tbuckley/cabot-search huggingface dataset:
p53 binds and regulates the PDGF β-receptor promoter
Authors: Keiko Funa, Weiwen Yang, Daniel Wetterskog, Yoshiki Matsumoto
Journal: Cancer Research (2007)

1202  Activated PDGF β-receptors (PDGFRB) serve as targets of drugs with proven anti-tumoral effects. Understanding the regulatory mechanism of the receptor expression is therefore important. We demonstrate that transient transfection of p53 repressed PDGFRB promoter activity in normal MEF cells as well as in p53 defective cells, such as p53-/- MEF and SAOS-2. However, induction of p53 in tet-on SAOS-2 cells caused the promoter activity to actually increase at early time points, but after 48 h the activity was repressed. EMSA revealed a direct binding of p53 to the promoter which contained the CCAAT-motif. After 8 h of tetracycline treatment the chromatin was precipitated with a p53 antibody and reprecipitated with antibodies against NF-YB and Sp1, thus being shown to co-exist closely. Chip assay and immunofluorescence staining with the SAOS-2 cells during the p53 induction confirmed the dynamic changes of the chromatin. As p53 increased, the previously bound p73, ΔNp73, myc, and HDAC1 disappeared from the promoter, followed by binding of p53 and p300, inducing PDGFRB. Along with further increase of the bound p53, p300 was replaced by HDAC1, resulting in disappearance of PDGFRB. The immunoprecipitated p53 was hyperphosphorylated at this time. These results suggest that the regulation of p53 on the PDGFRB promoter is a part of its program to orchestrate cellular responses, survival or apoptosis, to genomic stress.
Abstract 17510: B-Type Natriuretic Peptide May Be a Suitable Predictor for Sinus Maintenance After Pulmonary Vein Isolation in Patients With Enlarged Left Atrium
Authors: Koji Yasumoto, Masami Nishino, Kohei Ukita, Akito Kawamura, Motoki Yasunaga, Kyosuke Yanagawa, Hitoshi Nakamura, Yutaka Matsuhiro, Keisuke Yasumura, Akihiro Tanaka, Naoki Mori, Daisuke Nakamura, Masamichi Yano, Yasuyuki Egami, Ryu Shutta, Jun Tanouchi
Journal: Circulation (2017)

Background: Although in the patients with enlarged left atrium (LA) it is difficult to maintain sinus rhythm after pulmonary vein isolation (PVI), we occasionally experienced the patients who could...
A novel <i> <scp>NCSTN</scp> </i> missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease
Authors: T. Takeichi, T. Matsumoto, T. Nomura, M. Takeda, H. Niwa, M. Kono, H. Shimizu, T. Ogi, M. Akiyama
Journal: British Journal of Dermatology (2019)
Impact of absolute lymphocyte count on prognosis of aggressive non-Hodgkin lymphoma.
Authors: Anahat Kaur, Punita Grover, Sheetal Bulchandani, Thomas A Odeny, Sheshadri Madhusudhana, Anuj Shrestha
Journal: Journal of Clinical Oncology (2019)

e19034 Background: Multiple studies have attempted to identify parameters to predict prognosis and overall survival (OS) in Non-Hodgkin Lymphoma (NHL). Revised International Prognostic Index (R-IPI) is commonly used but does not capture all predictive risk factors in the Rituximab era. Low absolute lymphocyte count (ALC) on follow up after first line therapy has been reported to predict relapse. The prognostic value and exact cut off for low ALC at diagnosis is not known. We aimed to investigate whether ALC at time of diagnosis is an independent predictor for OS in aggressive NHL. Methods: We retrospectively evaluated patients with aggressive NHL treated at our center from 1/2000 to 12/2016 with at least 2 year longitudinal follow up after diagnosis. We retrieved data for baseline characteristics including age, sex, Ann Arbor stage, R-IPI score, HIV status, histopathological diagnosis (Diffuse Large B Cell Lymphoma (DLBCL), Burkitt′s lymphoma, Follicular Lymphoma Grade IIIB, high-grade B cell lymphoma), type of chemotherapy and clinical response. Patients were divided into four subgroups based on ALC at diagnosis: &lt; 500, 501-1000, 1001-1500 and &gt; 1500X10 9 /L. Statistical analysis was done using REDCAP and Stata v13. Results: A total of 92 patients were identified. The average age at diagnosis was 53.4 years, 63% were male and 73.5% were diagnosed with DLBCL. Per R-IPI score, 16.3% were high risk, 31.3% were high intermediate risk, 22.5% low intermediate risk and 30% were low risk. The median OS for patients with ALC &lt; 500 x109/L (5.4%) was 1.5 years, ALC 501-1000 (38%) was 2.3 years, ALC 1001-1500 (23.9%) was 4.25 years and ALC &gt; 1500 (32.6%) was 5.2 years. On multivariate analysis this difference was not statistically significant due to small sample size. Conclusions: We found that low ALC at diagnosis trended towards worse OS in aggressive NHL but did not reach statistical significance on multivariate analysis. Our study is limited by retrospective nature and sample size. Multicenter studies need to be done to validate these results. Studies are also needed to know the exact cut off for low ALC. [Table: see text]
Environmental exposure to traffic polycyclic aromatic hydrocarbons (PAHs) and risk of breast cancer
Authors: Jing Nie, Jan Beyea, Matthew Bonner, Daikwon Han, John Vena, Peter Rogerson, Dominica Vito, Paola Muti, Maurizio Trevisan, Jo Freudenheim
Journal: Cancer Research (2005)

