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renal cancer model

Jiajia Dong, Olajide E Olaleye, Rongrong Jiang, Jing Li, Chuang Lu, Feifei Du, Fang Xu, Junling Yang, Fengqing Wang, Weiwei Jia, Chuan Li
BACKGROUND AND PURPOSE: Intravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated into the management of liver diseases in China. This investigation was designed to elucidate the molecular mechanism underlying hepatobiliary excretion of glycyrrhizin and to investigate its potential for drug-drug interactions on organic anion-transporting polypeptides (OATP)1B. EXPERIMENTAL APPROACH: Human hepatic transporters were characterized for glycyrrhizin at the cellular and vesicular levels and compared with rat hepatic transporters...
June 16, 2018: British Journal of Pharmacology
Chang Liu, Tatiana Shaurova, Suzanne Shoemaker, Martin Petkovich, Pamela A Hershberger, Yun Wu
Mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene drives the development of lung cancer. EGFR tyrosine kinase inhibitors (EGFR TKI) including erlotinib and afatinib are initially effective in treating EGFR mutant non-small cell lung cancer (NSCLC). However, drug resistance quickly develops due to several mechanisms, including induction of the epithelial-mesenchymal transition (EMT). No effective therapies are currently available for patients who develop EMT-associated EGFR TKI resistance...
June 14, 2018: Molecular Pharmaceutics
Rola M Saleeb, Mina Farag, Zsuzsanna Lichner, Fadi Brimo, Jenni Bartlett, Georg Bjarnason, Antonio Finelli, Fabio Rontondo, Michelle R Downes, George M Yousef
Papillary renal cell carcinoma (PRCC) is the most common non-clear cell RCCs and is known to comprise two histological subtypes. PRCC2 is more aggressive and is molecularly distinct from the other subtypes. Despite this PRCCs are treated together as one entity, and they show poor response to the current therapies that do not target pathways implicated in their pathogenesis. We have previously detected ABCC2 (an ABC transporter), VEGF and mTOR pathways to be enriched in PRCC2. In this study, we assess the therapeutic potential of targeting these pathways in PRCC2...
June 13, 2018: Molecular Oncology
Daniela Schmid, Charles E Matthews, Michael F Leitzmann
BACKGROUND: The relations of physical activity and sedentary behavior to mortality risk among patients with renal cell cancer have not yet been evaluated. METHODS: We conducted a prospective cohort study among 667 renal cell cancer survivors aged 50-71 years of the National Institutes of Health (NIH)-AARP Diet and Health Study with a median follow-up time of 7.1 years. Post-diagnosis physical activity, TV viewing, and total sitting time were assessed using self-administered questionnaires...
2018: PloS One
Benjamin Bouyer, Annie Rudnichi, Rosemary Dray-Spira, Mahmoud Zureik, Joël Coste
BACKGROUND: Post-operative venous thromboembolism (VTE) is a severe complication, the risk of which after lumbar spine surgery (LBS) is not precisely known. OBJECTIVE: To estimate the incidence of VTE after LBS and to identify individual and surgical risk factors. METHODS: All patients over the age of 18 years who underwent LBS in France between 2009 and 2014 were identified. Among 477,024 patients screened, exclusions concerned recent VTE or surgery and multiple surgeries during the same hospital stay...
June 12, 2018: Journal of Thrombosis and Haemostasis: JTH
Koji Yamasaki, Shoichiro Mukai, Satoru Sugie, Takahiro Nagai, Kozue Nakahara, Toyoharu Kamibeppu, Hiromasa Sakamoto, Noboru Shibasaki, Naoki Terada, Yoshinobu Toda, Hiroaki Kataoka, Toshiyuki Kamoto
MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis...
June 8, 2018: Cancers
John D Lyons, Ching-Wen Chen, Zhe Liang, Wenxiao Zhang, Deena B Chihade, Eileen M Burd, Alton B Farris, Mandy L Ford, Craig Coopersmith
Patients with cancer who develop sepsis have a markedly higher mortality than patients who were healthy prior to the onset of sepsis. Potential mechanisms underlying this difference have previously been examined in two preclinical models of cancer followed by sepsis. Both pancreatic cancer/pneumonia and lung cancer/cecal ligation and puncture (CLP) increase murine mortality, associated with alterations in lymphocyte apoptosis and intestinal integrity. However, pancreatic cancer/pneumonia decreases lymphocyte apoptosis and increases gut apoptosis while lung cancer/CLP increases lymphocyte apoptosis and decreases intestinal proliferation...
