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https://www.readbyqxmd.com/read/29684420/novel-cancer-gene-variants-and-gene-fusions-of-triple-negative-breast-cancers-tnbcs-reveal-their-molecular-diversity-conserved-in-the-patient-derived-xenograft-pdx-model
#1
Jaeyun Jung, Kiwon Jang, Jung Min Ju, Eunji Lee, Jong Won Lee, Hee Jung Kim, Jisun Kim, Sae Byul Lee, Beom Seok Ko, Byung Ho Son, Hee Jin Lee, Gyungyup Gong, Sei Yeon Ahn, Jung Kyoon Choi, Shree Ram Singh, Suhwan Chang
Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors...
April 20, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29684110/mechanistic-insights-into-anticancer-properties-of-oligomeric-proanthocyanidins-from-grape-seeds-in-colorectal-cancer
#2
Preethi Ravindranathan, Divya Pasham, Uthra Balaji, Jacob Cardenas, Jinghua Gu, Shusuke Toden, Ajay Goel
Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines...
April 19, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29683208/a-novel-tricarbonylmethane-agent-cmc2-24-reduces-human-pancreatic-tumor-growth-in-mice-by-targeting-ras
#3
Naveen A Mallangada, Joselin M Vargas, Swaroopa Thomas, Matthew G DiGiovanni, Brandon M Vaeth, Matthew D Nemesure, Ruixue Wang, Joseph F LaComb, Jennie L Williams, Lorne M Golub, Francis Johnson, Gerardo G Mackenzie
Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (p < 0...
April 23, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29682179/antiapoptotic-bcl-2-proteins-determine-sorafenib-regorafenib-resistance-and-bh3-mimetic-efficacy-in-hepatocellular-carcinoma
#4
Anna Tutusaus, Milica Stefanovic, Loreto Boix, Blanca Cucarull, Aynara Zamora, Laura Blasco, Pablo García de Frutos, Maria Reig, Jose C Fernandez-Checa, Montserrat Marí, Anna Colell, Jordi Bruix, Albert Morales
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29675102/synergistic-antitumor-effects-of-cmet-inhibitor-in-combination-with-anti-vegf-in-colorectal-cancer-patient-derived-xenograft-models
#5
Xiangheng Chen, Zhonghai Guan, Jun Lu, Haohao Wang, Zhongkun Zuo, Fei Ye, Jiangsheng Huang, Lisong Teng
cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo ...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29672049/discovery-of-n-2-4-amino-cyclohexyl-9-cyclopentyl-n-6-4-morpholin-4-ylmethyl-phenyl-9-h-purine-2-6-diamine-as-a-potent-flt3-kinase-inhibitor-for-acute-myeloid-leukemia-with-flt3-mutations
#6
Tomas Gucky, Eva Řezníčková, Tereza Radosova Muchova, Radek Jorda, Zuzana Klejova, Veronika Malinkova, Karel Berka, Vaclav Bazgier, Haresh Ajani, Martin Lepsik, Vladimir Divoky, Vladimir Krystof
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29669759/multi-kinase-inhibitor-ct-707-targets-liver-cancer-by-interrupting-the-hypoxia-activated-igf-1r-yap-axis
#7
Hong Zhu, Dan-Dan Wang, Tao Yuan, Fang-Jie Yan, Chen-Ming Zeng, Xiao-Yang Dai, Zi-Bo Chen, Ying Chen, Tianyi Zhou, Guang-Han Fan, Meidan Ying, Ji Cao, Peihua Luo, Xi-Jie Liu, Yuandong Hu, Yong Peng, Qiaojun He, Bo Yang
Given that YAP signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling...