2183  Polycyclic aromatic hydrocarbons (PAHs) are an important component of air pollution and potential human carcinogens. While they have been shown to cause mammary cancer in animal studies, the association between PAH exposure and breast cancer risk is not well understood. Traffic emissions are one of the major sources of PAH exposure in cities. Further, growing evidence suggests that there may be critical time periods of exposure in breast cancer initiation and development. In this study, we examined the association between breast cancer risk and exposure to PAHs from traffic emissions estimated for each woman at menarche, at the time when she had her first pregnancy and birth, and at 20 and 10 years prior to interview, using data collected from the Western New York Exposures and Breast Cancer (WEB) study, a population based case control study in western New York. All participants were women, aged 35-79, residents of Erie and Niagara Counties. Cases had incident, primary, histologically-confirmed breast cancer. Controls were randomly selected and frequency-matched to cases on age, race and county. In-person interviews were used to collect data on potential breast cancer risk factors including self-reported lifetime residential history. Traffic volumes on roads were obtained from historical records for the years from 1960-2002. Tailpipe emission data were based on previous reports, including measurements carried out in tunnels or on individual vehicles run in place on test beds. A geographic model, developed by Dr. Beyea and colleagues from the Long Island Breast Cancer project, was used to reconstruct historical traffic PAHs, using BaP as a surrogate for total PAH exposure. Cruise emissions, cold engine emissions and intersection emissions were used to estimate total traffic PAH emissions. Meteorological information was also utilized in the geographic dispersion model to assign PAH exposure at each residence. The model was validated using data collected from both Long Island and our study area. We found evidence that higher exposure to traffic PAH emissions at menarche was associated with increased risk of premenopausal breast cancer (OR 2.07, 95% CI 0.91-4.72, p for trend 0.03) and emissions at the time of a woman’s first birth was associated with postmenopausal breast cancer (OR 2.58, 95% CI 1.15-5.83, p for trend 0.19). Both associations were limited to lifetime non-smokers. There was no association of traffic emissions with risk for any of the other time periods. These findings provide evidence for both the potential importance of early exposures and the potential importance of an environmental agent in risk of breast cancer.
Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma
Authors: Xiaolong Li, Emmanuel Martinez-Ledesma, Chen Zhang, Feng Gao, Siyuan Zheng, Jie Ding, Shaofang Wu, Nghi Nguyen, Stephan C. Clifford, Patrick Y. Wen, Keith L. Ligon, W.K. Alfred Yung, Dimpy Koul
Journal: Cancer Research (2019)

Abstract PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere–forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor–induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. Significance: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.
Differential gene expression associated with the tropism between hepatic and pulmonary metastases in colorectal cancers.
Authors: Sung-Hyun Kim, So-Jung Choi, Jinseon Lee, Jhingook Kim
Journal: Journal of Clinical Oncology (2012)

