tbuckley/cabot-search huggingface dataset:
The B-Cell Receptor Signaling Inhibitor Molecules CD305 and CD307b Are Markers of Favorable Prognosis in Chronic Lymphocytic Leukemia with Both Mutated and Unmutated IGHV Gene Status
Authors: Dania Benedetti, Claudia Perini, Erika Tissino, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Francesca Rossi, Massimo Degan, Alessandro Poggi, Mahdi Shabani, Fazel Shokri, Francesco Zaja, Gabriele Pozzato, Annalisa Chiarenza, Francesco Di Raimondo, Giovanni Del Poeta, Valter Gattei, Antonella Zucchetto
Journal: Blood (2016)
Abstract 2549: A long non-coding RNA regulates the androgen receptor and mediates prostate cancer progression
Authors: Sethuramasundaram Pitchiaya, Rohit Malik, Marcin Cieslik, Yajia Zhang, Xia Jiang, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract The pervasive expression of long non-coding RNAs (lncRNAs) and their roles in a plethora of cellular processes has revolutionized our understanding of functional genetic elements. Emerging evidence suggest that lncRNAs are promising cancer biomarkers and dysregulation of lncRNAs results in attenuated or accelerated oncogenic phenotypes. In support of these findings, recent reports from the Chinnaiyan lab suggest that lncRNAs can potentially drive and act as independent predictors of aggressive prostate cancer (PCa). Central to PCa progression is the androgen receptor (AR), a nuclear hormone receptor, and the dysregulated transcription program it mediates. Consequently, androgen deprivation therapy (ADT) supplemented with anti-androgens is the initial standard-of-care in treating advanced PCa. Yet, the disease often manifests as a lethal, hormone-refractory castration-resistant prostate cancer (CRPC) after initial ADT and this phenomenon is linked to the resumption of AR activity. Therefore, we sought to identify novel and therapeutically actionable targets of AR that can detect the onset of PCa or stratify PCa variants. To this end, our lab recently characterized the transcriptional landscape of cancer and discovered &amp;gt; 50,000 novel transcripts, a significant fraction of which were tissue- and cancer-specific lncRNAs. Using this updated transcriptome as a reference and performing RNA-seq on PCa cells stimulated with dihydrotestosterone (an androgen), we identified Androgen Receptor regulated lncRNA-1 (ARlnc1) as an important PCa-specific, AR-regulated lncRNA that reciprocally regulates AR. By employing single-molecule fluorescence in situ hybridization (smFISH), we find that ARlnc1 and AR transcripts colocalize within the nucleus of PCa cells and that ARlnc1 promotes transcription of AR. Moreover, we found that ARlnc1 interacts with anti-apoptotic, stress-granule related proteins and regulates PCa cell proliferation in vitro and in mouse xenografts. We have additionally found that anti-sense oligonucleotides (ASOs) that target this lncRNA can reduce tumor growth in xenograft models. Taken together, our data suggests that ARlnc1 and AR reciprocally and positively modulate each other to promote PCa progression and that ARlnc1 may serve as an enhancer RNA that regulates AR transcription. Our data suggests that ARlnc1 can be therapeutically targeted to orthogonally modulate the AR signaling axis for PCa treatment. Citation Format: Sethuramasundaram Pitchiaya, Rohit Malik, Marcin Cieslik, Yajia Zhang, Xia Jiang, Arul M. Chinnaiyan. A long non-coding RNA regulates the androgen receptor and mediates prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2549. doi:10.1158/1538-7445.AM2017-2549
Abstract 4166: Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells
Authors: Chen Chen, Shujie Zhao, Xiangru Zhao, James W. Freeman
Journal: Cancer Research (2017)

Abstract Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) may show an initial objective response to chemotherapy that is usually of short duration. Our research goal is to understand the molecular mechanisms for this short duration response and to more fully define differences between chemosensitive and chemoresistant cells. Cancer cells that undergo an EMT and metastatic tumors show an increase in CD44s expression. In this study, we use CD44 Low and CD44 High isogenic cell models to identifying key molecular networks and potential targets that could benefit therapy. Experiments design: CFPAC1-CD44 Hi and Low cells were sorted by flowcytometry and single clone selection. Isogenic model systems were generated by overexpression CD44s in CF-Low cells. Western blot, MTT, migration and invasion assays had been used to characterize cell growth, invasiveness and gemcitabine sensitivity. Receptor Tyrosine Kinase arrays were used to identify the CD44 regulated molecular networks in these isogenic cell models treated with/without CD44 ligand hyaluronan acid (HA). Summary: CD44s high cells show an EMT phenotype (increase of vimentin and loss of E-cadherin) and increase invasion. Expression of CD44s in CD44 low cells was sufficient to drive EMT partially and drive invasion. By in vitro testing over expressing CD44s is not sufficient to decrease sensitivity to gemcitabine. By Receptor Tyrosine Kinase arrays, CD44 Hi clone cells show increase in IGF-1R phosphorylation. Preliminary data had shown that HA may stimulate ROR2, VEGFR1, and EphB2 phosphorylation in CD44 Hi clone cells. Conclusion: Our previous study suggested that CD44 could be a therapeutic target in Gemcitabine resistant PDAC cells. The current study will further identify the molecular targets that regulated by CD44 pathways. These newly identified targets could be hopefully used for the optimized multimodality therapy to sensitize the PDAC cells to therapy and to benefit the pancreatic cancer patients. Citation Format: Chen Chen, Shujie Zhao, Xiangru Zhao, James W. Freeman. Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4166. doi:10.1158/1538-7445.AM2017-4166
Norway ranks first on supporting elderly people, UK 11th
Authors: Nigel Hawkes
Journal: BMJ (2017)

