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https://www.readbyqxmd.com/read/29471542/specialized-pro-resolving-lipid-mediators-regulate-ozone-induced-pulmonary-and-systemic-inflammation
#1
Brita Kilburg-Basnyat, Sky W Reece, Miranda J Crouch, Bin Luo, Andria D Boone, Michael Yaeger, Myles Hodge, Christine Psaltis, Johanna L Hannan, Jonathan Manke, Michael L Armstrong, Nichole Reisdorph, Robert M Tighe, Saame Raza Shaikh, Kymberly M Gowdy
Exposure to ozone (O3) induces lung injury, pulmonary inflammation, and alters lipid metabolism. During tissue inflammation, specialized pro-resolving lipid mediators (SPMs) facilitate the resolution of inflammation. SPMs regulate the pulmonary immune response during infection and allergic asthma; however, the role of SPMs in O3-induced pulmonary injury and inflammation is unknown. We hypothesized that O3 exposure induces pulmonary inflammation by reducing SPMs. To evaluate this, male C57Bl/6J mice were exposed to filtered air (FA) or 1 ppm O3 for 3h and necropsied 24h after exposure...
February 19, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29464063/combined-inhibition-of-cdk-and-hdac-as-a-promising-therapeutic-strategy-for-both-cutaneous-and-uveal-metastatic-melanoma
#2
Renier Heijkants, Karen Willekens, Mark Schoonderwoerd, Amina Teunisse, Maaike Nieveen, Enrico Radaelli, Luuk Hawinkels, Jean-Christophe Marine, Aart Jochemsen
Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options. In this study we investigated as a potential novel therapeutic intervention for both cutaneous and uveal melanoma patients a combination of the broad spectrum HDAC inhibitor quisinostat and pan-CDK inhibitor flavopiridol. Both drugs are currently in clinical trials reducing time from bench to bedside...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29463565/an-fgfr3-myc-positive-feedback-loop-provides-new-opportunities-for-targeted-therapies-in-bladder-cancers
#3
Mélanie Mahe, Florent Dufour, Hélène Neyret-Kahn, Aura Moreno-Vega, Claire Beraud, Mingjun Shi, Imene Hamaidi, Virginia Sanchez-Quiles, Clementine Krucker, Marion Dorland-Galliot, Elodie Chapeaublanc, Remy Nicolle, Hervé Lang, Celio Pouponnot, Thierry Massfelder, François Radvanyi, Isabelle Bernard-Pierrot
FGFR3 alterations (mutations or translocation) are among the most frequent genetic events in bladder carcinoma. They lead to an aberrant activation of FGFR3 signaling, conferring an oncogenic dependence, which we studied here. We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates MYC mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates FGFR3 expression by binding to active enhancers upstream from FGFR3 Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing MYC transcription decreased cell viability in vitro and tumor growth in vivo A relevance of this loop to human bladder tumors was supported by the positive correlation between FGFR3 and MYC levels in tumors bearing FGFR3 mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an FGFR3 mutation...
February 20, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29463559/capecitabine-efficacy-is-correlated-with-tymp-and-rb-expression-in-pdx-established-from-triple-negative-breast-cancers
#4
Elisabetta Marangoni, Cécile Laurent, Florence Coussy, Rania El Botty, Sophie Chateau-Joubert, Jean-Luc Servely, Ludmilla de Plater, Franck Assayag, Ahmed Dahmani, Elodie Montaudon, Fariba Némati, Justine Fleury, Sophie Vacher, David Gentien, Audrey Rapinat, Pierre Foidart, Nor Eddine Sounni, Agnès Noël, Anne Salomon, Marick Lae, Didier Decaudin, Sergio Roman-Roman, Ivan Bièche, Martine Piccard, Fabien Reyal
PURPOSE: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. EXPERIMENTAL DESIGN: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29458007/a-genomically-characterized-collection-of-high-grade-serous-ovarian-cancer-xenografts-for-preclinical-testing
#5
Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
February 16, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29457830/mirna-124-3p-neuropilin-1-nrp-1-axis-plays-an-important-role-in-mediating-glioblastoma-growth-and-angiogenesis
#6
Guilong Zhang, Lukui Chen, Ahsan Ali Khan, Bingqian Li, Bin Gu, Fan Lin, Xinhui Su, Jianghua Yan
Glioblastoma Multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM is still lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In this study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. Firstly, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing...
