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https://www.readbyqxmd.com/read/29786784/generation-of-prostate-cancer-patient-derived-xenografts-to-investigate-mechanisms-of-novel-treatments-and-treatment-resistance
#1
Hung-Ming Lam, Holly M Nguyen, Eva Corey
Treatment advances lead to survival benefits of patients with advanced prostate cancer. These treatments are highly efficacious in a subset of patients; however, similarly to other cancers, after initial responses the tumors develop resistance (acquired resistance) and the patients succumb to the disease. Furthermore, there is a subset of patients who do not respond to the treatment at all (de novo resistance). Preclinical testing using patient-derived xenografts (PDXs) has led to successful drug development, and PDXs will continue to provide valuable resources to generate clinically relevant data with translational potential...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29778888/rapid-phenotyping-of-cancer-stem-cells-using-multichannel-nanosensor-arrays
#2
Yingying Geng, Hira L Goel, Ngoc B Le, Tatsuyuki Yoshii, Rubul Mout, Gulen Y Tonga, John J Amante, Arthur M Mercurio, Vincent M Rotello
Cancer stem cells (CSCs) contribute to multidrug resistance, tumor recurrence and metastasis, making them prime therapeutic targets. Their ability to differentiate and lose stem cell properties makes them challenging to study. Currently, there is no simple assay that can capture and trace the dynamic phenotypic changes on the CSC surface. Here, we report rapid discrimination of breast CSCs from non-CSCs using a nanoparticle-fluorescent-protein based sensor. This nanosensor was employed to discriminate CSCs from non-CSCs, as well CSCs that had differentiated in vitro in two breast cancer models...
May 17, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29775636/epithelial-proliferation-in-inflammatory-skin-disease-is-regulated-by-ttc7-in-fibroblasts-and-lymphocytes
#3
Ursina Nüesch, Andrea A Mauracher, Lennart Opitz, Benjamin Volkmer, Katarzyna Michalak-Mićka, Jivko Kamarachev, Tom Hartwig, Ernst Reichmann, Burkhard Becher, Stefano Vavassori, Jana Pachlopnik Schmid
BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and the immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: To identify whether TTC7A mutations dysregulate epithelial cells only, or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations...
May 15, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29774125/the-critical-role-that-stat3-plays-in-glioma-initiating-cells-stat3-addiction-in-glioma
#4
Debolina Ganguly, Meiyun Fan, Chuan He Yang, Blazej Zbytek, David Finkelstein, Martine F Roussel, Lawrence M Pfeffer
Glioma-Initiating Cells (GICs) are thought to be responsible for tumor initiation, progression and recurrence in glioblastoma (GBM). In previous studies, we reported the constitutive phosphorylation of the STAT3 transcription factor in GICs derived from GBM patient-derived xenografts, and that STAT3 played a critical role in GBM tumorigenesis. In this study, we show that CRISPR/Cas9-mediated deletion of STAT3 in an established GBM cell line markedly inhibited tumorigenesis by intracranial injection but had little effect on cell proliferation in vitro ...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29774094/selumetinib-based-therapy-in-uveal-melanoma-patient-derived-xenografts
#5
Didier Decaudin, Rania El Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Chloé Raymondie, Emma Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul D Smith, Nathalie Cassoux, Sophie Piperno-Neumann, Sergio Roman-Roman, Fariba Némati
The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29773987/celastrol-attenuates-the-invasion-and-migration-and-augments-the-anticancer-effects-of-bortezomib-in-a-xenograft-mouse-model-of-multiple-myeloma
#6
Muthu K Shanmugam, Kwang S Ahn, Jong H Lee, Radhamani Kannaiyan, Nurulhuda Mustafa, Kanjoormana A Manu, Kodappully S Siveen, Gautam Sethi, Wee J Chng, Alan P Kumar
Several lines of evidence have demonstrated that deregulated activation of NF-κB plays a pivotal role in the initiation and progression of a variety of cancers including multiple myeloma (MM). Therefore, novel molecules that can effectively suppress deregulated NF-κB upregulation can potentially reduce MM growth. In this study, the effect of celastrol (CSL) on patient derived CD138+ MM cell proliferation, apoptosis, cell invasion, and migration was investigated. In addition, we studied whether CSL can potentiate the apoptotic effect of bortezomib, a proteasome inhibitor in MM cells and in a xenograft mouse model...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29773600/the-interleukin-3-receptor-cd123-targeted-sl-401-mediates-potent-cytotoxic-activity-against-cd34-cd123-cells-from-acute-myeloid-leukemia-myelodysplastic-syndrome-patients-and-healthy-donors
#7
Rajeswaran Mani, Swagata Goswami, Bhavani Gopalakrishnan, Rahul Ramaswamy, Ronni Wasmuth, Minh Tranh, Xiaokui Mo, Amber Gordon, Donna Bucci, David M Lucas, Alice Mims, Christopher Brooks, Adrienne Dorrance, Alison Walker, William Blum, John C Byrd, Gerard Lozanski, Sumithira Vasu, Natarajan Muthusamy
Diseases with clonal hematopoiesis such as myelodysplastic syndrome and acute myeloid leukemia have high rates of relapse. Only a small subset of acute myeloid leukemia patients are cured with chemotherapy alone. Relapse in these diseases occurs at least in part due to the failure to eradicate leukemic stem cells or hematopoietic stem cells in myelodysplastic syndrome. CD123, the alpha chain of the interleukin-3 receptor heterodimer, is expressed on the majority of leukemic stem cells and myelodysplastic syndrome hematopoietic stem cells and in 80% of acute myeloid leukemia...
