tbuckley/cabot-search huggingface dataset:
A novel variant of estrogen receptor-alpha is expressed in ER-negative breast cancer and mediates membrane-initiated estrogen signaling
Authors: Xin-Tian Zhang, Shen Peng, Jiang Cao, Brian W. Loggie, Zhaoyi Wang
Journal: Cancer Research (2005)

1299  Since 1977, numerous studies have indicated the existence of a putative membrane-based estrogen receptor. However, the identity of this membrane-based estrogen receptor has not been established. Through an extensive homology search in Gene Bank, we recently identified and cloned a novel variant of ER-Α with a predicted molecular weight of 35.7 kDa. The transcript of this ER-Α variant is initiated from a previously unidentified promoter in the first intron of the original ER-Α gene. This ER-Α variant differs from the original ER-Α by lacking both transcriptional activation domains (AF-1 and AF-2) but retaining the dimerization, DNA-binding and partial ligand-binding domains. Its ligand-binding domain also possesses a unique 27 amino acid stretch that replaces the last 138 amino acids of the ER-Α. In transient transfection assays, this ER-Α variant exhibited no intrinsic transcriptional activity but strongly inhibited ligand-dependent and -independent transactivation activities mediated by the original ER-Α and ER-Β. Immunodetection and subcellular fractionation assays demonstrated that this ER-Α variant is expressed on the plasma membrane of mammary epithelial cells, and also in the cytoplasm and nucleus. In cells that express this ER-Α variant, 17Β-estradiol (E2) treatment activated a membrane-initiated effect of estrogen signaling by transiently activating the mitogen-activated protein kinase (MAPK) pathway that led to cell proliferation. Antiestrogens such as tamoxifen and ICI 182,780, however, strongly and persistently activated the MAPK pathway that then resulted in activation of the SAPK/JNK pathway. Immunohistochemistry analysis using a specific antibody aganst this ER-Α variant revealed that 26 of 38 cases (68%) breast cancer specimens examined express this ER-Αvariant on the plasma membrane and cytoplasm, and 12 out of 13 ER-negative breast caner specimens also express this ER-Α variant. Our findings demonstrate a physiologically important ER-Α variant that is involved in membrane-initiated estrogen signaling and suggest that aberrant expression of this ER-Α variant contributes to development of ER-positive and-negative human breast cancer.
Post-translational modification of BUB3, a mitotic checkpoint protein, by SUMO and ubiquitin in the development of cancer.
Authors: Jennifer Yeh, Bongha Shin, Louis Dubeau
Journal: Cancer Research (2007)

5210  Primary cultures derived from benign epithelial tumors (cystadenomas) were infected with an adenoviral vector for SV40 large T antigen, leading to the isolation of a cell strain called ML10. These cells can be propagated for at least 40 population doublings in vitro before undergoing a crisis characterized by severe numerical chromosomal instability resulting in aneuploidy. A clone of ML10, called MCV50, spontaneously immortalized, providing a longitudinal in vitro model of ovarian cancer development.  We hypothesized that the post-translational modifications catalyzed by ubiquitin and SUMO are associated with the phenomena of in vitro crisis and immortalization. Hence, nuclear protein extracts isolated from ML10 (mortal) and MCV50 (immortal) cells were separated by two-dimensional gel electrophoresis and analyzed by Western blotting using antibodies against ubiquitin and SUMO. Two protein complexes, with respective molecular weights of 40kDa and 105kDa, appeared to be differentially ubiquitinated and sumoylated in ML10 and MCV50 cells. Protein sequencing analyses revealed that both protein complexes contained BUB3, an important checkpoint protein that plays a critical role in mitotic regulation by ensuring that cells with misaligned chromosomes do not prematurely enter anaphase. This is achieved in part by inhibition of the anaphase promoting complex (APC), an ubiquitin ligase necessary for chromosomal separation. Western blot analysis of ML10 and MCV50 nuclear protein extracts confirmed that BUB3 co-immunoprecipitated with both post-translational modifier proteins in complexes of similar sizes to those observed in the two-dimensional gels. A higher abundance of the sumoylated 105kDa complex was seen in ML10, while a higher abundance of the ubiquitinated 40kDa complex was seen in MCV50.  Given that ML10 cells typically undergo a G2/M arrest as they approach crisis and given the role of BUB3 in ensuring proper chromosomal segregation, we hypothesize that formation of the sumoylated 105 kDa protein complex may be triggered by mitotic errors and plays an active role in the establishment of cell cycle arrest at the G2/M phase in response to such errors. This would explain why immortal cells such as MCV50, that have recovered from crisis and have a stable ploidy compared to cells in crisis, only show trace amounts of this sumoylated complex. The apparent inverse relationship between expression of the sumoylated 105kDa BUB3 complex and that of the ubiquitinated 40kDa BUB3 complex suggests a role for ubiquitination in down-regulation of the 105kDa complex.
Urinary 1-Hydroxypyrene Glucuronide: A Sensitive Exposure Marker of PAHs at Low Levels Encountered in Ambient Air
Authors: Yu Hu, Zongcan Zhou, Xiaonan Xue, Xiaomei Li, Juanling Fu, Beverly Cohen, Assieh A. Melikian, Meng-Shong Tang, Nirmal Roy, Jianya Sun, Qingshan Qu
Journal: Cancer Research (2005)

