bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rab37 mediates exocytosis of secreted frizzled-related protein 1 to inhibit Wnt signaling and thus suppress lung cancer stemness
Authors: Cho Shu-Huei , Kuo I-Ying , Lu Pei-Jung Frank , Tzeng Hong-Tai , Lai Wu-Wei , Su Wu-Chou , Wang Yi-Ching 
Published: August 2018

AbstractRecent studies have revealed that dysregulated Rab small GTPase-mediated vesicle trafficking pathways are associated with cancer progression. However, whether any of the Rabs plays a suppressor role in cancer stemness is least explored. Rab37 has been postulated as a tumor suppressive small GTPase for trafficking anti-tumor cargos. Here, we report a previously uncharacterized mechanism by which Rab37 mediates exocytosis of secreted frizzled-related protein-1 (SFRP1), an extracellular antagonist of Wnt, to suppress Wnt signaling and cancer stemness in vitro and in vivo. Reconstitution experiments indicate that SFRP1 secretion is crucial for Rab37-mediated cancer stemness suppression and treatment with SRPP1 recombinant protein reduces xenograft tumor initiation ability. Clinical results confirm that concordantly low Rab37, low SFRP1, and high Oct4 stemness protein expression profile can be used as a biomarker to predict poor prognosis in lung cancer patients. Our findings reveal that Rab37-mediated SFRP1 secretion suppresses cancer stemness, and dysregulated Rab37-SFRP1 pathway confers cancer stemness via the activation of Wnt signaling. Rab37-SFRP1-Wnt axis could be a potential therapeutic target for attenuating lung cancer stemness.
HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis
Authors: Ding Xusheng , Ji Jun , Jiang Jinling , Cai Qu , Wang Chao , Shi Min , Yu Yingyan , Zhu Zhenggang , Zhang Jun 
Published: August 2018

AbstractCancer-associated fibroblasts (CAFs) are important components of tumor stroma and play a key role in tumor progression. CAFs involve in crosstalk with tumor cells through various kinds of cytokines. In the present study, we screened hepatocyte growth factor (HGF) as a cytokine predominantly originating from CAFs. CAFs-derived HGF was found to promote MET-unamplified gastric cancer (GC) proliferation, migration, and invasion through the activation of HGF/c-Met/STAT3/twist1 pathway. It also activated interleukin (IL)-6/IL-6R/JAK2/STAT3/twist1 pathway by up-regulating IL-6R expression. As IL-6 was also found to upregulate c-Met expression, we identified the cooperation of HGF and IL-6 in enhancing the characteristics of CAFs. In vivo experiments revealed that CAFs-derived HGF promoted tumorigenesis and metastasis of MET-unamplified GC. Gene set enrichment analysis (GSEA) was performed to confirm our findings. Our study found that the increased expression of HGF in CAFs induced by MET-unamplified GC contributed to the malignant phenotype of both MET-unamplified GC and CAFs in tumor microenvironment.
Zinc induces CDK5 activation and neuronal death through CDK5-Tyr15 phosphorylation in ischemic stroke
Authors: Tuo Qing-Zhang , Liuyang Zhen-Yu , Lei Peng , Yan Xiong , Shentu Yang-Ping , Liang Jia-Wei , Zhou Huan , Pei Lei , Xiong Yan , Hou Tong-Yao , Zhou Xin-Wen , Wang Qun , Wang Jian-Zhi , Wang Xiao-Chuan , Liu Rong 
Published: August 2018