e21062 Background: In metastatic colorectal cancers tumor cells were already disseminated, prior to surgical resection of the primary tumors, but micrometastases remain dormant until proper colonization mechanisms are activated. Specific aims of this study are, 1) to examine the colonization pathways and genes newly activated in metastatic tumors by longitudinal pair-wise comparisons between primary-to-metastatic tumors and 2) to understand tropism between colon-to-liver and colon-to-lung metastases at gene expression level. Methods: Total 24 tumor samples were prepared as longitudinal pairs from 6 hepatic, and 6 pulmonary cases. In these samples mRNA levels were quantitatively determined for 215 genes that were previously reported to play roles in metastasis, cytokines signaling, or angiogenesis, as provided as RT 2 Profiler TM PCR arrays (PAHS-022, 024, 028). Unsupervised hierarchical clustering of Ct values and heat map analyses of DCt values were carried out using web based data analysis program, and 17-gene tropism signature was selected for stratification of the hepatic and the pulmonary metastases. Results: Ct values of 23 duplicated genes and 5 house-keeping genes showed plate-to-plate correlation of 0.92. Unsupervised hierarchical clustering of the Ct values from the Metastasis Arrays revealed that the hepatic metastases were indistinguishable from the primary colorectal cancers (n=5/6), but the lung metastases were highly diversified (n=6/6). Cytokine Array data also showed the divergence of pulmonary metastases from the primary colorectal cancers (n=6/6). Heat map analyses of DCt values from the Metastasis Arrays identified 17-gene tropism signature that was sufficient not only to distinguish the liver and the lung metastases, but also reconstitute the clustering of primary tumors with the hepatic metastases. Conclusions: Intrinsic difference existed between the pulmonary and hepatic metastases of colorectal origins among the tested samples. 17-gene tropism signature was identified, and further genomic and clinical studies are in process to validate their potentials as therapeutic targets to treat pulmonary metastases of colorectal cancers.
Gluten and Celiac Disease Risk
Authors: Maureen M. Leonard, Alessio Fasano
Journal: JAMA (2019)

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AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells
Authors: Jimena Trillo-Tinoco, Rosa A. Sierra, Eslam Mohamed, Yu Cao, Álvaro de Mingo-Pulido, Danielle L. Gilvary, Carmen M. Anadon, Tara Lee Costich, Sheng Wei, Elsa R. Flores, Brian Ruffell, José R. Conejo-Garcia, Paulo C. Rodriguez
Journal: Cancer Research (2019)

Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.
Hydroquinone, a benzene metabolite, produces chromosomal endoreduplication and translocations associated with catalytic inhibition of DNA topoisomerase II
Authors: Zhiying Ji, Luoping Zhang, Weihong Guo, Martyn Smith
Journal: Cancer Research (2008)

594  Benzene is an established human leukemogen, but the mechanism of its leukemogenesis remains unclear. Inhibition of DNA topoisomerase II (topo II) by conversion of hydroquinone (HQ) to benzoquinone in the bone marrow is one potential mechanism underlying the carcinogenic effects of benzene. Topo II is a nuclear enzyme that catalyzes topological changes in DNA. Topo II inhibitors are generally classified into two groups, poisons and catalytic inhibitors, on the basis of their mechanisms of action. Topo II poisons, such as etoposide, induce DNA double strand breaks through the stabilization of the covalent “cleavable complex” between the enzyme and DNA and cause translocations of the MLL gene at 11q23. In contrast, topo II catalytic inhibitors affect the enzyme activity without stabilizing the cleavable complex and induce chromosomal translocations that confer a good prognosis such as t(8;21), and endoreduplication, a rare mitotic phenomenon. Endoreduplcation consists of two successive rounds of DNA replication without intervening mitosis, i.e. segregation of daughter chromatids. In order to explore the mechanism and consequences of topo II inhibition by benzene and its metabolites in intact cells, we treated TK6 cells, a human lymphoblastoid cell line, with HQ (0, 5, 10, 15 and 20 μM) or etoposide (0, 0.05 and 0.1 μM) for 48 h. Metaphase spreads were arrested following colcemid addition for 2 h and examined to determine levels of endoreduplication. Translocations of chromosomes 11 and 21 were detected using fluorescence in situ hybridization (FISH) specific probes. HQ produced a dose-dependent increase in the frequency of endoreduplication in TK6 cells (Ptrend
Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial (Nature Medicine, (2019), 25, 6, (920-928), 10.1038/s41591-019-0432-4)
Authors: Leonie Voorwerk, Maarten Slagter, Hugo M. Horlings, Karolina Sikorska, Koen K. van de Vijver, Michiel de Maaker, Iris Nederlof, Roelof J. C. Kluin, Sarah Warren, SuFey Ong, Terry G. Wiersma, Nicola S. Russell, Ferry Lalezari, Philip C. Schouten, Noor A. M. Bakker, Steven L. C. Ketelaars, Dennis Peters, Charlotte A. H. Lange, Erik van Werkhoven, Harm van Tinteren, Ingrid A. M. Mandjes, Inge Kemper, Suzanne Onderwater, Myriam Chalabi, Sofie Wilgenhof, John B. A. G. Haanen, Roberto Salgado, Karin E. de Visser, Gabe S. Sonke, Lodewyk F. A. Wessels, Sabine C. Linn, Ton N. Schumacher, Christian U. Blank, Marleen Kok
Journal: Nature Medicine (2019)
Filthy Lucre or Fitting Offer? Understanding Worries About Payments to Research Participants
Authors: Emily A. Largent, Ezekiel J. Emanuel, Holly Fernandez Lynch
Journal: The American Journal of Bioethics (2019)

