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Cancer Research

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https://www.readbyqxmd.com/read/29222400/nkg2d-based-car-t-cells-and-radiotherapy-exert-synergistic-efficacy-in-glioblastoma
#1
Tobias Weiss, Michael Weller, Matthias Guckenberger, Charles L Sentman, Patrick Roth
Chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapy against several malignancies including glioblastoma, the most common and most aggressive malignant primary brain tumor in adults. The challenges in solid tumor immunotherapy comprise heterogenously expressed tumor target antigens and restricted trafficking of CAR T cells to and impaired long-term persistence at the tumor site, as well as the unaddressed integration of CAR T cell therapy into conventional anti-cancer treatments. We addressed these questions using a NKG2D-based chimeric antigen receptor construct (chNKG2D) in fully immunocompetent orthotopic glioblastoma mouse models...
December 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217764/radiotherapy-activated-cancer-associated-fibroblasts-promote-tumor-progression-through-paracrine-igf-1r-activation
#2
Joke Tommelein, Elly De Vlieghere, Laurine Verset, Elodie Melsens, Justine Leenders, Benedicte Descamps, Annelies Debucquoy, Christian Vanhove, Patrick Pauwels, Christian P Gespach, Anne Vral, Astrid De Boeck, Karin Haustermans, Pascal de Tullio, Wim Ceelen, Pieter Demetter, Tom Boterberg, Marc Bracke, Olivier De Wever
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer (RC), a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAF are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer (CRC) cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell cycle arrest, and secretion of paracrine mediators including insulin-like growth factor-1 (IGF-1)...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217763/improved-tumor-penetration-and-single-cell-targeting-of-antibody-drug-conjugates-increases-anticancer-efficacy-and-host-survival
#3
Cornelius Cilliers, Bruna Menezes, Ian Nessler, Jennifer Linderman, Greg Thurber
Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small molecule payload and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADC is poorly understood. Here we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, co-administration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared to T-DM1 alone...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217762/sirt6-is-a-target-of-regulation-by-ube3a-that-contributes-to-liver-tumorigenesis-in-an-anxa2-dependent-manner
#4
Saishruti Kohli, Abhishek Bhardwaj, Richa Kumari, Sanjeev Das
UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic function. Thus, UBE3A-mediated SIRT6 degradation promoted the proliferative capacity, migration potential and invasiveness of cells...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217761/aptamer-conjugated-extracellular-nanovesicles-for-targeted-drug-delivery
#5
Yuan Wan, Lixue Wang, Chuandong Zhu, Qin Zheng, Guoxiang Wang, Jinlong Tong, Yuan Fang, Yiqiu Xia, Gong Cheng, Xia He, Si-Yang Zheng
Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins and nucleic acids that contribute to intercellular communication. ENV have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes, however, neither approach has met clinical requirements...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29217760/tumor-associated-fatigue-in-cancer-patients-develops-independently-of-interleukin-1-signaling
#6
Aaron J Grossberg, Elisabeth G Vichaya, Diana L Christian, Jessica M Molkentine, Daniel W Vermeer, Phillip S Gross, Paola D Vermeer, John H Lee, Robert Dantzer
Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central pro-inflammatory cytokine, interleukin-1 (IL-1). The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity...
December 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212857/mutational-mechanisms-that-activate-wnt-signaling-and-predict-outcomes-in-colorectal-cancer-patients
#7
William C Hankey, Michael A McIlhatton, Kenechi Ebede, Brian Kennedy, Baris Hancioglu, Jie Zhang, Guy N Brock, Kun Huang, Joanna L Groden
APC biallelic loss-of-function mutations are the most prevalent genetic changes in colorectal tumors, but it is unknown whether these mutations phenocopy gain-of-function mutations in the CTNNB1 gene encoding ß-catenin that also activate canonical WNT signaling. Here we demonstrate that these two mutational mechanisms are not equivalent. Further, we show how differences in gene expression produced by these different mechanisms can stratify outcomes in more advanced human colorectal cancers. Gene expression profiling in Apc-mutant and Ctnnb1-mutant mouse colon adenomas identified candidate genes for subsequent evaluation of human TCGA data for colorectal cancer outcomes...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212856/tamoxifen-resistance-in-breast-cancer-is-regulated-by-the-ezh2-er%C3%AE-greb1-transcriptional-axis
#8
Yanming Wu, Zhao Zhang, Mauro E Cenciarini, Cecilia J Proietti, Matias F Amasino, Tao Hong, Mei Yang, Yiji Liao, Huai-Chin Chiang, Virginia Kaklamani, Rinath Jeselsohn, Ratna K Vadlamudi, Tim H-M Huang, Rong Li, Carmine De Angelis, Xiaoyong Fu, Patricia V Elizalde, Rachel Schiff, Myles Brown, Kexin Xu
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212855/t-cell-densities-in-brain-metastases-are-associated-with-patient-survival-times-and-diffusion-tensor-mri-changes
#9
Rasheed Zakaria, Angela Platt-Higgins, Nitika Rathi, Mark Radon, Sumit Das, Kumar Das, Maneesh Bhojak, Andrew Brodbelt, Emmanuel Chavredakis, Michael D Jenkinson, Philip S Rudland
Brain metastases are common and are usually detected by magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is a derivative MRI technique which can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain-tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity (MD) and fractional anisotropy (FA). The tissue samples were analysed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212854/a-systems-approach-to-prostate-cancer-classification-response
#10
LETTER
Sungyong You, Michael R Freeman
No abstract text is available yet for this article.