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Abstract 4477: HnRNP Q1 translationally increases the expression of Aurora-A and promotes tumorigenesis in colorectal cancer
Authors: Liang-Yi Hung
Journal: Cancer Research (2017)

Abstract Abnormally elevated Aurora-A can cause mitotic defects and aneuploidy, which might lead to genomic instability and tumorigenesis. According to the literatures, overexpressed Aurora-A may result from gene amplification, RNA transcriptional activation, or increased protein stability. Our previous study has demonstrated that Aurora-A can be translational upregulated in colorectal cancer. By biotin pull-down assay and in vivo translational assay, we found that Aurora-A mRNA can be translational upregulated by heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, a RNA binding protein. Hn RNP Q1 has been implicated in many posttranscriptional regulatory processes including mRNA splicing, RNA metabolism and translation. In this study, we further clarified the regulatory mechanism of hnRNP Q1 in translational regulating Aurora-A mRNA, as well as investigated the clinical role of hnRNP Q1 in colorectal carcinogenesis. Our results indicated that hnRNP Q1 can bind to the Aurora-A mRNA 5’-untranslated region (5’-UTR). Ribosomal protein S6-IP assay further indicated that hnRNP Q1 can enhance the translational efficacy of Aurora-A mRNA. Ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1. Overexpression of hnRNP Q1 promotes cell proliferation and tumor growth. The expression level of hnRNP Q1 is positively correlated with Aurora-A in colorectal cancer. Taken together, our data indicate hnRNP Q1 is a novel trans-acting factor that binds to Aurora-A mRNA 5’-UTRs and regulates its translation, which increases cell proliferation and contributes to tumorigenesis in colorectal cancer. Citation Format: Liang-Yi Hung. HnRNP Q1 translationally increases the expression of Aurora-A and promotes tumorigenesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2017-4477
Abstract 1731: Analysis of prostate cancer circulating tumor cells at the mRNA and protein level using a microfluidic graphene oxide chip
Authors: Molly Kozminsky, Kathleen C. Day, Guadalupe Lorenzatti Hiles, Shamileh Fouladdel, Ebrahim Azizi, Mark L. Day, Todd Morgan, Sunitha Nagrath
Journal: Cancer Research (2017)

Abstract While the relative five-year survival rate for men with localized prostate cancer is nearly 100%, it plummets to 28% in the case of distant metastases. This underscores the importance of investigating those cells able to spread and form these metastases: circulating tumor cells (CTCs). Though rare and surrounded by other blood cells, CTCs can be isolated using the sensitive nanomaterial-based microfluidic technology the graphene oxide (GO) Chip. Whole blood samples from 54 prostate cancer patients were obtained with consent and processed on parallel chips for immunofluorescence and RNA analysis. All of the samples were analyzed for CTC enumeration, where captured cells were stained for cytokeratin 7/8 (CK), CD45, and DAPI. CTCs were identified as DAPI+/CK+/CD45- cells. CTCs were detected in all of the samples. Interestingly, 25 samples showed CTC clusters ranging from 2-10 CTCs per cluster. To explore the potential role of EGFR in metastatic progression and CTC survival, a subset of samples was also assayed for EGFR expression with 9/10 samples showing EGFR+ CTCs. RNA extracted from a parallel device was reverse transcribed to cDNA. The cDNA was analyzed via qPCR for expression levels of 96 genes of interest, including housekeeping genes; epithelial and mesenchymal genes; oncogenes and tumor suppressor genes; prostate specific genes; extracellular matrix and inflammatory genes; and others. The results show our ability to examine RNA from CTCs to examine the role of relevant pathways in the cells in transit. With analysis capabilities at both the RNA and protein levels, the GO Chip is an example of a clinically relevant microfluidic technology. Citation Format: Molly Kozminsky, Kathleen C. Day, Guadalupe Lorenzatti Hiles, Shamileh Fouladdel, Ebrahim Azizi, Mark L. Day, Todd Morgan, Sunitha Nagrath. Analysis of prostate cancer circulating tumor cells at the mRNA and protein level using a microfluidic graphene oxide chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2017-1731
Abstract 211: Aldehyde Dehydrogenase 2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction
Authors: Aijun Sun, Jianquan Liao, Xieye Qing, Xueting Jin, Toyoshi Isse, Toshihiro Kawamoto, Yunzeng Zou, Junbo Ge
Journal: Circulation Research (2012)

