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Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

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https://www.readbyqxmd.com/read/30012567/metformin-inhibits-prostate-cancer-progression-by-targeting-tumor-associated-inflammatory-infiltration
#1
Qiuli Liu, Dali Tong, Gaolei Liu, Jie Gao, Lin-Ang Wang, Jing Xu, Xingxia Yang, Qiubo Xie, Yiqiang Huang, Jian Pang, Luofu Wang, Yong He, Dianzheng Zhang, Qiang Ma, Weihua Lan, Jun Jiang
PURPOSE: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer. EXPERIMENTAL DESIGN: By using TRAMP mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30012566/the-splicing-factor-ptbp1-promotes-expression-of-oncogenic-splice-variants-and-predicts-poor-prognosis-in-patients-with-non-muscle-invasive-bladder-cancer
#2
Pamela Bielli, Valentina Panzeri, Rossano Lattanzio, Simona Mutascio, Marco Pieraccioli, Elisabetta Volpe, Vincenzo Pagliarulo, Mauro Piantelli, Antonella Giannantoni, Savino M Di Stasi, Claudio Sette
PURPOSE: Non-muscle invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e. PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in NMIBC patients...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30012565/evolutionary-expression-of-her2-conferred-by-chromosome-aneuploidy-on-circulating-gastric-cancer-cells-contributes-to-developing-targeted-and-chemotherapeutic-resistance
#3
Yilin Li, Xiaotian Zhang, Dan Liu, Ji-Fang Gong, Daisy Dandan Wang, Shan Li, Zhi Peng, Yan Yan Li, Xiaojuan Wang, Peter P Lin, Min Li, Lin Shen
PURPOSE: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both HER2 phenotype and chromosome 8 aneuploidy on CTCs were co-examined in advanced gastric cancer (AGC) patients. EXPERIMENTAL DESIGN: Total of 115 AGC patients, including 56 of histo-pathological HER2+ (hHER2+ ) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2- patients who received chemotherapy alone, were prospectively enrolled...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30012564/activating-transcription-factor-4-modulates-tgf%C3%AE-induced-aggressiveness-in-triple-negative-breast-cancer-via-smad2-3-4-and-mtorc2-signaling
#4
Adrián González-González, Esperanza Muñoz-Muela, Juan A Marchal, Francisca Elvira Cara, Maria Pilar Molina, Marina Cruz-Lozano, Gema Jiménez, Akanksha Verma, Alberto Ramírez, Wei Qian, Wen Chen, Anthony J Kozielski, Olivier Elemento, M Dolores Martin-Salvago, Rafael Jesús Luque, Carmen Rosa-Garrido, David Landeira, María Quintana-Romero, Roberto R Rosato, María A García, César L Ramírez-Tortosa, Hanna Kim, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K Sood, José A Lorente, Pedro Sánchez-Rovira, Jenny C Chang, Sergio Granados-Principal
PURPOSE: Based on the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in triple negative breast cancer (TNBC) patients, but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on breast cancer patient survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30012563/phase-1-study-of-seviteronel-a-selective-cyp17-lyase-and-androgen-receptor-inhibitor-in-men-with-castration-resistant-prostate-cancer
#5
Shilpa Gupta, Luke T Nordquist, Mark T Fleming, William R Berry, Jingsong Zhang, Sharon L Ervin, Joel R Eisner, Edwina S Baskin-Bey, Neal D Shore
PURPOSE: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with anti-tumor activity in vitro and in vivo. This open-label phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics (PK) and activity of once daily (QD) seviteronel in male chemotherapy-naïve subjects with castrate-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: Seviteronel was administered at 600 mg QD with dose titration (DT) and in modified 3+3 dose escalation QD cohorts at 600 mg, 750 mg, and 900 mg without DT...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30012562/ifnl4-%C3%AE-g-allele-is-associated-with-an-interferon-signature-in-tumors-and-survival-of-african-american-men-with-prostate-cancer
#6
Wei Tang, Tiffany A Wallace, Ming Yi, Cristina Magi-Galluzzi, Tiffany H Dorsey, Olusegun O Onabajo, Adeola Obajemu, Symone V Jordan, Christopher A Loffredo, Robert M Stephens, Robert H Silverman, George R Stark, Eric A Klein, Ludmila Prokunina-Olsson, Stefan Ambs
PURPOSE: Men of African ancestry experience an excessive prostate cancer mortality that could be related to an aggressive tumor biology. We previously described an immune-inflammation signature in prostate tumors of African-American patients. Here, we further deconstructed this signature and investigated its relationships with tumor biology, survival, and a common germline variant in the interferon λ4 (IFNL4) gene. EXPERIMENTAL DESIGN: We analyzed gene expression in prostate tissue datasets and performed genotype and survival analyses...
