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Jaeyun Jung, Kiwon Jang, Jung Min Ju, Eunji Lee, Jong Won Lee, Hee Jung Kim, Jisun Kim, Sae Byul Lee, Beom Seok Ko, Byung Ho Son, Hee Jin Lee, Gyungyup Gong, Sei Yeon Ahn, Jung Kyoon Choi, Shree Ram Singh, Suhwan Chang
Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors...
April 20, 2018: Cancer Letters
Robert-Guenther Goetze, Soeren M Buchholz, Shilpa Patil, Golo Petzold, Volker Ellenrieder, Elisabeth Hessmann, Albrecht Neesse
The LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) mouse model represents an established and frequently used transgenic model to evaluate novel therapies in pancreatic cancer. Tumor onset is variable in the KPC model between 8 weeks and several months. Therefore, non-invasive imaging tools are required to screen for tumor onset and monitor for response to treatment. To address this issue, different approaches have emerged over the last years. High resolution ultrasound has major advantages such as non-invasiveness, fast session times and a high image resolution without radiation exposure...
April 7, 2018: Journal of Visualized Experiments: JoVE
Xiangheng Chen, Zhonghai Guan, Jun Lu, Haohao Wang, Zhongkun Zuo, Fei Ye, Jiangsheng Huang, Lisong Teng
cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo ...
2018: Journal of Cancer
Lan V Pham, Shengjian Huang, Hui Zhang, Jun Zhang, Taylor Bell, Shouhao Zhou, Elizabeth Pogue, Zhiyong Ding, Laura Lam, Jason R Westin, R Eric Davis, Ken H Young, L Jeffrey Medeiros, Richard J Ford, Krystle Nomie, Liang Zhang, Michael Wang
PURPOSE: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL)...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Gorka Ruiz de Garibay, Francesca Mateo, Agostina Stradella, Rafael Valdés-Mas, Luis Palomero, Jordi Serra-Musach, Diana A Puente, Ander Díaz-Navarro, Gardenia Vargas-Parra, Eva Tornero, Idoia Morilla, Lourdes Farré, María Martinez-Iniesta, Carmen Herranz, Emmet McCormack, August Vidal, Anna Petit, Teresa Soler, Conxi Lázaro, Xose S Puente, Alberto Villanueva, Miguel Angel Pujana
Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify loss of transcription factor 4 (TCF4) associated with this process. A triple-negative BRCA1 -mutated PDX was used to study the genetics of chemoresistance...
April 13, 2018: Disease Models & Mechanisms
Zhiwei Hu, Rulong Shen, Amanda Campbell, Elizabeth L McMichael, Lianbo Yu, Bhuvaneswari Ramaswamy, Cheryl A London, Tian Xu, William E Carson
Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells and cancer stem cells in several types of solid cancers including breast cancer. Here we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors...
April 5, 2018: Cancer Immunology Research
Ke Gong, Gao Guo, David E Gerber, Boning Gao, Michael Peyton, Chun Huang, John D Minna, Kimmo J Hatanpaa, Kemp Kernstine, Ling Cai, Yang Xie, Hong Zhu, Farjana Fattah, Shanrong Zhang, Masaya Takahashi, Bipasha Mukherjee, Sandeep Burma, Jonathan Dowell, Kathryn Dao, Vassiliki A Papadimitrakopoulou, Victor Olivas, Trever G Bivona, Dawen Zhao, Amyn A Habib
Although aberrant Epidermal Growth Factor Receptor (EGFR) signaling is widespread in cancer, EGFR inhibition is effective only in a subset of NSCLC (non-small cell lung cancer) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. Tumor necrosis factor (TNF) is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21 resulting in decreased TNF mRNA stability...
