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patient-derived xenograft

Anna Kovalchuk, Yaroslav Ilnytskyy, Rocio Rodriguez-Juarez, Amanda Katz, David Sidransky, Bryan Kolb, Olga Kovalchuk
While the refinement of existing and the development of new chemotherapeutic regimens has significantly improved cancer treatment outcomes and patient survival, chemotherapy still causes many persistent side effects. Central nervous system (CNS) toxicity is of particular concern, as cancer patients experience significant deficits in memory, learning, cognition, and decision-making. These chemotherapy-induced cognitive changes are termed chemo brain, and manifest in more than half of cancer survivors. Moreover, recent studies have emerged suggesting that neurocognitive deficits manifest prior to cancer diagnosis and treatment, and thus may be associated with tumor presence, a phenomenon recently termed "tumor brain...
2018: Frontiers in Genetics
Jonathan Welti, Adam Sharp, Wei Yuan, David I Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C Francis, Ashley Hughes, Wendy S Halsey, Alec Paschalis, Ram S Mani, Ganesh V Raj, Steve Plymate, Suzanne Carreira, Gunther Boysen, Arul M Chinnaiyan, Amanda Swain, Johann S de Bono
PURPOSE:  Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. EXPERIMENTAL DESIGN:  We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Stephen Keysar, Justin Eagles, Bettina Miller, Brian C Jackson, Farshad N Chowdhury, Julie Reisinger, Tugs-Saikhan Chimed, Phuong N Le, J Jason Morton, Hilary Somerset, Marileila Varella-Garcia, Aik-Choon Tan, John I Song, Daniel W Bowles, Mary E Reyland, Antonio Jimeno
PURPOSE: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however current models are limited both in their availability and suitability to characterize these rare cells. EXPERIMENTAL DESIGN: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Cunzhen Shi, Xiangqun Li, Xiaogan Wang, Ning Ding, Lingyan Ping, Yunfei Shi, Lan Mi, Yumei Lai, Yuqin Song, Jun Zhu
BACKGROUND: Mantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4-5 years. Mer tyrosine kinase (MerTK) has been reported to be aberrantly expressed in leukemia, melanoma, and gastric cancer, and plays a pivotal role in the process of oncogenesis. This study assessed the role of MerTK in MCL for the first time. METHODS: Immunohistochemistry and western blot were performed to figure out expression of MerTK in MCL...
March 20, 2018: Journal of Hematology & Oncology
Hyojin Eom, Neha Kaushik, Ki-Chun Yoo, Jin-Kyoung Shim, Munjin Kwon, Mi-Young Choi, Taeyoung Yoon, Seok-Gu Kang, Su-Jae Lee
Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient's response to chemotherapeutics. In vitro and in vivo assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors in vivo...
March 19, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Michelle Faria, Samaneh Karami, Sergio Granados-Principal, Prasenjit Dey, Akanksha Verma, Dong S Choi, Olivier Elemento, Tasneem Bawa-Khalfe, Jenny C Chang, Anders M Strom, Jan-Åke Gustafsson
Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that two of the variants of ERβ, namely ERβ2 and ERβ5, control aggressiveness of TNBC by regulating hypoxic signaling through stabilization of HIF-1α. RNA-seq of patient derived xenografts (PDX) from TNBC shows expression of ERβ2, ERβ4 and ERβ5 variants in more than half of the samples...
February 23, 2018: Oncotarget
Gamze Bildik, Nazli Akin, Filiz Senbabaoglu, Yashar Esmalian, Gizem Nur Sahin, Defne Urman, Sercin Karahuseyinoglu, Umit Ince, Erhan Palaoglu, Cagatay Taskiran, Macit Arvas, Yilmaz Guzel, Kayhan Yakin, Ozgur Oktem
Granulosa cell tumor of the ovary (GCT) is a very rare tumor, accounting for only 2% of all ovarian tumors. It originates from sex cords in the ovary and can be divided into adult (95%) and juvenile (5%) types based on histologic findings. To date, no clear etiologic process has been identified other than a missense point mutation in the FOXL2 gene. Our previous works showed that c-Jun N-terminal kinase (JNK) pathway plays critical role in cell cycle progression and mitosis of normal and immortalized granulosa cells and follicle growth in rodent ovaries...
March 16, 2018: Cell Death & Disease
Ruiting Lin, Siyuan Xia, Changliang Shan, Dong Chen, Yijie Liu, Xue Gao, Mei Wang, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Michael Rossi, Ragini R Kudchadkar, David H Lawson, Fadlo R Khuri, Sagar Lonial, Jing Chen
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors...
March 15, 2018: Molecular Cell
Sen Xu, Zong-Yuan Yang, Ping Jin, Xin Yang, Xiaoting Li, Xiao Wei, Ya Wang, Sixiang Long, Taoran Zhang, Gang Chen, Chaoyang Sun, Ding Ma, Qinglei Gao
Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells...
March 15, 2018: Molecular Cancer Therapeutics
Jun Hao, Xinpei Ci, Hui Xue, Rebecca Wu, Xin Dong, Stephen Yiu Chuen Choi, Haiqing He, Yu Wang, Fang Zhang, Sifeng Qu, Fan Zhang, Anne M Haegert, Peter W Gout, Amina Zoubeidi, Colin Collins, Martin E Gleave, Dong Lin, Yuzhuo Wang
BACKGROUND: Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. OBJECTIVE: To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. DESIGN, SETTING, AND PARTICIPANTS: Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers...