2186  A biomarker validation study has been being conducted in a Chinese population with occupational or environmental exposures to PAHs. So far, 106 subjects have been recruited from coke oven workers (workers), residents in a metropolitan area (residents), and gardeners in suburb (gardeners). All subjects were monitored twice for their personal exposures to PAHs. The biological samples were collected for measurements of 1-hydroxypyrene (1-OHP) in urine and identification of polymorphisms of genes encoding for metabolic enzymes, including CYP1A1, microsomal epoxide hydrolase (mEH), and GSTM1 in lymphocytes. The average personal exposure levels of pyrene, benz (a) anthracene (BaA) and benzo (a) pyrene (BaP) in exposed workers were 15.1 ± 48.2 μg/m3, 4.4 ± 8.3 μg/m3 and 4.3 ±9.9 μg/m3, respectively. The corresponding levels in residents were 0.057 ± 0.004 μg/m3, 0.034 ± 0.003 μg/m3 and 0.028 ± 0.002 μg/m3, and those in gardeners were 0.016 ± 0.017 μg/m3, 0.022 ± 0.011 μg/m3, and 0.011 ± 0.011 μg/m3 respectively. The conjugate of 1-OHP with glucuronide (1-OHP-G) is the predominant form of pyrene metabolite in urine and showed strong associations with exposures not only to pyrene but also to BaA, BaP, and total PAHs. Most importantly, a significant difference in 1-OHP-G was even detected between gardeners and residents with exposures to BaP at 0.011 and 0.028 μg/m3, suggesting that 1-OHP-G is a good marker that can be used for risk assessment of BaP exposure at ambient levels. Furthermore, multiple regression analyses of 1-OHP-G on PAHs exposure indicated that smoking was an important confounding factor on urinary 1-OHP-G level, especially when exposure to low level of environmental PAHs. The potential effects of gene polymorphisms on the formation of 1-OHP-G were examined based on either individual genotype or combination of genotypes of the four. However, none of the examinations showed any significant association of 1-OHP-G with polymorphisms of CYP1A1, mEH, GSTM1, and GSTT1 probably due to relatively small number of samples (supported by grants: OH007632; ES00260).
LncRNA-CASC7 enhances corticosteroid sensitivity via inhibiting the PI3K/AKT signaling pathway by targeting miR-21 in severe asthma
Authors: Jian-Hua Liu, Chen Li, Chang-Hong Zhang, Zhi-Hua Zhang
Journal: Pulmonology (2019)

Asthma, a common chronic inflammatory disease, is treated with corticosteroid in most cases, but corticosteroid resistance in severe asthma patients seriously impairs the therapeutic effects. LncRNA-CASC7 inhibits cell proliferation and enhances drug sensitivity, but the molecular mechanisms of corticosteroid resistance in severe asthma are still unknown. Airway smooth muscle cells (ASMCs) from healthy and severe asthmatic subjects were used in this study. The expression of CASC7 and miR-21 were modified by transfection with the pcDNA3.1-CASC7, miR-21 mimics and inhibitor. MTT assay was conducted to measure cell proliferation. ELISA assay was used to determine the secretion of CCL5, CCL11 and IL-6. The phosphorylation of glucocorticoid receptor (GR) and the PI3K/AKT signaling were assessed by western blotting assays. qRT-PCR was used to analyze the expression of CASC7, miR-21 and PTEN. Dual-luciferase reporter assay was used to assess the interaction among CASC7, miR-21 and PTEN. Compared with AMSCs from severe asthma patients, dexamethasone inhibited cytokines (CCL5, CCL11 and IL-6) and promoted the phosphorylation of GR more significantly in normal AMSCs. CASC7 expression was suppressed while miR-21 expression and AKT activity were promoted in ASMCs from severe asthma patients. CASC7 promoted PTEN expression via directly inhibiting miR-21 expression. Overexpression of CASC7 suppressed the PI3K/AKT signaling pathway and promoted the inhibition effects of dexamethasone on cell proliferation and cytokines secretion via targeting miR-21. CASC7 increased corticosteroid sensitivity by inhibiting the PI3K/AKT signaling pathway via targeting miR-21, which provided a promising potential target for designing novel therapeutic strategy for severe asthma.
The LATS2/KPM tumor suppressor is negative regulated by miR-373 in human esophageal cancer
Authors: Kuen-Haur Lee, Yih-Gang Goan, Yuh-Ling Chen, Pei-Jung Lu
Journal: Cancer Research (2008)

