bluuebunny/crossref_metadata_2025_split huggingface dataset:
FEZF1-AS1/miR-107/ZNF312B axis facilitates progression and Warburg effect in pancreatic ductal adenocarcinoma
Authors: Ye Huilin , Zhou Quanbo , Zheng Shangyou , Li Guolin , Lin Qing , Ye Liangtao , Wang Yingxue , Wei Lusheng , Zhao Xiaohui , Li Wenzhu , Fu Zhiqiang , Liu Yimin , Li Zhihua , Chen Rufu 
Published: January 2018

AbstractLong non-coding RNAs (lncRNAs) play a pivotal role in pathological processes. However, little information has been published regarding the underlying functions and mechanisms of lncRNAs in pancreatic ductal adenocarcinoma (PDAC). A novel lncRNA FEZF1-AS1 and its sense-cognate gene ZNF312B were found to be highly expressed in human PDAC tissues and cell lines, which is associated with disease progression and predicts clinical outcome in PDAC patients. Of note, bioinformatics analysis, luciferase assays and RNA immunoprecipitation assays indicated that FEZF1-AS1 may act as an endogenous sponge by competing for miR-107, thereby modulating the derepression of ZNF312B. Downregulation of FEZF1-AS1 or ZNF312B significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cells in vitro, whereas the miR-107 inhibitor abrogated the effect of dow-regulation of FEZF1-AS1 or ZNF312B in reducing oncogenic capacities of PDAC cells. In addition, FEZF1-AS1/miR-107/ZNF312B axis-induced promotion of PDAC cells proliferation appeared to be mediated by modulation of the apoptosis and the G1-S checkpoint. Furthermore, downregulation of FEZF1-AS1 repressed tumor growth in mouse xenograft models. In particular, our results highlight the contribution of FEZF1-AS1/miR-107/ZNF312B axis to Warburg effect maintenance of PDAC cells. Collectively, our findings demonstrate that the FEZF1-AS1/miR-107/ZNF312B axis regulatory network might provide a potential new therapeutic strategy for PDAC.
Sensitizing tumor cells to conventional drugs: HSP70 chaperone inhibitors, their selection and application in cancer models
Authors: Lazarev Vladimir F. , Sverchinsky Dmitry V. , Mikhaylova Elena R. , Semenyuk Pavel I. , Komarova Elena Y. , Niskanen Sergey A. , Nikotina Alina D. , Burakov Anton V. , Kartsev Viktor G. , Guzhova Irina V. , Margulis Boris A. 
Published: January 2018

AbstractHsp70 chaperone controls proteostasis and anti-stress responses in rapidly renewing cancer cells, making it an important target for therapeutic compounds. To date several Hsp70 inhibitors are presented with remarkable anticancer activity, however their clinical application is limited by the high toxicity towards normal cells. This study aimed to develop assays to search for the substances that reduce the chaperone activity of Hsp70 and diminish its protective function in cancer cells. On our mind the resulting compounds alone should be safe and function in combination with drugs widely employed in oncology. We constructed systems for the analysis of substrate-binding and refolding activity of Hsp70 and to validate the assays screened the substances representing most diverse groups of chemicals of InterBioScreen library. One of the inhibitors was AEAC, an N-amino-ethylamino derivative of colchicine, which toxicity was two-orders lower than that of parent compound. In contrast to colchicine, AEAC inhibited substrate-binding and refolding functions of Hsp70 chaperones. The results of a drug affinity responsive target stability assay, microscale thermophoresis and molecular docking show that AEAC binds Hsp70 with nanomolar affinity. AEAC was found to penetrate C6 rat glioblastoma and B16 mouse melanoma cells and reduce there the function of the Hsp70-mediated refolding system. Although the cytotoxic and growth inhibitory activities of AEAC were minimal, the compound was shown to increase the antitumor efficiency of doxorubicin in tumor cells of both types. When the tumors were grown in animals, AEAC administration in combination with doxorubicin exerted maximal therapeutic effect prolonging animal survival by 10–15 days and reducing tumor growth rate by 60%. To our knowledge, this is the first time that this approach to the high-throughput analysis of chaperone inhibitors has been applied, and it can be useful in the search for drug combinations that are effective in the treatment of highly resistant tumors.
EGFR activation triggers cellular hypertrophy and lysosomal disease in NAGLU-depleted cardiomyoblasts, mimicking the hallmarks of mucopolysaccharidosis IIIB
Authors: De Pasquale Valeria , Pezone Antonio , Sarogni Patrizia , Tramontano Alfonso , Schiattarella Gabriele Giacomo , Avvedimento Vittorio Enrico , Paladino Simona , Pavone Luigi Michele 
Published: January 2018

AbstractMucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease caused by the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The defective lysosomal clearance of undigested HS results in dysfunction of multiple tissues and organs. We recently demonstrated that the murine model of MPS IIIB develops cardiac disease, valvular abnormalities, and ultimately heart failure. To address the molecular mechanisms governing cardiac dysfunctions in MPS IIIB, we generated a model of the disease by silencing NAGLU gene expression in H9C2 rat cardiomyoblasts. NAGLU-depleted H9C2 exhibited accumulation of abnormal lysosomes and a hypertrophic phenotype. Furthermore, we found the specific activation of the epidermal growth factor receptor (EGFR), and increased phosphorylation levels of extracellular signal-regulated kinases (ERKs) in NAGLU-depleted H9C2. The inhibition of either EGFR or ERKs, using the selective inhibitors AG1478 and PD98059, resulted in the reduction of both lysosomal aberration and hypertrophy in NAGLU-depleted H9C2. We also found increased phosphorylation of c-Src and a reduction of the hypertrophic response in NAGLU-depleted H9C2 transfected with a dominant-negative c-Src. However, c-Src phosphorylation remained unaffected by AG1478 treatment, posing c-Src upstream EGFR activation. Finally, heparin-binding EGF-like growth factor (HB-EGF) protein was found overexpressed in our MPS IIIB cellular model, and its silencing reduced the hypertrophic response. These results indicate that both c-Src and HB-EGF contribute to the hypertrophic phenotype of NAGLU-depleted cardiomyoblasts by synergistically activating EGFR and subsequent signaling, thus suggesting that EGFR pathway inhibition could represent an effective therapeutic approach for MPS IIIB cardiac disease.
Monoglyceride lipase gene knockout in mice leads to increased incidence of lung adenocarcinoma
Authors: Liu Renyan , Wang Xin , Curtiss Christopher , Landas Steve , Rong Rong , Sheikh M. Saeed , Huang Ying 
Published: January 2018

AbstractMonoglyceride lipase (MGL) is a recently discovered cancer-related protein. The role of MGL in tumorigenesis remains to be fully elucidated. We have previously shown that MGL expression was reduced or absent in multiple human malignancies, and overexpression of MGL inhibited cancer cell growth. Here, we have generated the MGL knockout mice to further investigate the role of MGL in tumorigenesis in vivo. Our results indicate that MGL-deficient (MGL+/−, MGL−/−) mice exhibited a higher incidence of neoplasia in multiple organs, including the lung, spleen, liver and lymphoid tissues. Interestingly, lung neoplasms were the most common neoplastic changes in the MGL-deficient mice. Importantly, MGL-deficient animals developed premalignant high-grade dysplasia and adenocarcinomas in their lungs. Investigation of the MGL expression status in lung cancer specimens from patients also revealed that MGL expression was significantly reduced in the majority of primary human lung cancers when compared to corresponding matched normal tissues. Furthermore, mouse embryonic fibroblasts (MEFs) from MGL-deficient animals showed characteristics of cellular transformation including increased cell proliferation, foci formation and anchorage-independent growth. Our results also indicate that MGL deficiency was associated with activation of EGFR and ERK. In addition, pro-inflammatory molecules COX-2 and TNF-α were also activated in the MGL-deficient lung tissues. Thus, our results provide new insights into the novel role of MGL as an important negative regulator of EGFR, COX-2 and TNF-α. Accordingly, EGFR and COX-2/TNF-α activation/induction is expected to play important roles in MGL deficiency-driven lung tumors. Collectively, our results implicate the tumor suppressive role of MGL in preventing tumor development in vivo, particularly in context to the lung cancer, and highlight its role as a potential tumor suppressor.
Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells
Authors: Augello Giuseppa , Modica Martina , Azzolina Antonina , Puleio Roberto , Cassata Giovanni , Emma Maria Rita , Di Sano Caterina , Cusimano Antonella , Montalto Giuseppe , Cervello Melchiorre 
Published: January 2018

AbstractHepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action. MLN2238 inhibited cell viability in human HCC cells HepG2, Hep3B, and SNU475 in a time- and dose-dependent manner. Flow cytometry analysis demonstrated that MLN2238 induced G2/M cell cycle arrest and cellular apoptosis in HCC cells. Cell cycle arrest was associated with increased expression levels of p21 and p27. MLN2238-induced apoptosis was confirmed by caspase-3/7 activation, PARP cleavage and caspase-dependent β-catenin degradation. In addition, MLN2238 activated ER stress genes in HCC cells and increased the expression of the stress-inducible gene nuclear protein-1. Furthermore, MLN2238 treatment induced upregulation of myeloid cell leukemia-1 (Mcl-1) protein, and Mcl-1 knockdown sensitized HCC cells to MLN2238 treatment, suggesting the contribution of Mcl-1 expression to MLN2238 resistance. This result was also confirmed using the novel Mcl-1 small molecule inhibitor A1210477. Association of A1210477 and MLN2238 determined synergistic antitumor effects in HCC cells. Finally, in vivo orally administered MLN2238 suppressed tumor growth of Hep3B cells in xenograft models in nude mice. In conclusion, our results offer hope for a new therapeutic opportunity in the treatment of HCC patients.
Electric fields control the orientation of peptides irreversibly immobilized on radical-functionalized surfaces
Authors: Martin Lewis J. , Akhavan Behnam , Bilek Marcela M. M. 
Published: January 2018

AbstractSurface functionalization of an implantable device with bioactive molecules can overcome adverse biological responses by promoting specific local tissue integration. Bioactive peptides have advantages over larger protein molecules due to their robustness and sterilizability. Their relatively small size presents opportunities to control the peptide orientation on approach to a surface to achieve favourable presentation of bioactive motifs. Here we demonstrate control of the orientation of surface-bound peptides by tuning electric fields at the surface during immobilization. Guided by computational simulations, a peptide with a linear conformation in solution is designed. Electric fields are used to control the peptide approach towards a radical-functionalized surface. Spontaneous, irreversible immobilization is achieved when the peptide makes contact with the surface. Our findings show that control of both peptide orientation and surface concentration is achieved simply by varying the solution pH or by applying an electric field as delivered by a small battery.
Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours
Authors: Sidibe Adama , Ropraz Patricia , Jemelin Stéphane , Emre Yalin , Poittevin Marine , Pocard Marc , Bradfield Paul F. , Imhof Beat A. 
Published: January 2018

AbstractRecruitment of circulating monocytes is critical for tumour angiogenesis. However, how human monocyte subpopulations extravasate to tumours is unclear. Here we show mechanisms of extravasation of human CD14dimCD16+ patrolling and CD14+CD16+ intermediate proangiogenic monocytes (HPMo), using human tumour xenograft models and live imaging of transmigration. IFNγ promotes an increase of the chemokine CX3CL1 on vessel lumen, imposing continuous crawling to HPMo and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNF by tumour cells enables HPMo extravasation by inducing GATA3-mediated repression of CX3CL1 expression. Recruited HPMo boosts angiogenesis by secreting MMP9 leading to release of matrix-bound VEGF-A, which amplifies the entry of more HPMo into tumours. Uncovering the extravasation cascade of HPMo sets the stage for future tumour therapies.
Neuronal messenger ribonucleoprotein transport follows an aging Lévy walk
Authors: Song Minho S. , Moon Hyungseok C. , Jeon Jae-Hyung , Park Hye Yoon 
Published: January 2018