April 3, 2018: Journal of Clinical Investigation
Jian Gao, Yue Yuan, Yuqing Chen
In this study, we observed the differentiation potential of human ADMSCs (hADMSCs) into functional islet-like cells and the therapeutic effect of hADMSCs transplantation in diabetic rats. Firstly, the PDX1 gene was transfected into hADMSCs by an adenovirus. Cell differentiation and insulin secretion were identified and detected by dithizone staining and ELISA, respectively. Twenty male Sprague-Dawley rats were randomly divided into control group (n=4), diabetes group (n=8) and transplantation group (n=8). Rats in the latter two groups were subjected to making diabetic models by 65 mg/kg streptozotocin injection...
April 2, 2018: Die Pharmazie
Kirstin A Zettlitz, Wen-Ting K Tsai, Scott M Knowles, Naoko Kobayashi, Timothy R Donahue, Robert E Reiter, Anna M Wu
Pancreatic cancer has a high mortality rate due to late diagnosis and the tendency to invade surrounding tissues and metastasize at an early stage. A molecular imaging agent that enables both pre-surgery antigen-specific positron emission tomography (immunoPET) and intra-operative near-infrared fluorescent (NIRF)-guidance could benefit diagnosis, staging and surgical resection of pancreatic cancer, which remains the only curative treatment. Methods: A dually labeled probe was developed based on A2 cys-diabody (A2cDb) targeting the cell surface antigen prostate stem cell antigen (PSCA) that is expressed in a majority of pancreatic cancers...
March 30, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Mathieu Meunier, Charles Dussiau, Natacha Mauz, Anne Sophie Alary, Christine Lefebvre, Gautier Szymanski, Mylène Pezet, Françoise Blanquet, Olivier Kosmider, Sophie Park
Myelodysplastic syndromes (MDS) are oligoclonal disorders of the hematopoietic stem cells (HSC). Recurrent gene mutations are involved in the MDS physiopathology along with the medullar microenvironment. To better study the heterogeneity of MDS, it is necessary to create patient derived xenograft (PDX). We have reproduced a PDX model by xenografting HSC (CD34+ ) and mesenchymal stromal cells (MSC) in NOD/SCID/IL2rγ-/- mice with primary samples from one RAEB2, two RAEB1 and one RARS patients harboring karyotype abnormalities and gene mutations...
March 13, 2018: Oncotarget
Philipp Manegold, Keane K Y Lai, Yongfeng Wu, Jia-Ling Teo, Heinz-Josef Lenz, Yuri S Genyk, Stephen J Pandol, Kaijin Wu, David P Lin, Yibu Chen, Cu Nguyen, Yi Zhao, Michael Kahn
BACKGROUND: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras , the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer...
March 29, 2018: Cancers
Yuting Ruan, Nie Lin, Qiang Ma, Rongping Chen, Zhen Zhang, Weiheng Wen, Hong Chen, Jia Sun
BACKGROUND/AIMS: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. METHODS: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients...
March 22, 2018: Cellular Physiology and Biochemistry
Danielle M Burgenske, David J Monsma, Jeffrey P MacKeigan
Preclinical compounds tested in animal models often demonstrate limited efficacy when transitioned into patients. As a result, individuals are assigned to treatment regimens that may be ineffective at treating their disease. The development of more clinically relevant models, such as patient-derived xenografts (PDXs), will (1) more completely mimic the human condition and (2) more accurately predict tumor responses to previously untested therapeutics.PDX models are clinically relevant as tumor tissue is implanted directly from human donor to the mouse recipient...
2018: Methods in Molecular Biology
Dan Zhou, Bonnie M Alver, Shuang Li, Ryan A Hlady, Joyce J Thompson, Mark A Schroeder, Jeong-Heon Lee, Jingxin Qiu, Philip H Schwartz, Jann N Sarkaria, Keith D Robertson
BACKGROUND: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. RESULTS: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome...
March 27, 2018: Genome Biology
Tae Woo Jung, Yoon Hee Chung, Hyoung-Chun Kim, A M Abd El-Aty, Ji Hoon Jeong
Several studies have demonstrated that protectins, which are ω-3 fatty acid-derived proresolution mediators, may ameliorate inflammation. Recently, protectin DX (PDX) was also reported to attenuate inflammation and insulin resistance in several cell types. However, the effects of PDX on inflammation in adipocytes remain unclear. In this study, we found that PDX treatment suppressed adipogenesis as well as lipid accumulation during 3T3-L1 differentiation. Treatment of differentiated 3T3-L1 cells with PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation in a dose-dependent manner...