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of aldehyde dehydrogenase-2 knockout (KO) in the pathogenesis of heart underwent endoplasmic reticulum (ER) stress induction. Wild-type (WT) and ALDH2 KO mice were subjected to tunicamycin challenge and echocardiographic examination was performed. Protein levels of GRP78, p-eIF2α, CHOP, phosphorylation of Akt, p47phox NADPH oxidase, and 4-hydroxynonenal were determined by Western blot analysis. Cytotoxicity and apoptosis were estimated by MTT assay and caspase-3 activity respectively. ALDH2 deficiency exacerbated cardiac dysfunction and increased the protein levels of ER stress markers after ER stress induction characterized by the changes of ejection fraction and fractional shorting, when compared with WT mice. In vitro, tunicamycin significantly increased in the levels of GRP78, p-eIF2, CHOP and p47phox NADPH oxidase, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation of Akt. Inhibition of PI3-K with LY294002 did not negatively affect the inhibition of ER stress markers conferred by ALDH2, but reversed the anti-apoptotic role of ALDH2, which may be associated with p47phox NADPH oxidase. These results suggest that ALDH2 was implicated in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against cell death induced by ER stress was probably mediated by Akt signaling via p47phox NADPH oxidase. These findings indicate a critical role of ALDH2 in the pathogenesis of ER stress in heart disease.
Abstract 4837: Development of an in vitro 3D glioblastoma model system for patient-specific drug response profiling
Authors: Teresa DesRochers, Ashley Clark, Lauren O'Donnell, Qi Guo, Lillia Holmes, Lacey Dobrolecki, Michael Lewis, David Schammel, Jeff Edenfield, Charles Kanos, Fred Nelson, Steve Gardner, Michael Lynn, Philip Hodge, Christopher Corless, Paul Clark, Hal E. Crosswell, John Kuo
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) has a median survival of less than 2 years due to intra-tumoral and inter-patient heterogeneity, diffuse infiltration of adjacent brain tissue, and absence of effective therapies. Development of more efficacious therapies will require better GBM models for the testing and identification of novel agents; traditional 2D cell culture lacks biologic and clinical fidelity and orthotopic xenograft models are costly, low throughput, and time consuming. We have developed a complex, patient-specific 3D cultured GBM model to assay drug response that combines high-throughput drug response determination with neurosphere formation and next-generation sequencing (NGS). Neurosphere formation and the presence/quality of glioblastoma stem cells (GSCs) has been validate through limited dilution growth in vivo. Our 3D model system has been validated against the primary patient GBM tissue and/or patient-derived xenografts (PDX) and consists of histology, epigenetic and mRNA expression analysis, and comparison of in vivo drug response. This strategy enabled examination of MGMT methylation in relation to temozolomide response, and possible actionable genetic mutations with candidate targeted therapies. Using our 3D model, we have observed EGFR-amplified GBM sensitivity to the EGFR inhibitor afatanib, and PTEN mutant GBM sensitivity to dual PI3K/mTOR inhibitor dactolisib. These data suggest validation of clinical and molecular correlation with this new in vitro, patient-derived 3D GBM model for drug response profiling. Our data supports the further development and use of complex 3D models, neurosphere formation, and NGS profiling for patient-specific GBM analysis. This model system is currently being considered for preclinical assessment of novel therapies and may be a useful adjunct in future precision medicine applications to improve patient outcomes. Citation Format: Teresa DesRochers, Ashley Clark, Lauren O'Donnell, Qi Guo, Lillia Holmes, Lacey Dobrolecki, Michael Lewis, David Schammel, Jeff Edenfield, Charles Kanos, Fred Nelson, Steve Gardner, Michael Lynn, Philip Hodge, Christopher Corless, Paul Clark, Hal E. Crosswell, John Kuo. Development of an in vitro 3D glioblastoma model system for patient-specific drug response profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4837. doi:10.1158/1538-7445.AM2017-4837
Risk factors for uterine fibroids: reduced risk associated with oral contraceptives
Authors: H. Ratner
Journal: BMJ (1986)

