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Yo Sasaki, Amber R Hackett, Sungsu Kim, Amy Strickland, Jeffrey Milbrandt
The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD+ ) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD+ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD+ biosynthesis, specifically in SCs...
June 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Qian-Ru Zhao, Jun-Mei Lu, Zhao-Yang Li, Yan-Ai Mei
Neuritin is a neurotrophic factor that is activated by neural activity and neurotrophins. Its major function is to promote neurite growth and branching; however, the underlying mechanisms are not fully understood. To address this issue, the present study investigated the effects of neuritin on neurite and spine growth and intracellular Ca2+ concentration in rat cerebellar granule neurons (CGNs). Incubation of CGNs for 24 h with neuritin increased neurite length and spine density; this effect was mimicked by insulin and abolished by inhibiting insulin receptor (IR) or mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) activity...
June 19, 2018: Journal of Neurochemistry
Guo-Jin Wu, Jun Pen, Ying Huang, Su An, Ying Liu, Yang Yang, Qian Hao, Xiao-Xi Guo, Tian-Rui Xu
Aberrant activation of the Raf-MEK-ERK pathway has frequently been associated with various cancers, especially lung cancer. However, the key regulators of this pathway are largely unknown. Using functional proteomics screening, we found that KAP1 interacts with c-Raf. Knocking out KAP1 decreased c-Raf phosphorylation at serine 259 and increased its phosphorylation at serine 338, which activated MEK and ERK. We detected higher KAP1 expression in lung cancer tissues than in normal peri-tumoral tissues. KAP1 knockdown arrested A549 lung cancer cells in the G0/G1 phase of the cell cycle and attenuated cell growth, metastasis, the epithelial-mesenchymal transition, angiogenesis, stemness, and colony formation...
June 19, 2018: Molecular Carcinogenesis
Yuanyuan Wang, Xiangde Lin, Xinghao Fu, Wei Yan, Fusheng Lin, Penghao Kuang, Yezhe Luo, Ende Lin, Xiaoquan Hong, Guoyang Wu
Thyroid cancer is one of the most common malignant tumors of the endocrine system. Among all thyroid cancers, papillary thyroid carcinoma (PTC) is the most common type. The BRAF-activated non-coding RNA (BANCR) is a 693-bp nucleotide transcript which was first identified in melanoma. However, the role of BANCR in the development of thyroid cancer remains unclear. Therefore, the present study investigated the potential involvement of BANCR in the development of thyroid cancer in vitro using patient tissue samples and a panel of thyroid cancer cell lines, and in vivo using a xenograft mouse model...
June 18, 2018: Oncology Reports
Asunción Díaz-Serrano, Pablo Gella, Elisabeth Jiménez, Jon Zugazagoitia, Luis Paz-Ares Rodríguez
Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile...
June 18, 2018: Drugs
Nicholas Dompe, Christiaan Klijn, Sara A Watson, Katherine Leng, Jenna Port, Trinna Cuellar, Colin Watanabe, Benjamin Haley, Richard Neve, Marie Evangelista, David Stokoe
Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies...
2018: PloS One
Cuiping Li, Weiyi Lai, Hailin Wang
Embryonic stem (ES) cells have the potential to differentiate into any of the three germ layers (endoderm, mesoderm, or ectoderm), and can generate many lineages for regenerative medicine. ES cell culture in vitro has long been the subject of widespread concerns. Classically, mouse ES cells are maintained in serum and leukemia inhibitory factor (LIF)-containing medium. However, under serum/LIF conditions, cells show heterogeneity in morphology and the expression profile of pluripotency-related genes, and are mostly in a metastable state...
June 1, 2018: Journal of Visualized Experiments: JoVE
Jessie Peh, Matthew W Boudreau, Hannah M Smith, Paul J Hergenrother
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL)...
May 18, 2018: Cell Chemical Biology
Fatemeh Vahedi, Amanda J Lee, Susan E Collins, Marianne V Chew, Evan Lusty, Branson Chen, Anisha Dubey, Carl D Richards, Jordan J Feld, Rodney S Russell, Karen L Mossman, Ali A Ashkar
Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7...
June 13, 2018: Cytokine
Shuai Li, Wenbin Hua, Kun Wang, Yong Gao, Songfeng Chen, Wei Liu, Yu Song, Xinghuo Wu, Ji Tu, Liang Kang, Kangcheng Zhao, Liming Xiong, Yukun Zhang, Cao Yang
Autophagy dysfunction has been observed in intervertebral disc degeneration (IVDD) cells, a main contributing factor to cell death, but the precise role of autophagy during IVDD is still controversial. This study aimed to investigate the role of autophagy involved in the pathogenesis of human IVDD and determine the signal transduction pathways responsible for compression-induced autophagy in human nucleus pulposus (NP) cells. Autophagy, suppressing the induction of apoptosis, was activated in NP cells exposed to compression...
June 13, 2018: Experimental Cell Research
Laura Hüser, Sachindra, Karol Granados, Aniello Federico, Lionel Larribère, Daniel Novak, Viktor Umansky, Peter Altevogt, Jochen Utikal
Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs)...