This article refers to:How Payment for Research Participation Can Be Coercive“Paid to Endure”: Paid Research Participation, Passivity, and the Goods of Work
Mechanism of regulation of NTH1 in tumorigenesis of LEC rat liver
Authors: Sujata Choudhury, Shyama Prasad Sajankila, Rabindra Roy
Journal: Cancer Research (2005)

3045  Oxidative stress is arguably the most important cause of cellular genotoxicity, which is thought to cause diseases such as cancer and neurological disorders. Recent studies have linked oxidative stress and chronic inflammation with an increased risk of cancer. Certain diseases, characterized by oxyradical overload, such as Wilson’s disease (WD) also have been associated with the higher risk of liver cancer. The Long Evans Cinnamon (LEC) rat, an animal model for WD, proved to be very useful in studying mechanisms of spontaneous carcinogenesis. LEC rats are a mutant strain of Long-Evans rats and are genetically predisposed to spontaneous HCCs as compared with the wild-type control Long Evans Agouti (LEA) rats. Because of the genetic copper metabolism disorder LEC rats develop hepatitis 4 months after birth, followed by chronic hepatitis later in life, and eventually all of the surviving animals from liver injury and hepatitis develop spontaneous hepatocellular carcinomas. Thus, the LEC rats having this genetically induced oxidative condition are also found to be very useful model in our laboratory for the study of repair of endogenous DNA lesions and their relation to spontaneous carcinogenesis. Previously we have shown that the repair excision activity of mutagenic oxidized bases, mediated by DNA glycosylases such as NTH1, was significantly altered at different stages of HCC development in LEC rats compared to the control LEA rats (Choudhury et. al. Cancer Res. 63:7704, 2003). In addition to the alteration of enzymatic activity, mRNA level of NTH1 was also modulated significantly in LEC rat liver during tumorigenesis. This prompted us to elucidate the transcriptional regulatory mechanism of NTH1 expression in LEC rat liver during tumorigenesis. We have found that at different ages the expression profile of NTH1 in LEC and LEA rat livers is appreciably correlated with the activity pattern of NTH1. In LEC rat liver the expression of NTH1 mRNA was significantly decreased during acute hepatitis period and prior to the formation of preneoplastic foci. Moreover, the Electrophoretic Mobility Shift Assay revealed the binding of specific proteins to the Ets binding sites (EBS) in the the NTH1 promoter sequences. Notably, the EBS-protein complexes were significantly decreased at the same time period (acute hepatitis) in LEC rat liver and appear to be correlated with the expression of NTH1 gene. Furthermore, among the Ets family proteins, Eif-1 or related factors were found to play a major role in regulation of NTH1 gene expression during liver tumorigenesis in LEC rats (RO1 CA 92306).
ABC of conflict and disaster:Weapons of mass destruction threats and responses
Authors: Christine Gosden, Derek Gardener
Journal: BMJ (2005)

Weapons of mass destruction (WMD) include chemical, biological, and radiological agents with the potential to cause death at low doses and with serious long term health effects in survivors. This article provides general information relevant to all situations, from terrorist attacks in developed countries to conflict zones in Third World countries. WMD agents can be used to terrorise or subjugate populations and wreak economic damage. Many agents are cheap to produce and can be deployed in different ways. As well as overt use, such as in bombs or by aerial spraying, they can be used covertly such as in packages sent in the post, via animal vectors, or by poisoning of water and food supplies.

The classic scenario of WMD use against civilians (the basis of many current exercises) is the release of the nerve agent satin in the Tokyo subway. In this attack the actions of first responders and medical staff helped keep the final fatalities down to 12. Because they lacked protective clothing, however, many of these people absorbed sarin from victims' clothing and developed serious long term neurological complications. Other agents-such as mustard agent, VX, anthrax, and radiation-are more persistent and thus pose greater risks: doses to victims would be higher, attending staff would face protracted periods in protective clothing, and the threat would remain until full decontamination was achieved.

The diversity and gravity of threats are exemplified by the recent anthrax attack on the US Congress through the postal system. It claimed few victims, thanks to rapid intervention by bioweapons specialists, but it paralysed the postal system and cost over $6bn to clean up.

For the past seven years we have collaborated in a programme to treat and study the immediate and long term effects of WMD on the people of Halabja in northern Iraq. Our …