February 19, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29453226/modeling-the-human-bone-marrow-niche-in-mice-from-host-bone-marrow-engraftment-to-bioengineering-approaches
#7
REVIEW
Ander Abarrategi, Syed A Mian, Diana Passaro, Kevin Rouault-Pierre, William Grey, Dominique Bonnet
Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments...
February 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29452092/microrna-630-inhibitor-sensitizes-chemoresistant-ovarian-cancer-to-chemotherapy-by-enhancing-apoptosis
#8
Kyung Jin Eoh, So Hyun Lee, Hee Jung Kim, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam
MicroRNA-630 (miR-630) has been implicated in the development and progression of multiple cancers. The current study aimed to investigate the role of miR-630 in chemoresistant epithelial ovarian cancer. MiR-630 expression levels were detected in ovarian cancer cell line SKOV3 and paclitaxel-resistant SKOV3 (SKOV3-TR) via microarray and qRT-PCR. MiR-630 inhibitors and negative controls were transfected into SKOV3 and SKOV3-TR cells. Wound healing, invasion, chemosensitivity, and cell apoptosis assays were performed to determine proliferation and migration rates...
February 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29449529/gambogenic-acid-inhibits-fibroblast-growth-factor-receptor-signaling-pathway-in-erlotinib-resistant-non-small-cell-lung-cancer-and-suppresses-patient-derived-xenograft-growth
#9
Linfeng Xu, Xiaoxiao Meng, Naihan Xu, Wenwei Fu, Hongsheng Tan, Li Zhang, Qianjun Zhou, Jianan Qian, Shiwei Tu, Xueting Li, Yuanzhi Lao, Hongxi Xu
Erlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition...
February 15, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29444572/unraveling-the-role-of-a-flexible-tetradentate-ligand-in-the-aerobic-oxidative-carbon-carbon-bond-formation-with-palladium-complexes-a-computational-mechanistic-study
#10
Qian Peng, Zengwei Wang, Snezana D Zaric, Edward N Brothers, Michael B Hall
Mechanistic details of the aerobic oxidative coupling of methyl groups by a novel (MeL)PdII(Me)2 complex with the tetradentate ligand MeL = N,N-di-methyl-2,11-diaza[3.3](2,6)pyridinophane has been explored by density functional theory (DFT) calculations. The calculated mechanism sheds light on the role of this ligand's flexibility in several stages of the reaction, especially as the oxidation state of the Pd changes. Ligand flexibility leads to diverse axial coordination modes and it controls the availability of electrons by modulating the energies of high-lying molecular orbitals, particularly those with major dz2 character...
February 14, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29441566/aneustat-omn54-has-aerobic-glycolysis-inhibitory-activity-and-also-immunomodulatory-activity-as-indicated-by-a-first-generation-pdx-prostate-cancer-model
#11
Sifeng Qu, Hui Xue, Xin Dong, Dong Lin, Rebecca Wu, Noushin Nabavi, Colin C Collins, Martin E Gleave, Peter W Gout, Yuzhuo Wang
Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase-I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In the present study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer-generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune-related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells...
February 14, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29440294/in-vitro-and-in-vivo-activity-of-imgn853-an-antibody-drug-conjugate-targeting-folate-receptor-alpha-linked-to-dm4-in-biologically-aggressive-endometrial-cancers
#12
Gary Altwerger, Elena Bonazzoli, Stefania Bellone, Tomomi Egawa-Takata, Gulden Menderes, Francesca Pettinella, Anna Bianchi, Francesco Riccio, Jacqueline Feinberg, Luca Zammataro, Chanhee Han, Ghanshyam Yadav, Katherine Dugan, Ashley Morneault, Jose F Ponte, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Gloria S Huang, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR⍺) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR⍺ as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR⍺ was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR⍺...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29440177/ponatinib-shows-potent-antitumor-activity-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-sccoht-through-multi-kinase-inhibition
#13
Jessica D Lang, William P D Hendricks, Krystal A Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Nanyun Tang, Winnie S Liang, Megan Washington, Salvatore J Facista, Victoria L Zismann, Emily M Cousins, Michael B Major, Yemin Wang, Anthony N Karnezis, Aleksandar Sekulic, Ralf Hass, Barbara C Vanderhyden, Praveen Nair, Bernard E Weissman, David G Huntsman, Jeffrey M Trent
PURPOSE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. EXPERIMENTAL DESIGN: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib...