5066  Lats2 is a member of the Lats tumor suppressor family. LATS2 has been demonstrated to negatively regulate the cell cycle through regulating G1/S and/or G2/M transition. Recent studies have reported that Lats2 frequent polymorphic changes in esophageal squamous cell carcinoma (ESCC). In this study, we showed that the high expression of LATS2 protein level in human ESCC normal part tissues compared with the adjacent tumor parts. The regulatory mechanism of LATS2 protein level, however, remains nuclear. MiRNAs are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. A number of evidences also concluded that alteration of specific miRNAs expression affect on carcinogenesis. Our results indicated that the LATS2 protein expression may be controlled by microRNA (miRNA). In this study, we used miRNA oligonucleotide array platform to identify the up-regulation of miR-373 in five human ESCC tumor specimens. By quantitative RT-PCR analysis, our results showed that the up-regulation of miR-373 was exceeding 26% in ESCC tumor tissues versus normal tissues. This was consistent with the finding that the miR-373 level in ESCC cell lines is 32~85 fold higher than that of the esophageal normal tissues. Interestingly, miR-373 target protein-LATS2 shows low expression is 28% in ESCC tumor tissues examined. In addition, by in vitro transient transfection of miR-373, the expression of LATS2 protein was suppressed supported that miR-373 mediated the suppressed of translation. In conclusion, our finding suggested the roles of miRNA-373-mediated the LATS2 translational repression may play a role in esophageal cancer tumorigenesis.
Impact of <i>UGT1A4</i>, <i>UGT2B7</i>, and <i>UGT2B15</i> pharmacogenetics on tamoxifen (TAM) metabolism.
Authors: Joanne Siok-Liu Lim, Boian Ganchev, Onkar Singh, Thomas E Muerdter, Yoon Sim Yap, Raymond C.H. Ng, Nan Soon Wong, Matthias Schwab, Balram Chowbay
Journal: Journal of Clinical Oncology (2013)