June 15, 2018: International Journal of Cancer. Journal International du Cancer
Christin Bruchhagen, Marcel Jarick, Carolin Mewis, Tobias Hertlein, Silke Niemann, Knut Ohlsen, Georg Peters, Oliver Planz, Stephan Ludwig, Christina Ehrhardt
Influenza virus (IV) infections cause severe respiratory illnesses that can be complicated by bacterial super-infections. Previously, we identified the cellular Raf-MEK-ERK cascade as a promising antiviral target. Inhibitors of MEK, such as CI-1040, showed potent antiviral activity. However, it remained unclear if this inhibitor and its active form, ATR-002, might sensitize host cells to either IV or secondary bacterial infections. To address these questions, we studied the anti-pathogen activity of ATR-002 in comparison to CI-1040, particularly, its impact on Staphylococcus aureus (S...
June 14, 2018: Scientific Reports
Matthew Dankner, Mathieu Lajoie, Dan Moldoveanu, Tan-Trieu Nguyen, Paul Savage, Shivshankari Rajkumar, Xiu Huang, Maria Lvova, Alexei Protopopov, Dana Vuzman, David Hogg, Morag Park, Marie-Christine Guiot, Kevin Petrecca, Catalin Mihalcioiu, Ian R Watson, Peter M Siegel, April A N Rose
PURPOSE: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. EXPERIMENTAL DESIGN: Tumors from patients with BRAF WT, V600E (class I) and L597S (class II) metastatic melanoma were used to generate patient-derived-xenografts (PDX)...
June 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Guanhua Rao, In-Kyu Kim, Fabio Conforti, Jing Liu, Yu-Wen Zhang, Giuseppe Giaccone
PURPOSE: Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers. EXPERIMENTAL DESIGN: Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels...
June 11, 2018: European Journal of Cancer
Kazutaka Hosoda, Minako Motoishi, Takuya Kunimoto, Osamu Nishimura, Byulnim Hwang, Sumire Kobayashi, Shigenobu Yazawa, Makoto Mochii, Kiyokazu Agata, Yoshihiko Umesono
Planarians have established a unique body pattern along the anterior-posterior (AP) axis, which consists of at least four distinct body regions arranged in an anterior to posterior sequence: head, prepharyngeal, pharyngeal (containing a pharynx), and tail regions, and possess high regenerative ability. How they reconstruct the regional continuity in a head-to-tail sequence after amputation still remains unknown. We use as a model planarian Dugesia japonica head regeneration from tail fragments, which involves dynamic rearrangement of the body regionality of preexisting tail tissues along the AP axis, and show here that RNA interference of the gene D...
June 13, 2018: Development, Growth & Differentiation
Ashutosh Rai, B D Radotra, K K Mukherjee, S K Gupta, Pinaki Dutta
Here we describe data of a comprehensive phosphoproteomic evaluation of 20 non-functioning pituitary adenomas (NFPAs). Peptides from 20 tumor samples were enriched with TiO2 beads and fractioned using bRPLC and subjected to high throughput LC-MS/MS-Orbitrap Fusion™ Tribrid™ Mass Spectrometer for analysis. Upto 5 precursor ions were selected for MS/MS analysis. Data was analyzed using MASCOT and SEQUEST. Bioinformatics tools Phosphosite Plus, Gene Ontology, DAVID, and KEGG were used to determine the biological significance of identified phosphoproteins...
June 2018: Data in Brief
Katharina C Kähler, Christine Blome, Andrea Forschner, Ralf Gutzmer, Axel Hauschild, Lucie Heinzerling, Elisabeth Livingstone, Carmen Loquai, Tina Müller-Brenne, Dirk Schadendorf, Jochen Utikal, Tobias Wagner, Matthias Augustin
After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1...
May 25, 2018: Oncotarget
Ashley B Ward, Hina Mir, Neeraj Kapur, Dominique N Gales, Patrick P Carriere, Shailesh Singh
BACKGROUND: Despite recent advances in diagnosis and treatment, prostate cancer (PCa) remains the leading cause of cancer-related deaths in men. Current treatments offered in the clinics are often toxic and have severe side effects. Hence, to treat and manage PCa, new agents with fewer side effects or having potential to reduce side effects of conventional therapy are needed. In this study, we show anti-cancer effects of quercetin, an abundant bioflavonoid commonly used to treat prostatitis, and defined quercetin-induced cellular and molecular changes leading to PCa cell death...
June 14, 2018: World Journal of Surgical Oncology
Seul-Ki Cheon, Hwang-Phill Kim, Ye-Lim Park, Jee-Eun Jang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim
Although MEK blockade has been highlighted as a promising anti-tumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK...
June 13, 2018: Molecular Oncology
Farzad Nezhdbahadori, Mohamad Ali Abdoli, Majid Baghdadi, Fereydoun Ghazban
Oily sludge is a stable emulsion of water in oil, containing solid particles, oily hydrocarbons, and metals with different compositions, which is greatly hazardous to the environment; as a consequence, they must be removed or recovered. Recovery methods are usually preferable because of the possibility of valuable oily hydrocarbons recovery as well as environmental protection. Liquid extraction is one of the most effective methods of oily sludge recovery. In this research, hydrocarbon recoveries from oily sludge using liquid extraction with methyl ethyl ketone (MEK) and toluene as polar and non-polar solvents have been studied and compared to each other...
June 11, 2018: Environmental Monitoring and Assessment
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