April 18, 2018: Cancer Research
https://www.readbyqxmd.com/read/29666304/strategic-therapeutic-targeting-to-overcome-venetoclax-resistance-in-aggressive-b-cell-lymphomas
#8
Lan V Pham, Shengjian Huang, Hui Zhang, Jun Zhang, Taylor Bell, Shouhao Zhou, Elizabeth Pogue, Zhiyong Ding, Laura Lam, Jason R Westin, R Eric Davis, Ken H Young, L Jeffrey Medeiros, Richard J Ford, Krystle Nomie, Liang Zhang, Michael Wang
PURPOSE: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL)...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29666301/fratricide-of-nk-cells-in-daratumumab-therapy-for-multiple-myeloma-overcome-by-ex-vivo-expanded-autologous-nk-cells
#9
Yufeng Wang, Yibo Zhang, Tiffany Hughes, Jianying Zhang, Michael A Caligiuri, Don M Benson, Jianhua Yu
PURPOSE: Daratumumab and its use in combination with other agents is becoming a new standard of care for treatment of multiple myeloma (MM). We mechanistically studied how daratumumab acts on NK cells. EXPERIMENTAL DESIGN: Quantities of NK cells in peripheral blood (PB) and/or bone marrow (BM) of MM patients or healthy donors were examined by flow cytometry. NK cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29666142/tumor-xenograft-modeling-identifies-tcf4-itf2-loss-associated-with-breast-cancer-chemoresistance
#10
Gorka Ruiz de Garibay, Francesca Mateo, Agostina Stradella, Rafael Valdés-Mas, Luis Palomero, Jordi Serra-Musach, Diana A Puente, Ander Díaz-Navarro, Gardenia Vargas-Parra, Eva Tornero, Idoia Morilla, Lourdes Farré, María Martinez-Iniesta, Carmen Herranz, Emmet McCormack, August Vidal, Anna Petit, Teresa Soler, Conxi Lázaro, Xose S Puente, Alberto Villanueva, Miguel Angel Pujana
Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify loss of transcription factor 4 (TCF4) associated with this process. A triple-negative BRCA1 -mutated PDX was used to study the genetics of chemoresistance...
April 13, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29664709/non-clinical-efficacy-and-safety-studies-on-g1xcgd-a-lentiviral-vector-for-ex-vivo-gene-therapy-of-x-linked-chronic-granulomatous-disease
#11
Christian Brendel, Michael Rothe, Giorgia Santilli, Sabine Charrier, Stefan Stein, Hana Kunkel, Daniela Abriss, Uta Müller-Kuller, Bobby Gaspar, Ute Modlich, Anne Galy, Axel Schambach, Adrian J Thrasher, Manuel Grez
Chronic granulomatous disease (CGD) is a debilitating primary immunodeficiency affecting phagocyte function due to the absence of nicotinamide dinucleotide phosphate (NADPH) oxidase activity. The vast majority of CGD patients in the Western world have mutations within the X-linked CYBB gene encoding for gp91phox (NOX2), the redox center of the NADPH oxidase complex (XCGD). Current treatments of XCGD are not entirely satisfactory, and prior attempts at autologous gene therapy using gammaretrovirus vectors did not provide long-term curative effects...
April 17, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#12
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29661776/targeting-the-leukemia-antigen-pr1-with-immunotherapy-for-the-treatment-of-multiple-myeloma
#13
Gheath Alatrash, Alexander A Perakis, Celine Kerros, Haley L Peters, Pariya Sukhumalchandra, Mao Zhang, Haroon Jakher, Madhushree Zope, Rebecca S Patenia, Anna Sergeeva, Shuhua Yi, Ken H Young, Anne V Philips, Amanda C Herrmann, Haven R Garber, Na Qiao, Jinsheng Weng, Lisa S St John, Sijie Lu, Karen Clise-Dwyer, Elizabeth A Mittendorf, Qing Ma, Jeffrey J Molldrem
PURPOSE: PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. Since multiple myeloma (MM) is derived from B cells, we investigated whether MM is also capable of PR1 cross-presentation and subsequently capable of being targeted using PR1 immunotherapies...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29661755/a-cd123-targeting-antibody-drug-conjugate-imgn632-designed-to-eradicate-aml-while-sparing-normal-bone-marrow-cells
#14
Yelena Kovtun, Gregory E Jones, Sharlene Adams, Lauren Harvey, Charlene A Audette, Alan Wilhelm, Chen Bai, Lingyun Rui, Rassol Laleau, Fenghua Liu, Olga Ab, Yulius Setiady, Nicholas C Yoder, Victor S Goldmacher, Ravi V J Chari, Jan Pinkas, Thomas Chittenden
The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29659677/targeting-the-human-epidermal-growth-factor-receptor-2-her2-oncogene-in-colorectal-cancer
#15
S Siena, A Sartore-Bianchi, S Marsoni, H I Hurwitz, S J McCall, F Penault-Llorca, S Srock, A Bardelli, L Trusolino
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors are driven by amplification or mutation of HER2. MATERIALS AND METHODS: This paper reviews the role of HER2 as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type...