2588 Background: The aims were to characterize the genetic profiles of UGT1A4, UGT2B7 and UGT2B15in Asian healthy populations (Chinese, Malay, Indians, N=80 each) and investigate the effects of these SNPs on the disposition of TAM in Asian breast cancer patients (N=202). Methods: Healthy Asian subjects and Asian breast cancer patients were genotyped for UGT1A4, UGT2B7 and UGT2B15 SNPs. Plasma levels of tamoxifen and its metabolites in Asian patients were determined via LC-MS/MS analysis. Genotypic-phenotypic differences were examined using non-parametric tests. Haplotypic effects were examined using haplotype-specific generalized linear model. Results: Screening of the 5′ upstream, exonic, exonic-intronic junctions and 3′ downstream regions identified 61, 77 and 47 SNPs in UGT1A4, UGT2B7 and UGT2B15respectively. A total of 16, 14 and 20 tag-SNPs were identified in these genes respectively and genotyped in patients. Haplotypic analysis revealed associations between LD block 1 (-1548A&gt;G, -1531C&gt;T, -419G&gt;A, -219C&gt;T, -163G&gt;A, 142T&gt;G, 448T&gt;C, 804G&gt;A, IVS1+196T&gt;C, IVS1+346T&gt;G, IVS1+414A&gt;G, IVS2+307A&gt;G) and higher plasma Tam-N-Gluc level and MR TAM-N-Gluc/TAM after adjustment for significant covariates. The median (range) MR TAM-N-Gluc/TAM was 2.1- and 1.9-fold higher among patients carrying one and two copies of H2 (GCATAGCACTGG), respectively, compared to patients who carried two copies of H1 haplotype (ACGCGTTGTTAA) [H1/H1 vs H1/H2 vs H2/H2: 0.35 (0.11 - 2.09) vs 0.74 (0.19 - 3.60) vs 0.66 (0.52 - 1.66), P &lt; 0.0001]. Similar association was observed between H2 and Tam-N-Gluc level [H1/H1 vs H1/H2 vs H2/H2: 0.75 (0.15 - 4.45) vs 1.29 (0.19 - 9.20) vs 1.66 (0.62 - 2.83) ng/ml, P= 0.004]. UGT2B15 LD block 3 (1568A&gt;C, *168C&gt;T, *186A&gt;T, *+630C&gt;G and *+888A&gt;G) was associated with modest decrease and increase in (E)-END and MR Z-NDM-4-O-GLUC/E-END , respectively. UGT2B7haplotypes were not associated with O-glucuronidations of 4-OHT and END. Conclusions: This study highlights the involvement of UGT1A4 haplotypes in the variability in TAM N-glucuronidation while UGT2B7 and UGT2B15 variants played limited role in the variabilities of O-glucuronidations of 4-OHT and END in Asian breast cancer patients. Clinical trial information: 0822570P.
Effect of isoflavones on oral squamous cell carcinoma cell lines.
Authors: Tara Johnson, Maria B. Lai, Shilpa Puli, Solomon W. Leung, James Ck Lai, Alok Bhushan
Journal: Cancer Research (2006)

5086  High morbidity and mortality associated with oral squamous cell carcinoma (OSCC) are largely due to late stage diagnosis. Despite significant advances in therapeutic strategies, the five-year survival rate for oral cancer remains at about fifty percent. A chemopreventive approach may be an effective alternative or adjunct to current therapies. Previous studies have shown anti-tumor effects of soy isoflavones in several cancers, including oral cancer. However, their mechanisms of action are still unclear. We hypothesized that soy isoflavones may inhibit multiple signaling pathways implicated in oral carcinogenesis. Our aim was to investigate the in vitro effects of three isoflavone derivatives, genistein, biochanin A, and daidzein, on SCC15 and SCC25 squamous cell carcinoma cell lines. In cell proliferation experiments, using MTT assays, we found that genistein, biochanin A, and daidzein inhibited SCC15 and SCC25 cell growth with an IC50 of 42μM, 48μM, and 67μM, respectively. We investigated the effect of isoflavones on ERK and AKT pathways. Our results, from western blot analysis, suggest that both genistein and biochanin A induced decreases in phosphorylation of ERK and AKT at 50μM and 100μM concentrations. Taken together, our results clearly demonstrate a differential regulation of oncogenic pathways by various soy isoflavones in OSCC cell lines. Thus, in vitro tumor progression models can be utilized to study the preventive and therapeutic roles of soy isoflavones in OSCC. (Our work was supported, in part, the University Research Committee, ISU, grant #FY2002-09 and NIH/NCRR INBRE, grant #P20RR16454.)
The Amount of Evidence Needed to Support ERBB2 as a Biomarker for Resistance to EGFR Inhibitors in Metastatic Colorectal Cancer
Authors: Kanwal Raghav, John H. Strickler
Journal: JAMA Oncology (2019)

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The association between cadmium exposure and chronic airflow limitation and emphysema: the Swedish CArdioPulmonary BioImage Study (SCAPIS pilot)
Authors: Kjell Torén, Anna-Carin Olin, Åse Johnsson, Jenny Vikgren, Niklas Forsgard, Göran Bergström, Gerd Sallsten, Lars Barregård
Journal: European Respiratory Journal (2019)

<b>In this general population sample with detailed control for smoking habits there is an association between blood cadmium and emphysema based on lung computed tomography</b>http://bit.ly/2K9S39J
Ret finger protein mediates MBD2- and MBD4-dependent transcriptional repression
Authors: Shinichi Fukushige, Zhaodi Gu, Emiko Kondo, Akira Horii
Journal: Cancer Research (2006)

