan-Shan Liu, Jin-Mei Yu, Feng Wang, Cheng Zhang, Bo Huang, Zhuo-Wei Hu
BACKGROUND & AIMS: Activation of Wnt signaling to beta-catenin contributes to development of colorectal cancer (CRC). Expression of tribbles pseudokinase 3 (TRIB3) is increased in some colorectal tumors and associated with poor outcome. We investigated whether increased TRIB3 expression promotes stem cell features of CRC cells and tumor progression by interacting with the Wnt signaling pathway. METHODS: We performed studies with C57BL/6J-ApcMin /J mice injected with an adeno-associated virus vector that expresses a small hairpin RNA against Trib3 mRNA (ApcMin /J-Trib3KD ) or a control vector (ApcMin /J-Ctrl)...
October 23, 2018: Gastroenterology
Peng A, Xinyi Xu, Chenglin Wang, Ling Ye, Jing Yang
Colorectal carcinoma is one of the common cancers in human. It has been intensely debated whether the in vitro cancer cell lines are closely enough for recapitulating the original tumor in understanding the molecular characteristic of CRC. Organoid as a new in vitro 3D culture system has sprang out in CRC study for the capability in reviving the original tissue. The aim of this study is to profile the gene expression of CRC organoid. The gene expression GSE64392 was from GEO database contained 20-patients-derived 37 organoid samples, including 22 colorectal tumor organoid samples and 15 paired healthy samples...
2018: BioMed Research International
Steve Wagner, Georgios Vlachogiannis, Alexis De Haven Brandon, Melanie Valenti, Gary Box, Liam Jenkins, Caterina Mancusi, Annette Self, Floriana Manodoro, Ioannis Assiotis, Penny Robinson, Ritika Chauhan, Alistair G Rust, Nik Matthews, Kate Eason, Khurum Khan, Naureen Starling, David Cunningham, Anguraj Sadanandam, Clare M Isacke, Vladimir Kirkin, Nicola Valeri, Steven R Whittaker
Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines...
October 23, 2018: Oncogene
Jumpei Kondo, Tomoya Ekawa, Hiroko Endo, Kanami Yamazaki, Norio Tanaka, Yoji Kukita, Hiroaki Okuyama, Jiro Okami, Fumio Imamura, Masayuki Ohue, Kikuya Kato, Taisei Nomura, Arihiro Kohara, Seiichi Mori, Shingo Dan, Masahiro Inoue
Patient-derived cancer organoid culture is an important live material that reflects clinical heterogeneity. However, the limited amount of organoids available for each case as well as the considerable amount of time and cost to expand in vitro makes it impractical to perform high-throughput drug screening using organoid cultures from multiple patients. Here, we report an advanced system for the high-throughput screening of 2427 drugs using the cancer tissue-originated spheroid (CTOS) method. In this system, we apply the CTOS method in an ex vivo platform from xenograft tumors, using machines to handle CTOS and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs...
October 21, 2018: Cancer Science
Konrad Aden, Kareen Bartsch, Joseph Dahl, Martin A M Reijns, Daniela Esser, Raheleh Sheibani-Tezerji, Anupam Sinha, Felix Wottawa, Go Ito, Neha Mishra, Katharina Knittler, Adam Burkholder, Lina Welz, Johan van Es, Florian Tran, Simone Lipinski, Nassim Kakavand, Christine Boeger, Ralph Lucius, Witigo von Schoenfels, Clemens Schafmayer, Lennart Lenk, Athena Chalaris, Hans Clevers, Christoph Röcken, Christoph Kaleta, Stefan Rose-John, Stefan Schreiber, Thomas Kunkel, Björn Rabe, Philip Rosenstiel
BACKGROUND & AIMS: RNase H2 is a holoenzyme comprising 3 subunits (ribonuclease H2 subunits A, B, and C) that cleaves RNA:DNA hybrids and removes misincorporated ribonucleotides from genomic DNA via ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis...