May 17, 2018: Haematologica
https://www.readbyqxmd.com/read/29769644/translational-models-of-prostate-cancer-bone-metastasis
#8
REVIEW
Richard B Berish, Aymon N Ali, Patrick G Telmer, John A Ronald, Hon S Leong
Metastatic disease is the principal cause of prostate-cancer-related mortality. Our ability to accurately recapitulate the spread of prostate cancer to bone - the most common site of metastasis - is critical to the development of novel metastasis-directed therapies. Several translational models of prostate cancer bone metastasis have been developed, including animal models, cell line injection models, 3D in vitro models, bone implant models, and patient-derived xenograft models. The use of these models has led to numerous advances in elucidating the molecular mechanisms of metastasis and innovations in targeted therapy...
May 16, 2018: Nature Reviews. Urology
https://www.readbyqxmd.com/read/29769286/targeted-inhibition-of-histone-h3k27-demethylation-is-effective-in-high-risk-neuroblastoma
#9
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29769196/an-in-vivo-screen-identifies-pygo2-as-a-driver-for-metastatic-prostate-cancer
#10
Xin Lu, Xiaolu Pan, Chang-Jiun Wu, Di Zhao, Shan Feng, Yong Zang, Rumi Lee, Sunada Khadka, Samirkumar B Amin, Eun-Jung Jin, Xiaoying Shang, Pingna Deng, Yanting Luo, William R Morgenlander, Jacqueline Weinrich, Xuemin Lu, Shan Jiang, Qing Chang, Nora M Navone, Patricia Troncoso, Ronald A DePinho, Y Alan Wang
Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen...
May 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29768500/clinically-relevant-inflammatory-breast-cancer-patient-derived-xenograft-derived-ex-vivo-model-for-evaluation-of-tumor-specific-therapies
#11
Bedrich L Eckhardt, Maria Gagliardi, LaKesla Iles, Kurt Evans, Cristina Ivan, Xiuping Liu, Chang-Gong Liu, Glauco Souza, Arvind Rao, Funda Meric-Bernstam, Naoto T Ueno, Geoffrey A Bartholomeusz
Inflammatory breast cancer (IBC) is a rare and aggressive presentation of invasive breast cancer with a 62% to 68% 5-year survival rate. It is the most lethal form of breast cancer, and early recognition and treatment is important for patient survival. Like non-inflammatory breast cancer, IBC comprises multiple subtypes, with the triple-negative subtype being overrepresented. Although the current multimodality treatment regime of anthracycline- and taxane-based neoadjuvant therapy, surgery, and radiotherapy has improved the outcome of patients with triple-negative IBC, overall survival continues to be worse than in patients with non-inflammatory locally advanced breast cancer...
2018: PloS One
https://www.readbyqxmd.com/read/29766688/assessing-effects-of-pressure-on-tumor-and-normal-tissue-physiology-using-an-automated-self-calibrated-pressure-sensing-probe-for-diffuse-reflectance-spectroscopy
#12
Gregory M Palmer, Hengtao Zhang, Chen-Ting Lee, Husam Mikati, Joseph A Herbert, Marlee Krieger, Jesko von Windheim, Dave Koester, Daniel Stevenson, Daniel J Rocke, Ramon Esclamado, Alaatin Erkanli, Nirmala Ramanujam, Mark W Dewhirst, Walter T Lee
Diffuse reflectance spectroscopy (DRS) represents a quantitative, noninvasive, nondestructive means of assessing vascular oxygenation, vascularity, and structural properties. However, it is known that such measurements can be influenced by the effects of pressure, which is a major concern for reproducible and operator-independent assessment of tissues. Second, regular calibration is a necessary component of quantitative DRS to account for factors such as lamp decay and fiber bending. Without a means of reliably controlling for these factors, the accuracy of any such assessments will be reduced, and potentially biased...