AbstractCDK5 activation promotes ischemic neuronal death in stroke, with the recognized activation mechanism being calpain-dependent p35 cleavage to p25. Here we reported that CDK5-Tyr15 phosphorylation by zinc induced CDK5 activation in brain ischemic injury. CDK5 activation and CDK5-Tyr15 phosphorylation were observed in the hippocampus of the rats that had been subjected to middle cerebral artery occlusion, both of which were reversed by pretreatment with zinc chelator; while p35 cleavage and calpain activation in ischemia were not reversed. Zinc incubation resulted in CDK5-Tyr15 phosphorylation and CDK5 activation, without increasing p35 cleavage in cultured cells. Site mutation experiment confirmed that zinc-induced CDK5 activation was dependent on Tyr15 phosphorylation. Further exploration showed that Src kinase contributed to zinc-induced Tyr15 phosphorylation and CDK5 activation. Src kinase inhibition or expression of an unphosphorylable mutant Y15F-CDK5 abolished Tyr15 phosphorylation, prevented CDK5 activation and protected hippocampal neurons from ischemic insult in rats. We conclude that zinc-induced CDK5-Tyr15 phosphorylation underlies CDK5 activation and promotes ischemic neuronal death in stroke.
Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells
Authors: Kim Tae Woo , Lee Seon Young , Kim Mia , Cheon Chunhoo , Ko Seong-Gyu 
Published: August 2018

AbstractKaempferol, a flavonoid, found in traditional medicine, fruits, and vegetables, and an HDAC inhibitor, is a powerful anti-cancer reagent against various cancer cell lines. However, detailed mechanisms involved in the treatment of gastric cancer (GC) using kaempferol are not fully understood. In our study, we investigated the biological activity and molecular mechanism involved in kaempferol-mediated treatment of GC. Kaempferol promoted autophagy and cell death, and increased LC3-I to LC3-II conversion and the downregulation of p62 in GC. Furthermore, our results showed that kaempferol induces autophagic cell death via the activation of the IRE1-JNK-CHOP signaling, indicating ER stress response. Indeed, the inhibition of ER stress suppressed kaempferol-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further showed that kaempferol mediates epigenetic change via the inhibition of G9a (HDAC/G9a axis) and also activates autophagic cell death. Taken together, our findings indicate that kaempferol activates the IRE1-JNK-CHOP signaling from cytosol to nucleus, and G9a inhibition activates autophagic cell death in GC cells.
Presenilin 1 deficiency suppresses autophagy in human neural stem cells through reducing γ-secretase-independent ERK/CREB signaling
Authors: Chong Cheong-Meng , Ke Minjing , Tan Yuan , Huang Zhijian , Zhang Ke , Ai Nana , Ge Wei , Qin Dajiang , Lu Jia-Hong , Su Huanxing 
Published: August 2018

AbstractAutophagy impairment is commonly implicated in the pathological characteristic of Alzheimer’s disease (AD). Presenilin 1 (PS1) expression in human brain gradually decreases with age and its mutations account for the most common cases of early-onset familial Alzheimer’s disease (FAD). The dominant autophagy phenotypes occur in PS1-knockout and PS1 mutant neurons; it is still unknown whether PS1 deficiency causes serious autophagy impairment in neural stem cells (NSCs). Herein, we generated the heterozygote and homozygote of PS1 knockout in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9-based gene editing and differentiated them into human NSCs. In these human PS1-deficient NSCs, reduced autophagosome formation and downregulated expression of autophagy–lysosome pathway (ALP)-related mRNAs, as well as proteins were observed. Mechanistically, ERK/CREB inhibition and GSK3β activation had key roles in reducing TFEB expression in PS1-knockout NSCs. Pharmacological inhibition of GSK3β upregulated the expression of TFEB and ALP-related proteins in PS1-knockout NSCs, whereas this effect could be blocked by CREB inhibition. These findings demonstrate that PS1 deficiency causes autophagy suppression in human NSCs via downregulating ERK/CREB signaling.
The activation of microRNA-520h–associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression
Authors: Zhang Jing , Liu Wenxue , Shen Fangqian , Ma Xiaoling , Liu Xiaorui , Tian Fuju , Zeng Weihong , Xi Xiaowei , Lin Yi 
Published: August 2018