June 8, 2018: Shock
Tina T Thomas, Sahiti Chukkapalli, Raelene A Van Noord, Melanie Krook, Mark J Hoenerhoff, Jonathan R Dillman, Elizabeth R Lawlor, Valerie P Opipari, Erika A Newman
Preclinical testing of anticancer therapies relies on relevant xenograft models that mimic the innate tendencies of cancer. Advantages of standard subcutaneous flank models include procedural ease and the ability to monitor tumor progression and response without invasive imaging. Such models are often inconsistent in translational clinical trials and have limited biologically relevant characteristics with low proclivity to produce metastasis, as there is a lack of a native microenvironment. In comparison, orthotopic xenograft models at native tumor sites have been shown to mimic the tumor microenvironment and replicate important disease characteristics such as distant metastatic spread...
May 25, 2018: Journal of Visualized Experiments: JoVE
Rachel E Kosa, Sarah Lazzaro, Yi-An Bi, Brendan Tierney, Dana Gates, Sweta Modi, Chester Costales, A David Rodrigues, Larry M Tremaine, Manthena V Varma
We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP) and talinolol (P-gp) were obtained in cynomolgus monkey - alone or in combination with transporter inhibitors...
June 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Shreyas S Joshi, Elizabeth A Handorf, Matthew Zibelman, Elizabeth R Plimack, Robert G Uzzo, Alexander Kutikov, Marc C Smaldone, Daniel M Geynisman
BACKGROUND: Higher treatment facility (TF) volume has been linked with improved oncologic treatment outcomes. OBJECTIVE: To determine the association between TF volume and overall survival in patients with metastatic renal cell carcinoma (mRCC). DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Database (NCDB) was queried for all patients with mRCC with survival data available (2004-2013, cohort A). Overall survival was assessed based on TF volumes, and increasingly narrow inclusion criteria were used to confirm the cohort A association: cohort B=mRCC patients with active treatment; cohort C=mRCC patients with systemic therapy; cohort D=mRCC patients with systemic therapy at the reporting institution; and cohort E=mRCC patients with systemic therapy at the reporting institution with known liver and lung metastatic status...
June 4, 2018: European Urology
Paulo Rodrigues, Saroor A Patel, Louise Harewood, Ioana Olan, Erika Vojtasova, Saiful E Syafruddin, M Nazhif Zaini, Emma K Richardson, Johanna Burge, Anne Y Warren, Grant D Stewart, Kourosh Saeb-Parsy, Shamith A Samarajiwa, Sakari Vanharanta
Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples...
June 6, 2018: Cancer Discovery
Heike Miess, Beatrice Dankworth, Arvin M Gouw, Mathias Rosenfeldt, Werner Schmitz, Ming Jiang, Becky Saunders, Michael Howell, Julian Downward, Dean W Felsher, Barrie Peck, Almut Schulze
Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells...
June 5, 2018: Oncogene
Monika Gjorgjieva, Laure Monteillet, Julien Calderaro, Gilles Mithieux, Fabienne Rajas
Glycogen storage disease type I (GSDI) is a rare genetic pathology characterized by glucose-6 phosphatase (G6Pase) deficiency, translating in hypoglycemia during short fasts. Besides metabolic perturbations, GSDI patients develop long-term complications, especially chronic kidney disease (CKD). In GSDI patients, CKD is characterized by an accumulation of glycogen and lipids in kidneys, leading to a gradual decline in renal function. At a molecular level, the activation of the renin-angiotensin system is responsible for the development of renal fibrosis, eventually leading to renal failure...
June 4, 2018: Journal of Inherited Metabolic Disease
Arnaud Méjean, Alain Ravaud, Simon Thezenas, Sandra Colas, Jean-Baptiste Beauval, Karim Bensalah, Lionnel Geoffrois, Antoine Thiery-Vuillemin, Luc Cormier, Hervé Lang, Laurent Guy, Gwenaelle Gravis, Frederic Rolland, Claude Linassier, Eric Lechevallier, Christian Beisland, Michael Aitchison, Stephane Oudard, Jean-Jacques Patard, Christine Theodore, Christine Chevreau, Brigitte Laguerre, Jacques Hubert, Marine Gross-Goupil, Jean-Christophe Bernhard, Laurence Albiges, Marc-Olivier Timsit, Thierry Lebret, Bernard Escudier
Background Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. Methods In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone...
