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Sara Bignulin, Edmondo Falleti, Sara Cmet, Dario Cappello, Annarosa Cussigh, Ilaria Lenisa, Denis Dissegna, Fabio Pugliese, Cinzia Vivarelli, Carlo Fabris, Pierluigi Toniutto
No abstract text is available yet for this article.
November 2016: Annals of Hepatology
Jane Antony, Tuan Zea Tan, Zoe Kelly, Jeffrey Low, Mahesh Choolani, Chiara Recchi, Hani Gabra, Jean Paul Thiery, Ruby Yun-Ju Huang
Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal ("Mes") subtype have a poorer prognosis than patients with tumors of an epithelial ("Epi") subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines...
October 4, 2016: Science Signaling
Leona Rohrbeck, Jia-Nan Gong, Erinna F Lee, Andrew J Kueh, Andreas Behren, Lin Tai, Guillaume Lessene, David C S Huang, Walter D Fairlie, Andreas Strasser, Marco J Herold
A large proportion of melanomas harbour the activating BRAF(V600E) mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAF(V600E) kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM...
September 30, 2016: Cell Death and Differentiation
Vino T Cheriyan, Magesh Muthu, Ketan Patel, Sreeja Sekhar, Walajapet Rajeswaran, Scott D Larsen, Lisa Polin, Edi Levi, Mandip Singh, Arun K Rishi
Doxorubicin and Cisplatin are the frontline therapeutics for treatment of the triple negative breast cancers (TNBCs). Emergence of drug-resistance often contributes to failure of drugs and poor prognosis, and thus necessitates development of new and improved modalities to treat TNBCs. We generated and characterized chemotherapy-resistant TNBC cells following their culture in chronic presence of Doxorubicin or Cisplatin, and tested whether their viabilities were inhibited by a novel class of CARP- 1 functional mimetic (CFM) compounds...
September 28, 2016: Oncotarget
Nele Van Der Steen, Christian Rolfo, Elisa Giovannetti, Pablo Reclusa, Godefridus J Peters, Patrick Pauwels
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
David Arguello, Andreas Voss, Zoran Gatalica, Ryan Bender
No abstract text is available yet for this article.
October 2016: Journal of Thoracic Oncology
Raffaella Castoldi, Jürgen Schanzer, Christian Panke, Ute Jucknischke, Natalie J Neubert, Rebecca Croasdale, Werner Scheuer, Johannes Auer, Christian Klein, Gerhard Niederfellner, Sebastian Kobold, Claudio Sustmann
Monoclonal antibody-based targeted tumor therapy has greatly improved treatment options for patients. Antibodies against oncogenic receptor tyrosine kinases (RTKs), especially the ErbB receptor family, are prominent examples. However, long-term efficacy of such antibodies is limited by resistance mechanisms. Tumor evasion by a priori or acquired activation of other kinases is often causative for this phenomenon. These findings led to an increasing number of combination approaches either within a protein family, e...
October 2016: Protein Engineering, Design & Selection: PEDS
I Dagogo-Jack, A T Shaw
In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
George Yaghmour, Philippe Prouet, Eric Wiedower, Omer Hassan Jamy, Rebecca Feldman, Jason C Chandler, Manjari Pandey, Mike G Martin
BACKGROUND: As we have previously reported, small cell carcinoma of the ovary (SCCO) is a rare, aggressive form of ovarian cancer associated with poor outcomes. In an effort to identify new treatment options, we utilized comprehensive genomic profiling to assess the potential for novel therapies in SCCO. METHODS: Patients with SCCO, SCCO-HT (hypercalcemic type), neuroendocrine tumors of the ovary (NET-O), and small cell carcinoma of the lung (SCLC) profiled by Caris Life Sciences between 2007-2015 were identified...
2016: Journal of Ovarian Research
Brett L Ecker, Laura Taylor, Paul J Zhang, Emma E Furth, Gregory G Ginsberg, Matthew T McMillan, Jashodeep Datta, Brian J Czerniecki, Robert E Roses
Overexpression of receptor tyrosine kinases (RTK), including members of the HER family, has prognostic and therapeutic significance in invasive esophagogastric carcinoma. RTK expression in premalignant gastroesophageal lesions has not been extensively explored. Formalin-fixed paraffin-embedded tissue samples of esophageal biopsy specimens from 73 patients with Barrett's esophagus with either low-grade dysplasia (LGD) (n = 32) or high-grade dysplasia (HGD) (n = 59) were analyzed for HER1, HER2, HER3 and CMET expression by immunohistochemistry (IHC)...
2016: PloS One
Seung-Min Park, Jae Young Lee, Soongweon Hong, Sang Hun Lee, Ivan K Dimov, Hojae Lee, Susie Suh, Qiong Pan, Keyu Li, Anna M Wu, Shannon M Mumenthaler, Parag Mallick, Luke P Lee
Recently, single-cell molecular analysis has been leveraged to achieve unprecedented levels of biological investigation. However, a lack of simple, high-throughput single-cell methods has hindered in-depth population-wide studies with single-cell resolution. We report a microwell-based cytometric method for simultaneous measurements of gene and protein expression dynamics in thousands of single cells. We quantified the regulatory effects of transcriptional and translational inhibitors on cMET mRNA and cMET protein in cell populations...
October 7, 2016: Lab on a Chip
Samuel Gonçalves-Ribeiro, Natalia Guillen Díaz-Maroto, Mireia Berdiel-Acer, Antonio Soriano, Jordi Guardiola, Mercedes Martínez-Villacampa, Ramon Salazar, Gabriel Capellà, Alberto Villanueva, Eva Martínez-Balibrea, David G Molleví
The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear. Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells...
