bluuebunny/crossref_metadata_2025_split huggingface dataset:
Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway
Authors: Sun Xuerong , Shi Benyan , Zheng Huiling , Min Ling , Yang Jie , Li Xiaoyi , Liao Xiaoxin , Huang Weixing , Zhang Mingmeng , Xu Shun , Zhu Zhe , Cui Hongjing , Liu Xinguang 
Published: February 2018

AbstractAlthough targeted therapy and immunotherapy greatly improve the outcome of melanoma, drug resistance and low response rates still maintain the unsubstitutability of traditional chemotherapy. Cisplatin (CDDP) is widely used in different types of tumours with high response rates, but it generally has low efficiency in melanoma. The mechanisms underpinning the phenomena are not sufficiently understood. Here we demonstrated that various melanoma cell lines adopted senescence phenotype after CDDP treatment in contrast to the other types of tumour cells. CDDP treatment induced melanoma A375 cells into senescence through the sequential activation of the DNA damage response and the P53/P21 pathway. All the senescent melanoma cells induced by CDDP alone or the combination of CDDP and dacarbazine developed robust senescence-associated secretory phenotype (SASP), that is, the secretion of multiple cytokines. IL-1α was an early component and an upstream regulator of SASP. Similarly, CDDP either alone or combined with dacarbazine could induce melanoma cell senescence and SASP in either A375 or B16F10 melanoma xenograft mice. The supernatant of senescent A375 cells promoted the growth of normal non-senescent A375 cells and enhanced their expression and secretion of IL-8 through the activation of the ERK1/2-RSK1 pathway. The transplantation of non-senescent and senescent A375 cells together into nude mice showed accelerated tumour growth compared with transplanting non-senescent cells alone; no tumours developed when transplanting senescent cells alone. Following CDDP administration in A375-bearing mice, the intratumour injection of neutralisation antibodies targeting the SASP factors IL-1α or IL-8 evidently delayed tumour growth. The results suggest that the CDDP-induced senescent melanoma cells promote non-senescent cells proliferation through the activation of ERK1/2-RSK1 pathway by the SASP factors. Cell senescence and concomitant SASP may be the particular mechanisms for melanoma to resist chemotherapeutics.
CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis
Authors: Sun Huaqin , Wang Yan , Zhang Jieting , Chen Yan , Liu Yanyan , Lin Ziyuan , Liu Mingfeng , Sheng Kai , Liao Huijuan , Tsang Kam Sze , Zhang Xiaohu , Jiang Xiaohua , Xu Wenming , Mao Meng , Chan Hsiao Chang 
Published: February 2018

AbstractMutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) with a multitude of clinical manifestations. Some CF patients develop clinically significant anemia, suggesting that CFTR may regulate hematopoiesis. Here, we report that cftr mutant zebrafish model exhibits primitive and definitive hematopoietic defects with impaired Wnt signaling. Cftr is found to interact, via its PDZ-binding domain (PDZBD), with Dishevelled (Dvl), a key component of Wnt signaling required for hematopoietic progenitor specification, thus protecting Dvl from Dapper1 (Dpr1)-induced lysosomal degradation. Defective hematopoiesis and impaired Wnt signaling in cftr mutant can be rescued by overexpression of wild-type or channel function-defective G551D mutant CFTR with an intact PDZBD, but not Cftr with mutations in the PDZBD. Analysis of human database (http://r2.amc.nl) shows that CFTR is positively correlated with DVL2 and Wnt-related hematopoietic factors in human blood system. The results reveal a previously unrecognized role of CFTR, which is independent of its channel function, in regulating DVL degradation and thus Wnt signaling required for hematopoiesis in both zebrafish and humans, providing an explanation for the anemic phenotype of CF patients.
Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth
Authors: Xu Linfeng , Meng Xiaoxiao , Xu Naihan , Fu Wenwei , Tan Hongsheng , Zhang Li , Zhou Qianjun , Qian Jianan , Tu Shiwei , Li Xueting , Lao Yuanzhi , Xu Hongxi 
Published: February 2018

AbstractErlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition. In this study, we investigated the mechanism of action of GNA in erlotinib-resistant NSCLC and patient-derived cells. The inhibition of GNA on FGFR signaling pathway was examined using biochemical kinase assays. NSCLC cell lines (HCC827, HCC827-Erlotinib-resistant, and H1650) and primary cells from patients with NSCLC with clinical resistance to erlotinib were treated with GNA, erlotinib, or their combination. Both kinase assays and cell- based assays showed that GNA inhibits the phosphorylation of multiple kinases in FGFR signaling pathway in NSCLC. The combination of GNA and erlotinib significantly attenuates the tumor growth of HCC827 and erlotinib-resistant HCC827 xenografts with low toxicity. Importantly, GNA significantly suppresses tumor growth in a lung patient-derived xenograft (PDX) model with FGFR fusion and low EGFR expression. Our findings provide preclinical evidence for using GNA as an FGFR signaling pathway inhibitor to overcome erlotinib resistance in NSCLC treatment or to enhance erlotinib efficacy when used as a combined administration.
PEAK1, acting as a tumor promoter in colorectal cancer, is regulated by the EGFR/KRas signaling axis and miR-181d
Authors: Huang Lanlan , Wen Chuangyu , Yang Xiangling , Lou Qiong , Wang Xiaoyan , Che Jia , Chen Junxiong , Yang Zihuan , Wu Xiaojian , Huang Meijin , Lan Ping , Wang Lei , Iwamoto Aikichi , Wang Jianping , Liu Huanliang 
Published: February 2018

AbstractPEAK1 is upregulated in multiple human malignancies and has been associated with tumor invasion and metastasis, but little is known about the role of PEAK1 in colorectal cancer (CRC) progression. We investigated the expression pattern, function and regulatory mechanisms of PEAK1 in CRC. Here, we found that PEAK1 is overexpressed in CRC tissues and that high PEAK1 expression predicts poor survival in colon cancer but not rectal cancer. Functionally, silencing PEAK1 inhibits cell proliferation, migration, and invasion in vitro and inhibits the growth of tumor xenografts in nude mice. Mechanistic studies revealed that PEAK1 is induced by epidermal growth factor receptor (EGFR) signaling and that PEAK1 is required for KRas-induced CRC cell growth and metastasis. Furthermore, we demonstrated that miR-181d directly targets PEAK1. Ectopic expression of miR-181d reduces the expression of PEAK1 and inhibits the growth and metastasis of CRC cells in vitro. Clinically, miR-181d is downregulated in CRC samples, and low miR-181d is correlated with poor patient survival. Our study demonstrates the importance of PEAK1 in CRC progression and suggests a potential mechanism by which increasing PEAK1 expression in CRC might be the result of EGFR/KRas signal activation and consequent miR-181d repression.
Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer
Authors: Hu Cheng , Liu Ying , Lin Yuan , Liang Jian-Kai , Zhong Wen-Wen , Li Ke , Huang Wen-Tao , Wang De-Juan , Yan Guang-Mei , Zhu Wen-Bo , Qiu Jian-Guang , Gao Xin 
Published: February 2018

AbstractMuscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.
The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence
Authors: Ong Siew-Min , Hadadi Eva , Dang Truong-Minh , Yeap Wei-Hseun , Tan Crystal Tze-Ying , Ng Tze-Pin , Larbi Anis , Wong Siew-Cheng 
Published: February 2018