AbstractAmong the gynaecological cancers, epithelial ovarian cancer (EOC) has the highest lethality because of the high incidence of tumour progression and metastasis. Exploration of the detailed mechanisms underlying EOC metastasis and the identification of crucial targets is important to better estimate the prognosis and improve the treatment of this disease. The present study aimed to identify the role of miR-520h in the prognosis of patients with EOC, and the mechanisms of its involvement in EOC progression. We showed that miR-520h was upregulated in 116 patients with EOC, especially in those with advanced-stage disease, and high miR-520h expression predicted poor outcome. Furthermore, ectopic expression of miR-520h enhanced EOC cell proliferation, migration and invasion, and induced epithelial–mesenchymal transition in vitro and in vivo. miR-520h promoted EOC progression by downregulating Smad7, and subsequently activating the TGF-β signalling pathway. Most importantly, TGF-β1 stimulation increased miR-520h expression in EOC cells by upregulating its transcription factor c-Myb. In conclusion, we described the role of the TGF-β1/c-Myb/miR-520h/Smad7 axis in EOC metastasis, and highlighted the possible use of miR-520h as a prognostic marker for EOC.
Structural and biochemical insights into small RNA 3′ end trimming by Arabidopsis SDN1
Authors: Chen Jiayi , Liu Li , You Chenjiang , Gu Jiaqi , Ruan Wenjie , Zhang Lu , Gan Jianhua , Cao Chunyang , Huang Ying , Chen Xuemei , Ma Jinbiao 
Published: August 2018

AbstractA family of DEDDh 3′→5′ exonucleases known as Small RNA Degrading Nucleases (SDNs) initiates the turnover of ARGONAUTE1 (AGO1)-bound microRNAs in Arabidopsis by trimming their 3′ ends. Here, we report the crystal structure of Arabidopsis SDN1 (residues 2-300) in complex with a 9 nucleotide single-stranded RNA substrate, revealing that the DEDDh domain forms rigid interactions with the N-terminal domain and binds 4 nucleotides from the 3′ end of the RNA via its catalytic pocket. Structural and biochemical results suggest that the SDN1 C-terminal domain adopts an RNA Recognition Motif (RRM) fold and is critical for substrate binding and enzymatic processivity of SDN1. In addition, SDN1 interacts with the AGO1 PAZ domain in an RNA-independent manner in vitro, enabling it to act on AGO1-bound microRNAs. These extensive structural and biochemical studies may shed light on a common 3′ end trimming mechanism for 3′→5′ exonucleases in the metabolism of small non-coding RNAs.
Exploring Peltier effect in organic thermoelectric films
Authors: Jin Wenlong , Liu Liyao , Yang Tao , Shen Hongguang , Zhu Jia , Xu Wei , Li Shuzhou , Li Qing , Chi Lifeng , Di Chong-an , Zhu Daoben 
Published: August 2018

AbstractOrganic materials are emerging thermoelectric candidates for flexible power generation and solid-cooling applications. Although the Peltier effect is a fundamental thermoelectric effect that enables site-specific and on-demand cooling applications, the Peltier effect in organic thermoelectric films have not been investigated. Here we experimentally observed and quasi-quantitatively evaluated the Peltier effect in a poly(Ni-ett) film through the fabrication of thermally suspended devices combined with an infrared imaging technique. The experimental and simulation results confirm effective extraction of the Peltier effect and verify the Thomson relations in organic materials. More importantly, the working device based on poly(Ni-ett) film yields maximum temperature differences as large as 41 K at the two contacts and a cooling of 0.2 K even under heat-insulated condition. This exploration of the Peltier effect in organic thermoelectric films predicts that organic materials hold the ultimate potential to enable flexible solid-cooling applications.
Genomic and expression profiling reveal molecular heterogeneity of disseminated tumor cells in bone marrow of early breast cancer
Authors: Magbanua Mark Jesus M. , Rugo Hope S. , Hauranieh Louai , Roy Ritu , Scott Janet H. , Lee Jen Chieh , Hsiao Feng , Sosa Eduardo V. , van’t Veer Laura , Esserman Laura J. , Park John W. 
Published: August 2018

AbstractDetection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance.
Correlating nuclear morphometric patterns with estrogen receptor status in breast cancer pathologic specimens
Authors: Rawat Rishi R. , Ruderman Daniel , Macklin Paul , Rimm David L. , Agus David B. 
Published: August 2018