March 12, 2018: European Urology
Nicholas Calvert, Jiansha Wu, Sophie Sneddon, Jennifer Woodhouse, Richard Carey-Smith, David Wood, Evan Ingley
Background: Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations. Methods: A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study...
2018: Clinical Sarcoma Research
Kei Kawaguchi, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Kentaro Miyake, Tasuku Kiyuna, Masuyo Miyake, Bartosz Chemielwski, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Arun S Singh, Mark A Eckardt, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3 , the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i...
February 16, 2018: Oncotarget
Antoneicka L Harris, Samantha E Lee, Louis K Dawson, Laura A Marlow, Brandy H Edenfield, William F Durham, Thomas J Flotte, Michael Thompson, Daniel L Small, Aidan J Synnott, Svetomir N Markovic, John A Copland
Patient-derived tumor xenograft (PDTX) mouse models were used to discover new therapies for naïve and drug resistant BRAF V600E -mutant melanoma. Tumor histology, oncogenic protein expression, and antitumor activity were comparable between patient and PDTX-matched models thereby validating PDTXs as predictive preclinical models of therapeutic response in patients. PDTX models responsive and non-responsive to BRAF/MEK standard of care (SOC) therapy were used to identify efficacious combination therapies. One such combination includes a CDK4/6 inhibitor that blocks cell cycle progression...
February 16, 2018: Oncotarget
Yukimasa Makita, Mika Teratani, Shumpei Murata, Yasutaka Hoashi, Satoru Matsumoto, Yuji Kawamata
It has been widely reported that patient-derived tumor xenografts (PDXs) are more similar to tumor tissues than conventional cancer cell lines. Kinetochore-associated protein 2 (KNTC2) is known to be upregulated specifically in tumor tissues of cancer patients and is recognized as a potential target for cancer therapy. Previously, in vivo antitumor activities of KNTC2 short interfering RNA encapsulated into a lipid nanoparticle (KNTC2-LNP) were reported in orthotopic hepatocellular carcinoma mouse models. However, it remains unclear whether KNTC2-LNP exhibits antitumor activities against lung cancer PDXs...
April 2018: Oncology Letters
Chunqing Dou, Mingming Han, Bao Zhang, Liyuan Sun, Xin Jin, Tao Li
Previous studies have indicated that chrysotoxene may be a potential drug used to treat tumors, however the effect of chrysotoxene on hepatoblastoma remains unknown. Therefore, the present study aimed to investigate the cytotoxic effect and elucidate the potential molecular mechanism of chrysotoxene on human hepatoblastoma HepG2 cells. Chrysotoxene (5-40 µg/ml) exhibited cytotoxic activity against HepG2 cells with inhibitory rates of 24.67-84.06% (half maximal inhibitory concentration, 19.64 µg/ml), observed from a Cell Counting Kit-8 assay...
April 2018: Oncology Letters
Guangzhong Xu, Kai Li, Nengwei Zhang, Bin Zhu, Guosheng Feng, Qing Fan
Colorectal cancer is a common malignancy with a high prevalence and associated mortality rate. However, the preclinical tools currently used for drug development are insufficient. The aim of the present study was to establish and characterize a specific patient-derived colon cancer xenograft (PDCCX) mouse model for drug testing. Primary colon tumors were obtained from 10 patients by surgical resection, and tumor tissues were subsequently grafted into nude mice followed by consecutive passages. Primary tumors and xenograft tumors were collected and processed for DNA sequencing, histological evaluation and immunohistochemical staining...
April 2018: Oncology Letters
Yousef Zakharia, Arup Bhattacharya, Youcef M Rustum
Selenium (Se)-containing molecules exert antioxidant properties and modulate targets associated with tumor growth, metastasis, angiogenesis, and drug resistance. Prevention clinical trials with low-dose supplementation of different types of Se molecules have yielded conflicting results. Utilizing several xenograft models, we earlier reported that the enhanced antitumor activity of various chemotherapeutic agents by selenomethione and Se-methylselenocysteine in several human tumor xenografts is highly dose- and schedule-dependent...
February 13, 2018: Oncotarget
Jiaolong Shi, Fengping Li, Xingxing Yao, Tingyu Mou, Zhijun Xu, Zheng Han, Siyu Chen, Wende Li, Jiang Yu, Xiaolong Qi, Hao Liu, Guoxin Li
Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo...
March 14, 2018: Oncogene
Deling Wang, Jia-Rui Li, Yu-Hang Zhang, Lei Chen, Tao Huang, Yu-Dong Cai
Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX) model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS), random forest (RF), and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors...
March 12, 2018: Genes
Tia H Turner, Mohammad A Alzubi, Sahib S Sohal, Amy L Olex, Mikhail G Dozmorov, J Chuck Harrell
PURPOSE: Basal-like breast cancers are aggressive and often metastasize to vital organs. Treatment is largely limited to chemotherapy. This study aims to characterize the efficacy of cancer therapeutics in vitro and in vivo within the primary tumor and metastatic setting, using patient-derived xenograft (PDX) models. METHODS: We employed two basal-like, triple-negative PDX models, WHIM2 and WHIM30. PDX cells, obtained from mammary tumors grown in mice, were treated with twelve cancer therapeutics to evaluate their cytotoxicity in vitro...
March 12, 2018: Breast Cancer Research and Treatment
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