July 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30006485/the-oncometabolite-d-2-hydroxyglutarate-is-an-intercellular-mediator-in-idh-mutant-gliomas-that-inhibits-both-complement-and-t-cells
#7
Lingjun Zhang, Mia Sorensen, Bjarne W Kristensen, Guido Reifenberger, Thomas M McIntyre, Feng Lin
PURPOSE: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of-function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2-hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment. D 2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied...
July 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30002079/advantages-and-adversities-of-the-weighted-toxicity-score
#8
Ulka Vaishampayan
It is imperative to develop a comprehensive toxicity score that will capture, convey and compare adverse events of agents that are therapeutic options for the same disease state. The weighted toxicity score tool is a valuable aid in the shared decision making process of therapeutic choice between patients and providers.
July 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29991503/immunotherapy-combinations-and-sequences-in-urothelial-cancer-facts-and-hopes
#9
Alejo Rodriguez-Vida, José Luis Pérez-Gracia, Joaquim Bellmunt
Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer (UC). Overall, these agents have shown objective response rates of around 20-23%, which indicates that a significant proportion of patient does not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement on the median duration of response compared to chemotherapy, still only half of the patients develop long-term maintained remissions...
July 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29986850/emerging-targeted-therapy-for-tumors-with-ntrk-fusion-proteins
#10
Ed S Kheder, David S Hong
The oncogenesis-promoting role of chromosomal rearrangements for several hematological and solid malignancies is well recognized. However, identifying targetable, actionable, and druggable chromosomal rearrangements remains a challenge. Targeting gene fusions and chromosomal rearrangements is an effective strategy in treating gene rearrangement-driven tumors. The NTRK (Neurotrophic Tyrosine Receptor Kinase) gene family encodes three tropomyosin-related kinase (TRK) receptors that preserve central and peripheral nervous system development and function...
July 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29980533/forestalling-braf-inhibitor-resistance-in-a-shocking-way
#11
Ryan J Sullivan
Targeting BRAF in BRAF-mutant melanoma is highly effective, but most patients develop resistance. Heat shock protein 90 (HSP90) has been implicated and identified as a therapeutic target. Ultimately, early stage clinical investigation will be necessary to provide proof-of-principle of this approach, and if appropriate randomized trials to confirm promising findings.
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29980532/functions-and-mechanisms-of-tumor-necrosis-factor-%C3%AE-and-noncoding-rnas-in-bone-invasive-pituitary-adenomas
#12
Haibo Zhu, Jing Guo, Yutao Shen, Wei Dong, Hua Gao, Yazhou Miao, Chuzhong Li, Yazhuo Zhang
Purpose-To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPAs). Experimental Design-A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including 5 BIPAs and 5 nonbone-invasive pituitary adenomas (NBIPAs). The targeted molecular markers were validated by qRT-PCR, immunohistochemistry, elisa and osteoclast differentiation. Results-Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR) and tumor regrowth...
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29980531/molecular-imaging-of-radiolabeled-bispecific-t-cell-engager-89zr-amg211-targeting-cea-positive-tumors
#13
Stijn J H Waaijer, Frank-Jan Warnders, Sabine K Stienen, Matthias Friedrich, Alexander Sternjak, Hung-Kam Cheung, Anton G T Terwisscha van Scheltinga, Carolina P Schröder, Elisabeth G de Vries, Marjolijn N Lub-de Hooge
BACKGROUND: AMG 211, a bispecific T‑cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T‑cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor targeting properties. EXPERIMENTAL DESIGN: 89Zr‑AMG211 was administered to mice bearing CEA‑positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA‑negative HL‑60 promyelocytic leukemia xenografts...