AbstractIn this pilot study, we introduce a machine learning framework to identify relationships between cancer tissue morphology and hormone receptor pathway activation in breast cancer pathology hematoxylin and eosin (H&E)-stained samples. As a proof-of-concept, we focus on predicting clinical estrogen receptor (ER) status—defined as greater than one percent of cells positive for estrogen receptor by immunohistochemistry staining—from spatial arrangement of nuclear features. Our learning pipeline segments nuclei from H&E images, extracts their position, shape and orientation descriptors, and then passes them to a deep neural network to predict ER status. After training on 57 tissue cores of invasive ductal carcinoma (IDC), our pipeline predicted ER status in an independent test set of patient samples (AUC ROC = 0.72, 95%CI = 0.55–0.89, n = 56). This proof of concept shows that machine-derived descriptors of morphologic histology patterns can be correlated to signaling pathway status. Unlike other deep learning approaches to pathology, our system uses deep neural networks to learn spatial relationships between pre-defined biological features, which improves the interpretability of the system and sheds light on the features the neural network uses to predict ER status. Future studies will correlate morphometry to quantitative measures of estrogen receptor status and, ultimately response to hormonal therapy.
An external quantum efficiency of >20% from solution-processed poly(dendrimer) organic light-emitting diodes
Authors: Maasoumi Fatemeh , Jansen-van Vuuren Ross D. , Shaw Paul E. , Puttock Emma V. , Nagiri Ravi Chandra Raju , McEwan Jake A. , Bown Mark , O’Connell Jenny L. , Dunn Christopher J. , Burn Paul L. , Namdas Ebinazar B. 
Published: August 2018

AbstractControlling the orientation of the emissive dipole has led to a renaissance of organic light-emitting diode (OLED) research, with external quantum efficiencies (EQEs) of >30% being reported for phosphorescent emitters. These highly efficient OLEDs are generally manufactured using evaporative methods and are comprised of small-molecule heteroleptic phosphorescent iridium(III) complexes blended with a host and additional layers to balance charge injection and transport. Large area OLEDs for lighting and display applications would benefit from low-cost solution processing, provided that high EQEs could be achieved. Here, we show that poly(dendrimer)s consisting of a non-conjugated polymer backbone with iridium(III) complexes forming the cores of first-generation dendrimer side chains can be co-deposited with a host by solution processing to give highly efficient devices. Simple bilayer devices comprising the emissive layer and an electron transport layer gave an EQE of >20% at luminances of up to ≈300 cd/m2, showing that polymer engineering can enable alignment of the emissive dipole of solution-processed phosphorescent materials.
Role of proteins in the degradation of relatively inert alloys in the human body
Authors: Hedberg Yolanda S. 
Published: August 2018

AbstractMany biomedical materials used today for applications such as orthopedic, dental, and cardiovascular implants and devices are made of corrosion-resistant, ‘inert’, metallic materials of the cobalt–chromium, titanium, and stainless steel alloy groups. This perspective focuses on the role of proteins in the degradation of these materials in a human body environment. After adsorption, the proteins interact relatively slowly with the metal and metal surface oxide. A number of factors, including the individual body chemistry (especially the presence of inflammatory cells producing oxidative species), determine whether the proteins can bind to metals in the surface oxide and whether the metal–protein conjugates can detach from the surface. Metals in the forms of protein-bound metal ions or nanosized particles can also increase protein–protein interactions and aggregation, which can cause some health effects and change the material degradation mechanism. While proteins in some short-term studies (<6 h) even decrease material degradation due to shielding effects and better lubrication, they may increase degradation after longer time periods due to relatively slow binding, detachment, and combined corrosion processes. In-vitro material degradation studies of relatively corrosion-resistant alloys for biomedical applications should therefore include long-term studies, complexing agents or proteins, and realistic oxidative environments simulating inflammatory conditions.
Generation of therapeutic antisera for emerging viral infections
Authors: Schmidt Rebecca , Beltzig Lea C. , Sawatsky Bevan , Dolnik Olga , Dietzel Erik , Krähling Verena , Volz Asisa , Sutter Gerd , Becker Stephan , von Messling Veronika 
Published: August 2018