May 2018: Journal of Biomedical Optics
https://www.readbyqxmd.com/read/29765518/increasing-aggressiveness-of-patient-derived-xenograft-models-of-cervix-carcinoma-during-serial-transplantation
#13
Catherine S Wegner, Anette Hauge, Lise Mari K Andersen, Ruixia Huang, Trude G Simonsen, Jon-Vidar Gaustad, Einar K Rofstad
Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764852/combined-hdac-and-bromodomain-protein-inhibition-reprograms-tumor-cell-metabolism-and-elicits-synthetic-lethality-in-glioblastoma
#14
Yiru Zhang, Chiaki Tsuge Ishida, Wataru Ishida, Sheng-Fu L Lo, Junfei Zhao, Chang Shu, Elena Bianchetti, Giulio Kleiner, Maria Sanchez-Quintero, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D Siegelin
PURPOSE: Glioblastoma remain a challenge in oncology in part due to tumor heterogeneity. EXPERIMENTAL DESIGN: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems. RESULTS: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that combined histone deacetylase (HDAC) inhibition and Bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells...
May 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29764505/xenograft-tumors-derived-from-malignant-pleural-effusion-of-the-patients-with-non-small-cell-lung-cancer-as-models-to-explore-drug-resistance
#15
Yunhua Xu, Feifei Zhang, Xiaoqing Pan, Guan Wang, Lei Zhu, Jie Zhang, Danyi Wen, Shun Lu
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively...
May 9, 2018: Cancer communications
https://www.readbyqxmd.com/read/29760405/arid1a-mutation-sensitizes-most-ovarian-clear-cell-carcinomas-to-bet-inhibitors
#16
Katrien Berns, Joseph J Caumanns, E Marielle Hijmans, Annemiek M C Gennissen, Tesa M Severson, Bastiaan Evers, G Bea A Wisman, Gert Jan Meersma, Cor Lieftink, Roderick L Beijersbergen, Hiroaki Itamochi, Ate G J van der Zee, Steven de Jong, René Bernards
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells...
May 15, 2018: Oncogene
https://www.readbyqxmd.com/read/29760161/ctcf-boundary-remodels-chromatin-domain-and-drives-aberrant-hox-gene-transcription-in-acute-myeloid-leukemia
#17
Huacheng Luo, Fei Wang, Jie Zha, Haoli Li, Bowen Yan, Qinghua Du, Fengchun Yang, Amin Sobh, Christopher Vulpe, Leylah Drusbosky, Christopher Cogle, Iouri Chepelev, Bing Xu, Stephen D Nimer, Jonathan Licht, Yi Qiu, Baoan Chen, Mingjiang Xu, Suming Huang
HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene expression patterns within confined chromatin domains for normal development. Here, we employed targeted pooled CRISPR-Cas9 knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci...
May 14, 2018: Blood
https://www.readbyqxmd.com/read/29759485/roles-of-alternative-rna-splicing-of-the-bif-1-gene-by-srrm4-during-the-development-of-treatment-induced-neuroendocrine-prostate-cancer
#18
Yu Gan, Yinan Li, Zhi Long, Ahn R Lee, Ning Xie, Jessica M Lovnicki, Yuxin Tang, Xiang Chen, Jiaoti Huang, Xuesen Dong
Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti-cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis-associated gene, which undergoes alternative RNA splicing in t-NEPC...
May 11, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29758929/mir-370-regulates-isg15-expression-and-influences-ifn-%C3%AE-sensitivity-in-hepatocellular-carcinoma-cells
#19
Zhuo Liu, Min Ma, Lei Yan, Shilin Chen, Sha Li, Darong Yang, Xiaohong Wang, Hua Xiao, Hongyu Deng, Haizhen Zhu, Chaohui Zuo, Man Xia
BACKGROUND: Interferon-α (IFN-α) is an adjuvant to chemotherapy and radiotherapy for hepatocellular carcinoma (HCC), but some HCC patients do not respond to treatment with IFN-α. METHODS: We performed loss-of-function and gain-of-function experiments to examine the role of ISG15 in the IFN-α sensitivity of LH86, HLCZ01, SMMC7721, and Huh7 cell lines and tumor samples. RESULTS: The overexpression of ISG15 reduced apoptosis in Huh7 and LH86 cells in the presence of IFN-α, whereas the shRNA-mediated knock down of ISG15 expression increased apoptosis in both Huh7 and LH86 cells...
May 5, 2018: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/29758120/concomitant-administration-of-radiation-with-eribulin-improves-the-survival-of-mice-harboring-intracerebral-glioblastoma
#20
Shunichiro Miki, Shoji Imamichi, Hiroaki Fujimori, Arata Tomiyama, Kenji Fujimoto, Kaishi Satomi, Yuko Matsushita, Sanae Matsuzaki, Masamichi Takahashi, Eiichi Ishikawa, Tetsuya Yamamoto, Akira Matsumura, Akitake Mukasa, Ryo Nishikawa, Kenkichi Masutomi, Yoshitaka Narita, Mitsuko Masutani, Koichi Ichimura
Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non-taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M-phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation-induced DNA damage. Several recent case reports demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors...
May 14, 2018: Cancer Science
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