AbstractHuman primary monocytes comprise a heterogeneous population that can be classified into three subsets based on CD14 and CD16 expression: classical (CD14high/CD16−), intermediate (CD14high/CD16+), and non-classical (CD14low/CD16+). The non-classical monocytes are the most pro-inflammatory in response to TLR stimulation in vitro, yet they express a remarkably high basal level of miR-146a, a microRNA known to negatively regulate the TLR pathway. This concurrence of a pro-inflammatory status and a high miR-146a level has been associated with cellular senescence in other cell types. Hence, we assessed the three monocyte subsets for evidence of senescence, including proliferative status, telomere length, cellular ROS levels, and mitochondrial membrane potential. Indeed, the non-classical subset exhibited the clearest hallmarks of senescence, followed by the intermediate and then the classical subset. In addition, the non-classical subset secreted pro-inflammatory cytokines basally in vitro. The highly pro-inflammatory nature of the non-classical monocytes could be a manifestation of the senescence-associated secretory phenotype (SASP), likely induced by a high basal NF-κB activity and IL-1α production. Finally, we observed an accumulation of the non-classical monocytes, in conjunction with higher levels of plasma TNF-α and IL-8, in the elderly. These factors may contribute to inflamm-aging and age-related inflammatory conditions, such as atherosclerosis and osteoarthritis. With our new understanding that the non-classical monocyte subset is a senescent population, we can now re-examine the role of this subset in disease conditions where this subset expands.
Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity
Authors: Achuthan Adrian , Aslam Ahmad S. M. , Nguyen Quyen , Lam Pui-Yeng , Fleetwood Andrew J. , Frye Ashlee T. , Louis Cynthia , Lee Ming-Chin , Smith Julia E. , Cook Andrew D. , Olshansky Moshe , Turner Stephen J. , Hamilton John A. 
Published: February 2018

AbstractGlucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated. Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions including their survival, the former is often associated with proinflammatory functions while the latter is important in lineage homeostasis. We report here that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes while having no impact on M-CSF-induced monocyte survival. To understand how GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions during inflammation, we firstly examined the transcriptomic changes elicited by these three agents in human monocytes, either acting alone or in combination. Transcriptomic and Ingenuity pathway analyses found that dexamethasone differentially modulated dendritic cell maturation and TREM1 signaling pathways in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be regulated by ERK1/2 activity. These analyses led us to provide evidence that the GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased tissue macrophage numbers, possibly from enhanced survival due to mediators such as GM-CSF, can correlate with inflammatory disease severity; also reduction in these numbers can correlate with the therapeutic benefit of a number of agents, including GCs. We propose that the ERK1/2 signaling pathway promotes survival of GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence inflammation.
Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy
Authors: Ravi Rajani , Noonan Kimberly A. , Pham Vui , Bedi Rishi , Zhavoronkov Alex , Ozerov Ivan V. , Makarev Eugene , V. Artemov Artem , Wysocki Piotr T. , Mehra Ranee , Nimmagadda Sridhar , Marchionni Luigi , Sidransky David , Borrello Ivan M. , Izumchenko Evgeny , Bedi Atul 
Published: February 2018

AbstractA majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody–ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
Biological methane production under putative Enceladus-like conditions
Authors: Taubner Ruth-Sophie , Pappenreiter Patricia , Zwicker Jennifer , Smrzka Daniel , Pruckner Christian , Kolar Philipp , Bernacchi Sébastien , Seifert Arne H. , Krajete Alexander , Bach Wolfgang , Peckmann Jörn , Paulik Christian , Firneis Maria G. , Schleper Christa , Rittmann Simon K.-M. R. 
Published: February 2018

AbstractThe detection of silica-rich dust particles, as an indication for ongoing hydrothermal activity, and the presence of water and organic molecules in the plume of Enceladus, have made Saturn’s icy moon a hot spot in the search for potential extraterrestrial life. Methanogenic archaea are among the organisms that could potentially thrive under the predicted conditions on Enceladus, considering that both molecular hydrogen (H2) and methane (CH4) have been detected in the plume. Here we show that a methanogenic archaeon, Methanothermococcus okinawensis, can produce CH4 under physicochemical conditions extrapolated for Enceladus. Up to 72% carbon dioxide to CH4 conversion is reached at 50 bar in the presence of potential inhibitors. Furthermore, kinetic and thermodynamic computations of low-temperature serpentinization indicate that there may be sufficient H2 gas production to serve as a substrate for CH4 production on Enceladus. We conclude that some of the CH4 detected in the plume of Enceladus might, in principle, be produced by methanogens.
Chiral Ag23 nanocluster with open shell electronic structure and helical face-centered cubic framework
Authors: Liu Chao , Li Tao , Abroshan Hadi , Li Zhimin , Zhang Chen , Kim Hyung J. , Li Gao , Jin Rongchao 
Published: February 2018