AbstractThe recent Ebola virus outbreak has highlighted the therapeutic potential of antisera and renewed interest in this treatment approach. While human convalescent sera may not be readily available in the early stages of an outbreak, antisera of animal origin can be produced in a short time frame. Here, we compared adjuvanted virus-like particles (VLP) with recombinant modified vaccinia virus Ankara and vesicular stomatitis virus (VSV), both expressing the Ebola virus antigens. The neutralizing antibody titers of rabbits immunized with adjuvanted VLPs were similar to those immunized with the replication-competent VSV, indicating that presentation of the antigen in its native conformation rather than de novo antigen expression is essential for production of functional antibodies. This approach also yielded high-titer antisera against Nipah virus glycoproteins, illustrating that it is transferable to other virus families. Multiple-step immunoglobulin G purification using a two-step 20–40% ammonium sulfate precipitation followed by protein A affinity chromatography resulted in 90% recovery of functionality and sustained in vivo stability. Adjuvanted VLP-based immunization strategies are thus a promising approach for the rapid generation of therapeutic antisera against emerging infections.
Sucrose Abstinence and Environmental Enrichment Effects on Mesocorticolimbic DARPP32 in Rats
Authors: Grimm Jeffrey W. , Glueck Edwin , Ginder Darren , Hyde Jeff , North Katherine , Jiganti Kyle 
Published: August 2018

AbstractDopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) is a signaling molecule that could serve as a molecular switch, promoting or restraining sucrose seeking. We measured DARPP32 and pThr34 DARPP32 in the brains of male Long-Evans rats with a history of sucrose self-administration followed by 1 or 30 days of abstinence and exposure to either overnight (acute) or one month (chronic) environmental enrichment (EE). Brains were extracted following a 1 h cue reactivity test or no exposure to the test environment. Micropunches (prelimbic, infralimbic, and anterior cingulate areas of the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, nucleus accumbens, and ventral tegmental area) were then processed using Western blot. Abstinence increased, while EE decreased, sucrose seeking. DARPP32 and pThr34 DARPP32 levels were affected by testing, abstinence, and/or EE in most regions. Especially salient results were observed in the nucleus accumbens core, a region associated with relapse behaviors. Both acute and chronic EE reduced DARPP32 in the nucleus accumbens core and acute EE increased the ratio of phosphorylated to total DARPP32. Degree of DARPP32 phosphorylation negatively correlated with sucrose seeking. These findings demonstrate a potential role for DARPP32 in mediating the “anti-craving” effect of EE.
Tyrosine kinase receptor TIE-1 mediates platinum resistance by promoting nucleotide excision repair in ovarian cancer
Authors: Ishibashi Masumi , Toyoshima Masafumi , Zhang Xuewei , Hasegawa-Minato Junko , Shigeta Shogo , Usui Toshinori , Kemp Christopher J. , Grandori Carla , Kitatani Kazuyuki , Yaegashi Nobuo 
Published: August 2018

AbstractPlatinum resistance is one of the most challenging problems in ovarian cancer treatment. High-throughput functional siRNA screening identified tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) as a gene that confers cells resistant to cisplatin. Conversely enforced over-expression of TIE-1 was validated to decrease cisplatin sensitivity in multiple ovarian cancer cell lines and up-regulation of TIE-1 was correlated with poor prognosis and cisplatin resistance in patients with ovarian cancer. Mechanistically, TIE-1 up-regulates the nucleotide excision repair (NER) system mediated by xeroderma pigmentosum complementation group C (XPC), thereby leading to decreased susceptibility to cisplatin-induced cell death without affecting cisplatin uptake and excretion. Importantly potentiation of therapeutic efficacy by TIE-1 inhibition was selective to DNA-adduct-type chemotherapeutic platinum reagents. Therefore, TIE-1 is suggested to promote XPC-dependent NER, rendering ovarian cancer cells resistant to platinum. Accompanied with novel findings, TIE-1 could represent as a novel therapeutic target for platinum-resistant ovarian cancer.