Professor Ron K Ross and others claim that oral contraceptive (OC) use reduces the risk of uterine fibroids (9 August p 359).  Their study group consisted of white married women who had been taking OCs for at least 5 months before their recruitment during the period 1968-1974.  Women who have already been taking the pill for 5 or more months exclude (a) those who for cautionary reasons concerning fibroids were not prescribed OCs in the 1st place and (b) those who were taking OCs but discontinued them before 5 months because of fibroid complications.  Virtually every informational paper I have reviewed since the very early 1960s through 1968-1974 when the study group was recruited has contained warnings about the use of OCs in women with fibroids.  For example:   the opinion of Planned Parenthood Federation of Americas Medical Committee the only contraindication to prescription of orals if preexisting fibromyoma (present in about 20% of women) which may enlarge during their use.  In contrast preexisting fibroids were not a contraindication in the controls--women using diaphragms and IUDs.  It would seem therefore that by omission of the women who had been taking OCs for less than 5 months the study is based on a selected group and the control cases are not comparable.  The study suffers from this major flaw.  (full text)
Abstract 1025: Controlled and endogenous depletion of a synthetic lethal target in human cancer cell lines via SMASh degron engineering
Authors: Florencia Rago, Matthew T. Dimare, Geoffrey Bushold, Avnish Kapoor, Hyo-eun C. Bhang, Zainab Jagani
Journal: Cancer Research (2017)

Abstract The SWI/SNF multi-subunit complexes play an important role in regulating processes such as gene transcription through ATP-dependent remodeling of chromatin. The importance of this role is highlighted by the prevalence of mutations in various SWI/SNF subunits across approximately 20% of cancers encompassing various lineages and subtypes. Functional genomics screening via pooled shRNAs has led to the discovery of distinct vulnerabilities of SWI/SNF mutant cancers to loss of mutually exclusive subunits. In particular, cancer cells with BRG1 loss become exquisitely dependent on the remaining BRG1 counterpart, BRM. To further understand the synthetic lethal relationship between BRM and BRG1, we have adapted a recently described degron, the small molecule assisted shutoff (SMASh) tag, showing for the first time the ability to apply this system to control endogenous levels of target protein, in this case BRM. We used the SMASh tag to target the endogenous BRM locus in both a BRG1 wild-type and mutant cancer cell line. Using these engineered cell lines, we were able to show that we can achieve tunable protein levels by varying the concentration of the effector molecule. The ability to tune BRM depletion allowed us to investigate the nature of the BRG1/BRM synthetic lethal relationship. Our data interestingly suggests that while modest depletion of BRM is sufficient to observe changes in the expression of a target gene regulated by SWI/SNF in a dose-dependent manner, a higher level of BRM depletion is required to elicit a growth arrest phenotype in the BRG1-mutant non-small cell lung cancer line. Together these results uncover a novel relationship between the catalytic SWI/SNF subunit and gene expression, where we find that the latter responds in a dose dependent manner to BRM levels. Additionally, we elucidate the level of BRM depletion required to observe the synthetic lethal phenotype, providing insight and informing on strategies for therapeutic targeting whether by protein degradation approaches, such as PROTAC, or other small molecule approaches. Finally, having provided a proof-of-concept, such tools can be readily adapted for application to endogenous degradation of other target proteins in different systems. Citation Format: Florencia Rago, Matthew T. Dimare, Geoffrey Bushold, Avnish Kapoor, Hyo-eun C. Bhang, Zainab Jagani. Controlled and endogenous depletion of a synthetic lethal target in human cancer cell lines via SMASh degron engineering [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1025. doi:10.1158/1538-7445.AM2017-1025
Abstract 5100: AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical activity
Authors: Petr Dzubak, Marian Hajduch, Pavla Perlikova, Gabriela Rylová, Petr Naus, Tomas Elbert, Eva Tloustova, Aurelie Bourderioux, Lenka Slavetinska, Kamil Motyka, Dalibor Dolezal, Pawel Znojek, Alice Nova, Monika Harvanova, Michal Siler, Jan Hlavac, Michal Hocek
Journal: Cancer Research (2017)

Abstract 7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, the formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK- OV-3, BT-549, HT-29 and MDA-MB231 xenografts. The results indicate that AB61 is a promising compound with the unique mechanism of action and deserves further development as an anticancer agent. This work was supported by the Ministry of Education of the Czech Republic (LO1304). Citation Format: Petr Dzubak, Marian Hajduch, Pavla Perlikova, Gabriela Rylová, Petr Naus, Tomas Elbert, Eva Tloustova, Aurelie Bourderioux, Lenka Slavetinska, Kamil Motyka, Dalibor Dolezal, Pawel Znojek, Alice Nova, Monika Harvanova, Michal Siler, Jan Hlavac, Michal Hocek. AB61, a new potent nucleoside cytostatic: Molecular mechanisms of action and preclinical activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2017-5100