August 8, 2016: Oncotarget
Jashdeep Bhattacharjee, Barun Das, Disha Sharma, Preeti Sahay, Kshama Jain, Alaknanda Mishra, Srikanth Iyer, Puja Nagpal, Vinod Scaria, Perumal Nagarajan, Prakash Khanduri, Asok Mukhopadhyay, Pramod Upadhyay
: : In view of the escalating need for autologous cell-based therapy for treatment of liver diseases, a novel candidate has been explored in the present study. The monocytes isolated from hepatitis B surface antigen (HBsAg) nucleic acid test (NAT)-positive (HNP) blood were differentiated to hepatocyte-like cells (NeoHep) in vitro by a two-step culture procedure. The excess neutrophils present in HNP blood were removed before setting up the culture. In the first step of culture, apoptotic cells were depleted and genes involved in hypoxia were induced, which was followed by the upregulation of genes involved in the c-MET signaling pathway in the second step...
July 28, 2016: Stem Cells Translational Medicine
Ping Zhang, Zhen-Fang Guo, Yu-Ming Xu, Yu-Sheng Li, Jing-Gui Song
N-Butylphthalide (NBP) has been known to have potential neuroprotective effects in Alzheimer's disease and stroke animal models. Hepatocyte-growth factor (HGF), with strong angiogenic properties, exerted protective role in brain injury. The present study was aimed to investigate the possible anti-inflammatory effects of NBP on the brain injury of rats with cerebral ischemia reperfusion (IR) and astrocytes activation induced by lipopolysaccharide (LPS) treatment. Our results showed that cerebral IR induced brain damage with down-regulation of HGF and astrocytes activation...
July 25, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
D-W Wu, T-C Chen, H-S Huang, H Lee
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show a clinical benefit when used to treat patients with EGFR-mutated non-small-cell lung cancer (NSCLC), but this treatment unfortunately fails in patients with TKI-resistant tumors. We here provide evidence that TC-N19 (N19), a novel dual inhibitor of EGFR and cMET, efficiently overcomes the EGFR-TKI resistance in EGFR-mutated NSCLC cells via simultaneous degradation of both proteins by ubiquitin proteasomes. Comparison with HSP90 inhibitor treatment and knockdown of EGFR and cMET by small hairpin RNAs reveal that the reduction of EGFR and cMET expression by N19 is responsible for overcoming the intrinsic TKI resistance mediated by paxillin (PXN) in high PXN-expressing cells, PXN-overexpressing PC9 cells (PC9-PXN), the EGFR-T790M-mediated TKI resistance in H1975 and CL97 cells, and the acquired resistance to gefitinib in gefitinib-resistant PC9 cells (PC9GR)...
2016: Cell Death & Disease
Brennan McCullar, Manjari Pandey, George Yaghmour, Felicia Hare, Kruti Patel, Matthew Stein, Rebecca Feldman, Jason C Chandler, Michael G Martin
Small cell carcinoma of the breast is a rare, aggressive form of breast cancer that is associated with extremely poor outcomes [1]. In an effort to identify possible targets for treatment, we utilized comprehensive genomic profiling in small cell carcinoma of the breast. Under an IRB approved protocol, we identified patients with small cell carcinoma of the breast and small cell carcinoma of the lung profiled by Caris Life Sciences between 2007 and 2015. Tumors were assessed with up to 25 immunohistochemical stains, in situ hybridization of cMET, EGFR, HER2, PIK3CA, and TOP2A, and next generation sequencing as well as Sanger sequencing of 47 genes...
July 2016: Breast Cancer Research and Treatment
Roop Ms Gill, Vedika Mehra, Emma Milford, Gurtej K Dhoot
The relative roles of SULF1 and SULF2 enzymes in tumour growth are controversial, but short SULF1/SULF2 splice variants predominate in human mammary tumours despite their non-detectable levels in normal mammary tissue. Compared with the normal, the level of receptor tyrosine kinase (RTK) activity was markedly increased in triple-positive mammary tumours during later stages of tumour progression showing increased p-EGFR, p-FGFR1 and p-cMet activity in triple-positive but not in triple-negative tumours. The abundance of catalytically inactive short SULF1/SULF2 variants permits high levels of HS sulphation and thus growth driving RTK cell signalling in primary mammary tumours...
October 2016: Histochemistry and Cell Biology
Prakash Narayan, Bin Duan, Kai Jiang, Jingsong Li, Latha Paka, Michael A Yamin, Scott L Friedman, Matthew R Weir, Itzhak D Goldberg
Ischemia-reperfusion-mediated acute kidney injury can necessitate renal replacement therapy and is a major cause of morbidity and mortality. We have identified BB3, a small molecule, which when first administered at 24 h after renal ischemia in rats, improved survival, augmented urine output, and reduced the increase in serum creatinine and blood urea nitrogen. Compared with control kidneys, the kidneys of BB3-treated animals exhibited reduced levels of kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and reduced tubular apoptosis and acute tubular necrosis but enhanced tubular regeneration...
August 1, 2016: American Journal of Physiology. Renal Physiology
Nele Van Der Steen, Elisa Giovannetti, Patrick Pauwels, Godefridus J Peters, David S Hong, Federico Cappuzzo, Fred R Hirsch, Christian Rolfo
The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials...
September 2016: Journal of Thoracic Oncology
Sheri L Moores, Mark L Chiu, Barbara S Bushey, Kristen Chevalier, Leopoldo Luistro, Keri Dorn, Randall J Brezski, Peter Haytko, Thomas Kelly, Sheng-Jiun Wu, Pauline L Martin, Joost Neijssen, Paul W H I Parren, Janine Schuurman, Ricardo M Attar, Sylvie Laquerre, Matthew V Lorenzi, G Mark Anderson
Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies...
July 1, 2016: Cancer Research
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