March 27, 2018: American Journal of Physiology. Endocrinology and Metabolism
Anna Makowska, Lora Wahab, Till Braunschweig, Nikiforos-Ioannis Kapetanakis, Christian Vokuhl, Bernd Denecke, Lian Shen, Pierre Busson, Udo Kontny
The combination of neoadjuvant chemotherapy, radiochemotherapy, and maintenance therapy with interferon beta (IFNβ) has led to superior results in the treatment of children and adolescents with nasopharyngeal carcinoma (NPC). However, nothing is known about the mechanism of the antitumor activity of IFNβ in NPC. Here, we investigate the role of IFNβ on apoptosis in NPC cells. Six NPC cell lines, one patient-derived NPC xenograft (PDX) and one SV40-transformed nasoepithelial cell line were used. Induction of apoptosis by IFNβ was measured by flow cytometric analysis of subG1-DNA-content, Hoechst 33258 staining and activation of caspase-3...
March 6, 2018: Oncotarget
Simona Corso, Marilisa Cargnelutti, Stefania Durando, Silvia Menegon, Maria Apicella, Cristina Migliore, Tania Capeloa, Stefano Ughetto, Claudio Isella, Enzo Medico, Andrea Bertotti, Francesco Sassi, Ivana Sarotto, Laura Casorzo, Alberto Pisacane, Monica Mangioni, Antonino Sottile, Maurizio Degiuli, Uberto Fumagalli, Giovanni Sgroi, Sarah Molfino, Giovanni De Manzoni, Riccardo Rosati, Michele De Simone, Daniele Marrelli, Luca Saragoni, Stefano Rausei, Giovanni Pallabazzer, Franco Roviello, Paola Cassoni, Anna Sapino, Adam Bass, Silvia Giordano
Patient-Derived Xenografts (PDXs), entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer. More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV) positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas...
March 22, 2018: Neoplasia: An International Journal for Oncology Research
Tae Woo Jung, Eun Jung Kyung, Hyoung-Chun Kim, Yong Kyu Shin, Sung Hoon Lee, Eon Sub Park, Ahmet Hacimuftuoglu, A M Abd El-Aty, Ji Hoon Jeong
Docosahexaenoic acid (DHA) and its bioactive compounds may have suppressive effects on inflammation, endoplasmic reticulum (ER) stress, and insulin resistance. Protectin DX (PDX), a double lipoxygenase product from docosahexaenoic acid (DHA) has shown a suppressive effect on inflammation and insulin resistance. However, the effects of PDX on ER stress and hepatic steatosis have not been elucidated yet. Herein we have found that PDX could stimulate the AMP-activated protein kinase (AMPK) phosphorylation, thereby upregulating oxygen-regulated protein 150 (ORP150) expression in a dose-dependent manner...
March 23, 2018: Journal of Pharmacology and Experimental Therapeutics
Xiaojin Wu, Weitao Wang, Yuanyuan Chen, Xiangqun Liu, Jindong Wang, Xiaobin Qin, Dawei Yuan, Tao Yu, Guangxia Chen, Yanyan Mi, Jie Mou, Jinpeng Cui, Ankang Hu, Yunxiang E, Dongsheng Pei
Lung cancer has very high mortality and glycyrrhizin was found to significantly inhibit the growth of lung cancer cells in vitro and tissues in mice. However, the detailed inhibitory role of glycyrrhizin in the growth of lung cancer is still unclear. In this study, we first found that glycyrrhizin inhibited the growth of lung tumor in PDX mice. And high level of HMGB1 promoted the migration and invasion of lung cancer cells, which was suppressed by glycyrrhizin. Moreover, glycyrrhizin reduced the activity of JAK/STAT signaling pathway, which is the upstream regulator of HMGB1...
2018: BioMed Research International
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
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