June 3, 2018: New England Journal of Medicine
Solange Moll, Yukari Yasui, Ahmed Abed, Takeshi Murata, Hideaki Shimada, Akira Maeda, Naoshi Fukushima, Masakazu Kanamori, Sabine Uhles, Laura Badi, Thomas Cagarelli, Ivan Formentini, Faye Drawnel, Guy Georges, Tobias Bergauer, Rodolfo Gasser, R Daniel Bonfil, Rafael Fridman, Hans Richter, Juergen Funk, Marcus J Moeller, Christos Chatziantoniou, Marco Prunotto
BACKGROUND: Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase extensively implicated in diseases such as cancer, atherosclerosis and fibrosis. Multiple preclinical studies, performed using either a gene deletion or a gene silencing approaches, have shown this receptor being a major driver target of fibrosis and glomerulosclerosis. METHODS: The present study investigated the role and relevance of DDR1 in human crescentic glomerulonephritis (GN)...
June 1, 2018: Journal of Translational Medicine
Yunchuan Kong, Tianwei Yu
Motivation: Gene expression data represents a unique challenge in predictive model building, because of the small number of samples (n) compared to the huge amount of features (p). This "n = p" property has hampered application of deep learning techniques for disease outcome classification. Sparse learning by incorporating external gene network information could be a potential solution to this issue. Still, the problem is very challenging because (1) there are tens of thousands of features and only hundreds of training samples, (2) the scale-free structure of the gene network is unfriendly to the setup of convolutional neural networks...
May 29, 2018: Bioinformatics
J Godlewski, J Kiezun, B E Krazinski, Z Kozielec, P M Wierzbicki, Z Kmiec
The aim of the study was to determine by immunohistochemistry cellular localization and immunoreactivity levels of YAP1 and LATS1 proteins in paired sections of tumor and unchanged renal tissues of 54 clear cell renal cell carcinoma (ccRCC) patients. Associations between clinical-pathological and overall survival (OS; median follow-up was 40.6 months) data of patients and YAP1 and LATS1 immunoreactivity were analyzed by uni- and multivariate Cox regression model and log-rank test. YAP1 immunoreactivity was found in the nuclei of tumor cells in 64...
2018: BioMed Research International
Seung Un Seo, Seon Min Woo, Hyun-Shik Lee, Sang Hyun Kim, Kyoung-Jin Min, Taeg Kyu Kwon
mTOR is an important regulator of cell growth and forms two complexes, mTORC1/2. In cancer, mTOR signaling is highly activated, and the regulation of this signaling, as an anti-cancer strategy, has been emphasized. However, PP242 (inhibitor of mTORC1 and mTORC2) alone did not induce human renal carcinoma cell death. In this study, we found that PP242 alone did not alter cell viability, but combined curcumin and PP242 treatment induced cell death. Combined PP242 and curcumin treatment induced Bax activation and decreased expression of Mcl-1 and Bcl-2...
May 30, 2018: Oncogene
Makoto Isono, Akinori Sato, Takako Asano, Kazuki Okubo, Tomohiko Asano
BACKGROUND/AIM: To investigate the efficacy against renal cancer cells of combining the HIV protease inhibitor ritonavir with the novel proteasome inhibitor delanzomib. MATERIALS AND METHODS: Renal cancer cell lines 769-P, 786-O, Caki-2 and Renca were treated with ritonavir and delanzomib in vitro and in vivo, and the efficacy of combination was evaluated. RESULTS: The combination of ritonavir and delanzomib synergistically inhibited renal cancer growth and suppressed colony formation...
June 2018: Anticancer Research
Xiao-Fei Ding, Jun Zhou, Guang Chen, Ying-Liang Wu
The majority of molecular targets of anticancer agents are limited to a subset of patients, and therefore identification of more specific biomarkers that can be used to improve clinical outcomes is of increasing interest. The present study showed that von Hippel‑Lindau tumor suppressor (VHL) tumor‑suppressor activity may influence the therapeutic response to Aurora kinase A (AURKA) inhibitors in human renal cell carcinoma (RCC). VHL protein (pVHL) expression was evaluated by immunoblotting in the human RCC cell lines CAKI, ACHN, 786‑O, 769‑P and A498...
May 17, 2018: Molecular Medicine Reports
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