February 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29437792/mechanistic-exploration-of-cancer-stem-cell-marker-voltage-dependent-calcium-channel-%C3%AE-2%C3%AE-1-subunit-mediated-chemotherapy-resistance-in-small-cell-lung-cancer
#14
Jiangyong Yu, Shuhang Wang, Wei Zhao, Jianchun Duan, Zhijie Wang, Hanxiao Chen, Yanhua Tian, Di Wang, Jun Zhao, Tongtong An, Hua Bai, Meina Wu, Jie Wang
PURPOSE: Chemo-resistance in small cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSCs). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. The current study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemo-resistant SCLC, and explored the potential mechanisms of α2δ1-mediated chemo-resistance and strategies of overcoming the resistance. EXPERIMENTAL DESIGN: α2δ1 positive cells were identified and isolated from SCLC cell lines and patient derived xenografts (PDXs) models, and CSC-like properties were subsequently verified...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29435104/niclosamide-suppresses-acute-myeloid-leukemia-cell-proliferation-through-inhibition-of-creb-dependent-signaling-pathways
#15
Hee-Don Chae, Nick Cox, Gary V Dahl, Norman J Lacayo, Kara L Davis, Samanta Capolicchio, Mark Smith, Kathleen M Sakamoto
CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29433585/characterization-and-validation-of-potential-therapeutic-targets-based-on-the-molecular-signature-of-patient-derived-xenografts-in-gastric-cancer
#16
Zuhua Chen, Wenwen Huang, Tiantian Tian, Wanchun Zang, Jingyuan Wang, Zhentao Liu, Zhongwu Li, Yumei Lai, Zhi Jiang, Jing Gao, Lin Shen
BACKGROUND: Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC). METHODS: The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry...
February 13, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29433538/microrna-193a-stimulates-pancreatic-cancer-cell-repopulation-and-metastasis-through-modulating-tgf-%C3%AE-2-tgf-%C3%AE-riii-signalings
#17
Chi Fang, Chen-Yun Dai, Zhu Mei, Ming-Jie Jiang, Dian-Na Gu, Qian Huang, Ling Tian
BACKGROUND: Pancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells...
February 13, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29421556/self-indicating-fully-active-pharmaceutical-ingredients-nanoparticles-fapin-for-multimodal-imaging-guided-trimodality-cancer-therapy
#18
Xiangdong Xue, Yee Huang, Xinshuai Wang, Zhongling Wang, Randy P Carney, Xiaocen Li, Ye Yuan, Yixuan He, Tzu-Yin Lin, Yuanpei Li
Conventional drug delivery systems contain substantial amounts of excipients such as polymers and lipids, typically with low drug loading capacity and lack of intrinsic traceability and multifunctionality. Here, we report fully active pharmaceutical ingredient nanoparticles (FAPIN) which were self-assembled by minimal materials, but seamlessly orchestrated versatile theranostic functionalities including: i) self-delivery: no additional carriers were required, all components in the formulation are active pharmaceutical ingredients; ii) self-indicating: no additional imaging tags were needed...
February 3, 2018: Biomaterials
https://www.readbyqxmd.com/read/29408314/fibroblast-growth-factor-receptor-inhibition-induces-loss-of-matrix-mcl1-and-necrosis-in-cholangiocarcinoma
#19
Ayano Kabashima, Petra Hirsova, Steven F Bronk, Matthew C Hernandez, Mark J Truty, Sumera Rizvi, Scott H Kaufmann, Gregory J Gores
BACKGROUND & AIMS: Myeloid cell leukemia1 (MCL1), a prosurvival member of the BCL2 protein family, plays a pivotal role in human cholangiocarcinoma (CCA) cell survival. We have previously reported that fibroblast growth factor receptor (FGFR) signaling mediates MCL1-dependent survival of CCA cells in vitro and in vivo. However, the mode and mechanisms of cell death in this model were not delineated. METHODS: Human CCA cell lines were treated with the pan-FGFR inhibitor LY2874455 and the mode of cell death examined by several complementary assays...
February 2, 2018: Journal of Hepatology
https://www.readbyqxmd.com/read/29404392/utilizing-panels-of-patient-derived-xenografts-to-aid-the-development-of-antibody-drug-conjugates
#20
Scott David Collins, Carl Uli Bialucha, Juliet Anne Williams, Hui Gao
Despite numerous endeavors in clinical trials there are few clinically approved Antibody Drug Conjugate (ADC) therapies. Here we comment on our recent publication demonstrating the power of using panels of patient-derived xenografts (PDX) prior to Phase 1, to assess the potential heterogeneity of response a clinical candidate may show across a population. Furthermore we discuss how the same approach has been used in an additional ADC program.
2018: Molecular & Cellular Oncology
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