AbstractLocalization of messenger ribonucleoproteins (mRNPs) plays an essential role in the regulation of gene expression for long-term memory formation and neuronal development. Knowledge concerning the nature of neuronal mRNP transport is thus crucial for understanding how mRNPs are delivered to their target synapses. Here, we report experimental and theoretical evidence that the active transport dynamics of neuronal mRNPs, which is distinct from the previously reported motor-driven transport, follows an aging Lévy walk. Such nonergodic, transient superdiffusion occurs because of two competing dynamic phases: the motor-involved ballistic run and static localization of mRNPs. Our proposed Lévy walk model reproduces the experimentally extracted key dynamic characteristics of mRNPs with quantitative accuracy. Moreover, the aging status of mRNP particles in an experiment is inferred from the model. This study provides a predictive theoretical model for neuronal mRNP transport and offers insight into the active target search mechanism of mRNP particles in vivo.
Evolutionary adaptations to new environments generally reverse plastic phenotypic changes
Authors: Ho Wei-Chin , Zhang Jianzhi 
Published: January 2018

AbstractOrganismal adaptation to a new environment may start with plastic phenotypic changes followed by genetic changes, but whether the plastic changes are stepping stones to genetic adaptation is debated. Here we address this question by investigating gene expression and metabolic flux changes in the two-phase adaptation process using transcriptomic data from multiple experimental evolution studies and computational metabolic network analysis, respectively. We discover that genetic changes more frequently reverse than reinforce plastic phenotypic changes in virtually every adaptation. Metabolic network analysis reveals that, even in the presence of plasticity, organismal fitness drops after environmental shifts, but largely recovers through subsequent evolution. Such fitness trajectories explain why plastic phenotypic changes are genetically compensated rather than strengthened. In conclusion, although phenotypic plasticity may serve as an emergency response to a new environment that is necessary for survival, it does not generally facilitate genetic adaptation by bringing the organismal phenotype closer to the new optimum.
C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
Authors: Selvaraj Bhuvaneish T. , Livesey Matthew R. , Zhao Chen , Gregory Jenna M. , James Owain T. , Cleary Elaine M. , Chouhan Amit K. , Gane Angus B. , Perkins Emma M. , Dando Owen , Lillico Simon G. , Lee Youn-Bok , Nishimura Agnes L. , Poreci Urjana , Thankamony Sai , Pray Meryll , Vasistha Navneet A. , Magnani Dario , Borooah Shyamanga , Burr Karen , Story David , McCampbell Alexander , Shaw Christopher E. , Kind Peter C. , Aitman Timothy J. , Whitelaw C. Bruce A. , Wilmut Ian , Smith Colin , Miles Gareth B. , Hardingham Giles E. , Wyllie David J. A. , Chandran Siddharthan 
Published: January 2018

AbstractMutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post-mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.
Facile storage and release of white phosphorus and yellow arsenic
Authors: Seitz Andreas E. , Hippauf Felix , Kremer Werner , Kaskel Stefan , Scheer Manfred 
Published: January 2018