September 28, 2018: Gastroenterology
Katia Beaudry, Marie-Josée Langlois, Amélie Montagne, Sébastien Cagnol, Julie C Carrier, Nathalie Rivard
The Ras/mitogen-activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual-specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal-regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions...
October 1, 2018: Journal of Cellular Physiology
Nobuo Sasaki, Hans Clevers
Intra-tumor heterogeneity (genotypic and functional diversity among cancer cells within the same tumor) represents one of the key challenges in cancer medicine. As heterogeneity of cancer cells constitutes an important parameter in the development of therapy resistance, an accurate assessment of intra-tumor heterogeneity is essential for the prediction of drug resistance and development of effective treatment. In this review, we evaluate primary patient derived-tumor organoid technology as a new tool for colorectal cancer research and treatment...
September 24, 2018: Current Opinion in Genetics & Development
Semiramis A Popova, Simon J A Buczacki
Cancer cell dormancy is an important source of treatment failure. We studied the molecular characteristics and functional behaviour of dormant colorectal cancer cells finding them to be a differentiated yet plastic population. Organoid drug screening identified itraconazole perturbs dormancy through non-canonical hedgehog signalling effects on the WNT pathway.
2018: Molecular & Cellular Oncology
Preethi Ravindranathan, Divya Pasham, Uthra Balaji, Jacob Cardenas, Jinghua Gu, Shusuke Toden, Ajay Goel
Combining anti-cancer agents in cancer therapies is becoming increasingly popular due to improved efficacy, reduced toxicity and decreased emergence of resistance. Here, we test the hypothesis that dietary agents such as oligomeric proanthocyanidins (OPCs) and curcumin cooperatively modulate cancer-associated cellular mechanisms to inhibit carcinogenesis. By a series of in vitro assays in colorectal cancer cell lines, we showed that the anti-tumorigenic properties of the OPCs-curcumin combination were superior to the effects of individual compounds...
September 14, 2018: Scientific Reports
Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi
Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial-mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells...
September 4, 2018: Oncogene
Stephanie Jaeckel, Markus Kaller, Rene Jackstadt, Ursula Götz, Susanna Müller, Sophie Boos, David Horst, Peter Jung, Heiko Hermeking
The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein. Here, we deleted Ap4 in ApcMin mice, a preclinical model of inherited colorectal cancer. Ap4 deficiency extends their average survival by 110 days and decreases the formation of intestinal adenomas and tumor-derived organoids. The effects of Ap4 deletion are presumably due to the reduced number of functional intestinal stem cells (ISCs) amenable to adenoma-initiating mutational events. Deletion of Ap4 also decreases the number of colonic stem cells and increases the number of Paneth cells...
September 3, 2018: Nature Communications
Anna L Means, Tanner J Freeman, Jing Zhu, Luke G Woodbury, Paula Marincola-Smith, Chao Wu, Anne R Meyer, Connie J Weaver, Chandrasekhar Padmanabhan, Hanbing An, Jinghuan Zi, Bronson C Wessinger, Rupesh Chaturvedi, Tasia D Brown, Natasha G Deane, Robert J Coffey, Keith T Wilson, J Joshua Smith, Charles L Sawyers, James R Goldenring, Sergey V Novitskiy, M Kay Washington, Chanjuan Shi, R Daniel Beauchamp
Background & Aims: Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods: The Smad4 gene was deleted specifically in adult murine intestinal epithelium...
2018: Cellular and Molecular Gastroenterology and Hepatology
Krijn K Dijkstra, Chiara M Cattaneo, Fleur Weeber, Myriam Chalabi, Joris van de Haar, Lorenzo F Fanchi, Maarten Slagter, Daphne L van der Velden, Sovann Kaing, Sander Kelderman, Nienke van Rooij, Monique E van Leerdam, Annekatrien Depla, Egbert F Smit, Koen J Hartemink, Rosa de Groot, Monika C Wolkers, Norman Sachs, Petur Snaebjornsson, Kim Monkhorst, John Haanen, Hans Clevers, Ton N Schumacher, Emile E Voest
Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer...
September 6, 2018: Cell
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