AbstractWe report the synthesis and crystal structure of a nanocluster composed of 23 silver atoms capped by 8 phosphine and 18 phenylethanethiolate ligands. X-ray crystallographic analysis reveals that the kernel of the Ag nanocluster adopts a helical face-centered cubic structure with C2 symmetry. The thiolate ligands show two binding patterns with the surface Ag atoms: tri- and tetra-podal types. The tetra-coordination mode of thiolate has not been found in previous Ag nanoclusters. No counter ion (e.g., Na+ and NO3−) is found in the single-crystal and the absence of such ions is also confirmed by X-ray photoelectron spectroscopy analysis, indicating electrical neutrality of the nanocluster. Interestingly, the nanocluster has an open shell electronic structure (i.e., 23(Ag 5s1)–18(SR) = 5e), as confirmed by electron paramagnetic resonance spectroscopy. Time-dependent density functional theory calculations are performed to correlate the structure and optical absorption/emission spectra of the Ag nanocluster.
PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation
Authors: Ronson George E. , Piberger Ann Liza , Higgs Martin R. , Olsen Anna L. , Stewart Grant S. , McHugh Peter J. , Petermann Eva , Lakin Nicholas D. 
Published: February 2018

AbstractPARP1 regulates the repair of DNA single-strand breaks generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whereas PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication-associated DNA damage owing to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and by stabilising replication forks that encounter BER intermediates.
High-efficiency RNA-based reprogramming of human primary fibroblasts
Authors: Kogut Igor , McCarthy Sandra M. , Pavlova Maryna , Astling David P. , Chen Xiaomi , Jakimenko Ana , Jones Kenneth L. , Getahun Andrew , Cambier John C. , Pasmooij Anna M. G. , Jonkman Marcel F. , Roop Dennis R. , Bilousova Ganna 
Published: February 2018

AbstractInduced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine; however, their potential clinical application is hampered by the low efficiency of somatic cell reprogramming. Here, we show that the synergistic activity of synthetic modified mRNAs encoding reprogramming factors and miRNA-367/302s delivered as mature miRNA mimics greatly enhances the reprogramming of human primary fibroblasts into iPSCs. This synergistic activity is dependent upon an optimal RNA transfection regimen and culturing conditions tailored specifically to human primary fibroblasts. As a result, we can now generate up to 4,019 iPSC colonies from only 500 starting human primary neonatal fibroblasts and reprogram up to 90.7% of individually plated cells, producing multiple sister colonies. This methodology consistently generates clinically relevant, integration-free iPSCs from a variety of human patient’s fibroblasts under feeder-free conditions and can be applicable for the clinical translation of iPSCs and studying the biology of reprogramming.
Application of kernel principal component analysis and computational machine learning to exploration of metabolites strongly associated with diet
Authors: Shiokawa Yuka , Date Yasuhiro , Kikuchi Jun 
Published: February 2018

AbstractComputer-based technological innovation provides advancements in sophisticated and diverse analytical instruments, enabling massive amounts of data collection with relative ease. This is accompanied by a fast-growing demand for technological progress in data mining methods for analysis of big data derived from chemical and biological systems. From this perspective, use of a general “linear” multivariate analysis alone limits interpretations due to “non-linear” variations in metabolic data from living organisms. Here we describe a kernel principal component analysis (KPCA)-incorporated analytical approach for extracting useful information from metabolic profiling data. To overcome the limitation of important variable (metabolite) determinations, we incorporated a random forest conditional variable importance measure into our KPCA-based analytical approach to demonstrate the relative importance of metabolites. Using a market basket analysis, hippurate, the most important variable detected in the importance measure, was associated with high levels of some vitamins and minerals present in foods eaten the previous day, suggesting a relationship between increased hippurate and intake of a wide variety of vegetables and fruits. Therefore, the KPCA-incorporated analytical approach described herein enabled us to capture input–output responses, and should be useful not only for metabolic profiling but also for profiling in other areas of biological and environmental systems.