21  The methyl-CpG binding domain protein 4, MBD4, has long been thought to be a thymine DNA glycosylase that repairs G-T mismatches originated by deamination of 5mC at CpG sites. However, recently we demonstrated that MBD4 also has the ability to repress transcription through methyl-CpG sequences and is associated with methylated promoters in p16INK4a and hMLH1 genes. In order to further investigate the role of MBD4 in methylation-based transcriptional repression, a yeast two-hybrid screen was performed and Ret finger protein (RFP) was found to interact with the transcriptional repression domain of MBD4. Because it has been reported that RFP was highly expressed in a variety of human and rodent tumor cell lines, and was involved in transcriptional repression through Enhancer of Polycomb 1 (EPC1) and Mi-2β, we assessed the functional implication of the MBD4-RFP association by examining the effect of RFP on repression activity of MBD4. Expression of RFP extremely enhanced the MBD4-mediated transcriptional repression in both methylated p16INK4a and hMLH1 promoters. Furthermore, RFP forms a protein complex with MBD2 and MBD3 through Mi-2β, and was also shown to be involved in transcriptional repression through MBD2. Therefore, these results suggest that RFP is one of essential components involved in transcriptional repression through MBD2, MBD3, and MBD4.
Identity leadership: Managing perceptions of conflict for collective action
Authors: Philip Pärnamets, Diego A. Reinero, Andrea Pereira, Jay J. Van Bavel
Journal: Behavioral and Brain Sciences (2019)

Abstract We argue that how players perceive the attack-defense game might matter far more than its actual underlying structure in determining the outcomes of intergroup conflict. Leaders can use various tactics to dynamically modify these perceptions, from collective victimization to the distortion of the perceived payoffs, with some followers being more receptive than others to such leadership tactics.
Abstract 269: Bedside Monitoring of Peripheral Blood Perfusion Using Pulse Oximetry Sensor and its Reliability and Clinical Usefulness Compared With Traditional Capillary Refill Measurement
Authors: Koichiro Shinozaki, Kota Saeki, Lee Jacobson, Julianne Falotico, Timmy Li, Lance B Becker
Journal: Circulation (2018)

Objective: The traditional capillary refill time (CRT) assessment is a manual measurement that is commonly used by clinicians to identify a shock status. Given that the measurement is manual only, it is a relatively subjective measurement. Our study tested an investigational CRT device, comprised of existing pulse oximeter technology paired with a novel measuring algorithm, at an emergency department (ED) setting to determine its reliability and clinical usefulness compared with the traditional, manual CRT assessment. Methods: Three healthcare providers (registered nurses or physician assistants) were selected to perform manual CRT assessments at the bedside to classify patients into either a normal (≤2 seconds) or abnormal (&gt;2 seconds) CRT groups. An attending ED physician, blinded from the healthcare providers’ classifications, quantitatively measured CRT using a chronograph (visual CRT). The pulse oximeter sensor was attached to the same hand used for visual CRT assessments but on a different fingertip. Visual and device CRTs were measured alternately and were repeated three times for each method. Device CRT data from 30 healthy volunteers in a previous study was used as a reference. Results: Thirty ED patients were recruited. Mean device CRT of ED patients (3.9±2.7 sec) was significantly longer than those of healthy volunteers (2.0±1.0 sec, p&lt;0.01). Mean visual CRT of ED patients was 1.9±0.8 seconds and was significantly correlated with device CRT (r=0.723, p&lt;0.001). Area under the receiver operator characteristic curve (AUC) to predict whether or not visual CRT was greater than or less than 2.0 seconds was 0.84 (95% CI 0.70-0.98). The ED physician identified 10 patients with abnormal CRT, while only two patients were classified to the abnormal CRT group by healthcare providers. Intra-rater reliability of the device CRT was 0.88 (95% CI 0.79-0.94) and that of the visual CRT was 0.92 (0.85-0.96). 12 patients were admitted to the hospital. AUC to predict patient admission was 0.67 (95% CI 0.46-0.87) by device CRT and 0.76 (0.58-0.94) by visual CRT. Conclusions: CRT assessments by healthcare providers were variable compared with those of the ED physician. Device CRT was as reliable and useful as the CRT measured quantitatively by the ED physician.
Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia
Authors: Ziyou Yu, Nevin Witman, Wenbo Wang, Dong Li, Bingqian Yan, Mingwu Deng, Xiangsheng Wang, Huijing Wang, Guangdong Zhou, Wei Liu, Makoto Sahara, Yilin Cao, Regina Fritsche-Danielson, Wenjie Zhang, Wei Fu, Kenneth R. Chien
Journal: Journal of Controlled Release (2019)