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212853/emergence-of-high-avidity-melan-a-specific-clonotypes-as-a-reflection-of-anti-pd-1-clinical-efficacy
#11
Sylvain Simon, Virginie Vignard, Emilie Varey, Tiphaine Parrot, Anne-Chantal Knol, Amir Khammari, Nadine Gervois, Francois Lang, Brigitte Dreno, Nathalie Labarriere
Therapeutic strategies using anti-PD-1-blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti-PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A-specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti-PD-1. We observed amplification of Melan-A-specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response...
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29212852/a-systems-approach-to-prostate-cancer-classification-letter
#12
LETTER
Elin Thysell, Erik Bovinder Ylitalo, Emma Jernberg, Anders Bergh, Pernilla Wikström
No abstract text is available yet for this article.
December 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/29208606/emerging-role-of-crispr-cas9-technology-for-micrornas-editing-in-cancer-research
#13
REVIEW
Guillermo Aquino-Jarquin
MicroRNAs (miRNA) are small, noncoding RNA molecules with a master role in the regulation of important tasks in different critical processes of cancer pathogenesis. Because there are different miRNAs implicated in all the stages of cancer, for example, functioning as oncogenes, this makes these small molecules suitable targets for cancer diagnosis and therapy. RNA-mediated interference has been one major approach for sequence-specific regulation of gene expression in eukaryotic organisms. Recently, the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system, first identified in bacteria and archaea as an adaptive immune response to invading genetic material, has been explored as a sequence-specific molecular tool for editing genomic sequences for basic research in life sciences and for therapeutic purposes...
December 5, 2017: Cancer Research
https://www.readbyqxmd.com/read/29191802/peripheral-neuropathy-induced-by-microtubule-targeted-chemotherapies-insights-into-acute-injury-and-long-term-recovery
#14
Krystyna M Wozniak, James J Vornov, Ying Wu, Ying Liu, Valentina A Carozzi, Virginia Rodriquez-Menendez, Elisa Ballarini, Paola Alberti, Eleonora Pozzi, Sara Semperboni, Brett M Cook, Bruce A Littlefield, Kenichi Nomoto, Krista Condon, Sean Eckley, Christopher DesJardins, Leslie Wilson, Mary Ann Jordan, Stuart C Feinstein, Guido Cavaletti, Michael Polydefkis, Barbara S Slusher
Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the anti-tubulin cancer drugs eribulin (ERIB), ixabepilone (IXA), paclitaxel (PACLI) or vinorelbine (VINO) at maximal tolerated doses...
November 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187407/modeling-the-subclonal-evolution-of-cancer-cell-populations
#15
Diego Chowell, James Napier, Rohan Gupta, Karen S Anderson, Carlo C Maley, Melissa A Wilson Sayres
Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1-4 dominant clones present at ≥10% frequency...
November 29, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187406/ptbp3-mediated-regulation-of-zeb1-mrna-stability-promotes-epithelial-mesenchymal-transition-in-breast-cancer
#16
Pingfu Hou, Lin Li, Fang Chen, Yansu Chen, Hui Liu, Jingjing Li, Jin Bai, Junnian Zheng
The RNA polypyrimidine tract binding protein PTBP3 is a little studied paralog of PTBP1 which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial-mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and enhance cell migration, invasion, and cancer stem-like cell properties...
November 29, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187405/her2-driven-breast-tumorigenesis-relies-upon-interactions-of-the-estrogen-receptor-with-coactivator-med1
#17
Yongguang Yang, Marissa Leonard, Yijuan Zhang, Dan Zhao, Mahmoud Charif, Shagufta Khan, Jiang Wang, Elyse Lower, Xiaoting Zhang
Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and impair tumor growth, metastasis and cancer stem-like cell formation in this model...
November 29, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187404/lsr-antibody-therapy-inhibits-ovarian-epithelial-tumor-growth-by-inhibiting-lipid-uptake
#18
Kosuke Hiramatsu, Satoshi Serada, Takayuki Enomoto, Yusuke Takahashi, Satoshi Nakagawa, Satoshi Nojima, Akiko Morimoto, Shinya Matsuzaki, Takuhei Yokoyama, Tsuyoshi Takahashi, Minoru Fujimoto, Hiroshi Takemori, Yutaka Ueda, Kiyoshi Yoshino, Eiichi Morii, Tadashi Kimura, Tetsuji Naka
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum...
November 29, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187403/photodynamic-priming-mitigates-chemotherapeutic-selection-pressures-and-improves-drug-delivery
#19
Huang-Chiao Huang, Imran Rizvi, Joyce Liu, Sriram Anbil, Ashish Kalra, Helen Lee, Yan Baglo, Nancy Paz, Douglas Hayden, Stephen P Pereira, Brian W Pogue, Jonathan B Fitzgerald, Tayyaba Hasan
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival...
November 29, 2017: Cancer Research
https://www.readbyqxmd.com/read/29187402/the-e3-ligase-ring1-targets-p53-for-degradation-and-promotes-cancer-cell-proliferation-and-survival
#20
Jiajia Shen, Pengyu Li, Xuejing Shao, Yang Yang, Xiu-Jun Liu, Min Feng, Qiang Yu, Ronggui Hu, Zhen Wang
As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation...
November 29, 2017: Cancer Research
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