April 6, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29653142/characterization-of-a-conjunctival-melanoma-cell-line-cm-as16-newly-established-from-a-metastatic-han-chinese-patient
#16
Yongyun Li, Qingfeng Shang, Peng Li, Jinfeng Cao, Liqi Zhu, Martine J Jager, Xianqun Fan, Shengfang Ge, Renbing Jia
Conjunctival melanoma (CM) is associated with metastases formation, can be fatal, and occurs in all different races. While cell lines are essential for experimental research, all available CM cell lines are derived from Caucasian patients. Furthermore, they are not derived from metastases. We aimed to establish a new CM cell line from a parotid metastasis in a Han Chinese patient and to depict its characteristics. The novel cell line, CM-AS16, was obtained from a surgical parotid sample and determined as a unique one with short tandem repeat (STR) analysis...
April 10, 2018: Experimental Eye Research
https://www.readbyqxmd.com/read/29630051/flow-cytometry-to-estimate-leukemia-stem-cells-in-primary-acute-myeloid-leukemia-and-in-patient-derived-xenografts-at-diagnosis-and-follow-up
#17
Thomas Boyer, Fanny Gonzales, Adriana Plesa, Pauline Peyrouze, Adeline Barthelemy, Soizic Guihard, Bruno Quesnel, Christophe Roumier, Claude Preudhomme, Meyling Cheok
Acute myeloid leukemia (AML) is a heterogeneous, and if not treated, fatal disease. It is the most common cause of leukemia-associated mortality in adults. Initially, AML is a disease of hematopoietic stem cells (HSC) characterized by arrest of differentiation, subsequent accumulation of leukemia blast cells, and reduced production of functional hematopoietic elements. Heterogeneity extends to the presence of leukemia stem cells (LSC), with this dynamic cell compartment evolving to overcome various selection pressures imposed upon during leukemia progression and treatment...
March 26, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29627364/animal-models-of-cholangiocarcinoma
#18
REVIEW
Emilien Loeuillard, Samantha R Fischbach, Gregory J Gores, Sumera Rizvi
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with a poor overall prognosis. There is a critical need to develop effective targeted therapies for the treatment of this lethal disease. In an effort to address this challenge, preclinical in vivo studies have become paramount in understanding CCA carcinogenesis, progression, and therapy. Various CCA animal models exist including carcinogen-based models in which animals develop CCA after exposure to a carcinogen, genetically engineered mouse models in which genetic changes are induced in mice leading to CCA, murine syngeneic orthotopic models, as well as xenograft tumors derived from xenotransplantation of CCA cells, organoids, and patient-derived tissue...
April 5, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29626519/polycomb-complex-protein-bmi1-confers-resistance-to-tamoxifen-in-estrogen-receptor-positive-breast-cancer
#19
Diane Ojo, Xiaozeng Lin, Ying Wu, Jessica Cockburn, Anita Bane, Damu Tang
We report that BMI1 promotes tamoxifen resistance in estrogen receptor (ER)-positive breast cancer (BC). BMI1 overexpression conferred MCF7 and TD47 cells resistance to tamoxifen; BMI1 knockdown sensitized the process. In MCF7-derived tamoxifen resistant cells, BMI1 expression was upregulated and BMI1 knockdown reduced the resistance. BMI1 is an oncogene; its oncogenic activity is attributed to BMI1-stimulated E3 ubiquitin ligase activity, a process that requires BMI1's ring finger (RF) domain. However, a BMI1 mutant without RF conferred tamoxifen resistance...
April 4, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29625193/icaritin-induces-ovarian-cancer-cell-apoptosis-through-activation-of-p53-and-inhibition-of-akt-mtor-pathway
#20
Lvfen Gao, Ming Chen, Yuan Ouyang, Ruobin Li, Xian Zhang, Xuesong Gao, Xiaoyu Wang, Shaoqiang Lin
AIMS: Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers. Currently, the first-line OC treatment consists of cytoreductive surgery and platinum-based chemotherapy. However, most patients develop chemoresistance after the first-line treatment limits the success of treatment. Therefore, there is an urgent need to identify effective therapeutic agents. MAIN METHODS: Cell viabilities were detected by MTS assay; Annexin V-FITC/PI assay and western blotting assay were performed to analyze the apoptotic cells in vitro; An immunofluorescence assay was performed to analyze the TUNEL+ apoptotic cells in vivo; Patient-derived xenografts were established to test the in vivo antitumor effects; The key proteins of p53, caspase-mediated apoptotic pathway and Akt/mTOR pathway were detected by Western blotting...
April 3, 2018: Life Sciences
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