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29980530/ercc2-helicase-domain-mutations-confer-nucleotide-excision-repair-deficiency-and-drive-cisplatin-sensitivity-in-muscle-invasive-bladder-cancer
#14
Qiang Li, Alexis Damish, Zoe J Frazier, David Liu, Elizaveta Reznichenko, Atanas Kamburov, Andrew Bell, HuiYong Zhao, Emmet J Jordan, Sizhi P Gao, Jennifer Ma, Phillip H Abbosh, Joaquim Bellmunt, Elizabeth R Plimack, Jean-Bernard Lazaro, David B Solit, Dean F Bajorin, Jonathan E Rosenberg, Alan D D'Andrea, Nadeem Riaz, Eliezer M Van Allen, Gopa Iyer, Kent W Mouw
PURPOSE: DNA damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. EXPERIMENTAL DESIGN: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown...
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29980529/neoantigens-in-ovarian-cancer-embarrassment-of-riches-or-needles-in-a-haystack
#15
Iain A McNeish
Comprehensive genomic and transcriptomic analysis demonstrates that tumor-infiltrating T lymphocytes that react to mutated neo-epitopes could be identified in recurrent ovarian cancer. Two of these T cell populations reacted against TP53 hotspot missense mutations that are present in a wide variety of malignancies.
July 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29967253/high-throughput-functional-evaluation-of-variants-of-unknown-significance-in-erbb2
#16
Shinji Kohsaka, Masaaki Nagano, Toshihide Ueno, Shinya Kojima, Kanju Saka, Hirotaro Iwase, Masahito Kawazu, Hiroyuki Mano
PURPOSE: The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the ERBB2 mutations in a high-throughput manner. EXPERIMENTAL DESIGN: We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous ERBB2 mutations using the mixed-all-nominated-in-one (MANO) method...
July 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29967252/cd8-t-cell-density-imaging-with-64cu-labeled-cys-diabody-informs-immunotherapy-protocols
#17
Jai Woong Seo, Richard Tavaré, Lisa M Mahakian, Matthew T Silvestrini, Sarah Tam, Elizabeth S Ingham, Felix B Salazar, Alexander D Borowsky, Anna M Wu, Katherine W Ferrara
Noninvasive and quantitative tracking of CD8+ T-cells by positron emission tomography (PET) has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design Radiolabeling of an anti-CD8 cys-diabody (169cDb) with 64Cu was developed. The accumulation of 64Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains (n = 8 per group studied with imaging and immunohistochemistry or flow cytometry) after intravenous administration...
July 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29967251/oligosaccharyltransferase-inhibition-reduces-receptor-tyrosine-kinase-activation-and-enhances-glioma-radiosensitivity
#18
Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W Mark Saltzman, Joseph N Contessa
PURPOSE: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK) targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and post-translational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. EXPERIMENTAL DESIGN: We investigated the effects of a small molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1...
July 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29967250/dynamics-of-genome-alterations-in-crohn-s-disease-associated-colorectal-carcinogenesis
#19
Daniela Hirsch, Darawalee Wangsa, Yuelin J Zhu, Yue Hu, Daniel C Edelman, Paul S Meltzer, Kerstin Heselmeyer-Haddad, Claudia Ott, Peter Kienle, Christian Galata, Karoline Horisberger, Thomas Ried, Timo Gaiser
PURPOSE: Patients with inflammatory bowel diseases, i.e., ulcerative colitis (UC) and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from UC, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. However, the pathways involved in the evolution of CRC in CD patients are poorly characterized. EXPERIMENTAL DESIGN: Here, we analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions, by targeted next generation sequencing of 563 cancer-related genes and array-based comparative genomic hybridization...
July 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29967249/the-anti-cancer-activity-of-a-first-in-class-small-molecule-targeting-pcna
#20
Long Gu, Robert G Lingeman, Fumiko Yakushijin, Emily Sun, Qi Cui, Jianfei Chao, Weidong Hu, Hongzhi Li, Robert J Hickey, Jeremy M Stark, Yate-Ching Yuan, Yuan Chen, Steven L Vonderfecht, Timothy W Synold, Yanhong Shi, Karen L Reckamp, David Horne, Linda H Malkas
PURPOSE: Proliferating cell nuclear antigen (PCNA) plays an essential role in regulating DNA synthesis and repair and is indispensable to cancer cell growth and survival. We previously reported a novel cancer associated PCNA isoform (dubbed caPCNA), which was ubiquitously expressed in a broad range of cancer cells and tumor tissues, but not significantly in non-malignant cells. We found the L126-Y133 region of caPCNA is structurally altered and more accessible to protein-protein interaction...
July 2, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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