AbstractThe storage of metastable compounds and modifications of elements are of great interest for synthesis and other, e.g., semiconductor, applications. Whereas white phosphorus is a metastable modification that can be stored under certain conditions, storage of the extremely (light- and air-)sensitive form of arsenic, yellow arsenic, is a challenge rarely tackled so far. Herein, we report on the facile storage and release of these tetrahedral E4 molecules (E = P, As) using activated carbon as a porous storage material. These loaded materials are air- and light-stable and have been comprehensively characterized by solid-state 31P{1H} MAS NMR spectroscopy, powder X-ray diffraction analysis, nitrogen adsorption measurements, and thermogravimetric analysis. Additionally, we show that these materials can be used as a suitable E4 source for releasing intact white phosphorus or yellow arsenic, enabling subsequent reactions in solution. Because the uptake and release of E4 are reversible, these materials are excellent carriers of these highly reactive modifications.
Investigation of radiomic signatures for local recurrence using primary tumor texture analysis in oropharyngeal head and neck cancer patients
Authors:   M. D. Anderson Cancer Center Head and Neck Quantitative Imaging Working Group, Elhalawani Hesham , Kanwar Aasheesh , Mohamed Abdallah S. R. , White Aubrey , Zafereo James , Wong Andrew , Berends Joel , Abohashem Shady , Williams Bowman , Aymard Jeremy M. , Perni Subha , Messer Jay , Warren Ben , Youssef Bassem , Yang Pei , Meheissen Mohamed A. M. , Kamal Mona , Elgohari Baher , Ger Rachel B. , Cardenas Carlos E. , Fave Xenia , Zhang Lifei , Mackin Dennis , Marai G. Elisabeta , Vock David M. , Canahuate Guadalupe M. , Lai Stephen Y. , Gunn G. Brandon , Garden Adam S. , Rosenthal David I. , Court Laurence , Fuller Clifton D. 
Published: January 2018

AbstractRadiomics is one such “big data” approach that applies advanced image refining/data characterization algorithms to generate imaging features that can quantitatively classify tumor phenotypes in a non-invasive manner. We hypothesize that certain textural features of oropharyngeal cancer (OPC) primary tumors will have statistically significant correlations to patient outcomes such as local control. Patients from an IRB-approved database dispositioned to (chemo)radiotherapy for locally advanced OPC were included in this retrospective series. Pretreatment contrast CT scans were extracted and radiomics-based analysis of gross tumor volume of the primary disease (GTVp) were performed using imaging biomarker explorer (IBEX) software that runs in Matlab platform. Data set was randomly divided into a training dataset and test and tuning holdback dataset. Machine learning methods were applied to yield a radiomic signature consisting of features with minimal overlap and maximum prognostic significance. The radiomic signature was adapted to discriminate patients, in concordance with other key clinical prognosticators. 465 patients were available for analysis. A signature composed of 2 radiomic features from pre-therapy imaging was derived, based on the Intensity Direct and Neighbor Intensity Difference methods. Analysis of resultant groupings showed robust discrimination of recurrence probability and Kaplan-Meier-estimated local control rate (LCR) differences between “favorable” and “unfavorable” clusters were noted.
Verification of Argentine ant defensive compounds and their behavioral effects on heterospecific competitors and conspecific nestmates
Authors: Welzel Kevin F. , Lee Shao Hung , Dossey Aaron T. , Chauhan Kamlesh R. , Choe Dong-Hwan 
Published: January 2018

AbstractThe invasive Argentine ant (Linepithema humile) has become established worldwide in regions with Mediterranean or subtropical climates. The species typically disrupts the balance of natural ecosystems by competitively displacing some native ant species via strong exploitation and interference competition. Here we report that Argentine ants utilize glandular secretions for inter and intra-specific communications during aggressive interactions with a heterospecific competitor, California harvester ant (Pogonomyrmex californicus). Chemical analyses indicated that Argentine ants deploy glandular secretions containing two major volatile iridoids, dolichodial and iridomyrmecin, on the competitor’s cuticular surface during aggressive interactions. Bioassays indicated that the glandular secretions function as a defensive allomone, causing high levels of irritation in the heterospecific. Furthermore, the same glandular secretions elicited alarm and attraction of conspecific nestmates, potentially enabling more rapid/coordinated defense by the Argentine ants. Two major volatile constituents of the glandular secretion, dolichodial and iridomyrmecin, were sufficient to elicit these responses in conspecifics (as a mixture or individual compounds). The current study suggests that invasive Argentine ants’ superior exploitation and interference competition may rely on the species’ effective semiochemical parsimony.