tbuckley/cabot-search huggingface dataset:
A Meta-Analysis of Gene Expression Studies Highlights the Role of Innate Immunity in the Pathogenesis of Sickle Cell Disease and Reveals Novel Potential Regulators at the Transcriptomic Level
Authors: Bidossessi Wilfried Hounkpe, Maiara Marx Luz Fiusa, Marina Pereira Colella, Loredana Nilkenes Gomes da Costa, Rafaela Oliveira Benatti, Sara Terezinha Olalla Saad, Fernando Ferreira Costa, Magnun Nueldo Santos, Erich Vinicius De Paula
Journal: Blood (2015)
Abstract 3123: miR-520b inhibits malignancy of head-neck cancer through suppression of cancer stemness by targeting to CD44 molecule
Authors: Ya-Ching Lu, Ann-Joy Cheng
Journal: Cancer Research (2015)

Abstract MicroRNAs (miRNAs) have been implicated playing important role in regulating malignant progression of cancer. Here, we characterized the functional effects and regulatory mechanism of miR-520b in head-neck cancer (HNC). Without affecting cell growth, exogenous transduction of miR-520b into HNC cell lines significantly increased sensitivity to the therapeutic drug and radiation treatment, indicating that miR-520b possesses pro-apoptotic function. Transduction of miR-520b also decreased cell adhesion and mobile ability, accompanying with the reversion of epithelial- mesenchymal transition. Significantly, miR-520b suppressed the conversion of cancer stem cell (CSC) as demonstrated by reduced expressions of stemness markers (nestin and CD44), inhibiting sphenoid cell formation, and inhibiting pluripotent stemness regulators (Twist, Nanog and Oct4). Furthermore, CD44 was identified the direct target of miR-520b, which was shown by the response to miR-520b modulation via either exogenous or antigomir transduction. Functional analyses also confirmed this regulatory mechanism. The altered cell mobility and sphenoid forming ability by miR-520b modulation were rescued upon CD44 silencing. The miR-520b induced stemness regulators were also inhibited when simultaneously silencing CD44. Study in xenografted mice showed that miR-520b knockdown led to an acceleration of tumorigenesis. Reversely, miR-520b transduction dramatically restrained tumor growth, along with the inhibition of stem cell regulatory proteins. Taken together, our finding demonstrated that miR-520b inhibits malignancy of HNC through regulation of cancer stemness by targeting to CD44 molecule. Our finding provides molecular mechanism of miR-520b in HNC, which may also yield insights as novel targeting therapeutic strategy for HNC. Citation Format: Ya-Ching Lu, Ann-Joy Cheng. miR-520b inhibits malignancy of head-neck cancer through suppression of cancer stemness by targeting to CD44 molecule. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3123. doi:10.1158/1538-7445.AM2015-3123
MYD88 Pathway Activation in Lymphoplasmacytic Lymphoma Drives Tumor Cell Growth and Cytokine Expression.
Authors: Stephen M Ansell, Frank J Secreto, Michelle Manske, Esteban Braggio, Lucy S. Hodge, Tammy Price-Troska, Steven C. Ziesmer, Asher Alban Chanan-Khan, Morie A Gertz, Ahmet Dogan, James R Cerhan, Anne J Novak
Journal: Blood (2012)
Epigenetic Modulation of STAT3 by Histone Deacetylase 6 (HDAC6) Regulates IL-10 Gene Expression and Immune Tolerance Mediated by Antigen-Presenting Cells (APCs)
Authors: Fengdong Cheng, Zi Wang, Hongwei Wang, Karrune V. Woan, Eva Sahakian, Jennifer Rock Klotz, Liqing Wang, Rongxiang Han, Oscar Merino, Susan Deng, Lianet Vazquez, Ajaypal S. Gill, Danay Marante, John Powers, Wayne W. Hancock, Javier Pinilla, Edward Seto, Eduardo M. Sotomayor, Alejandro Villagra
Journal: Blood (2011)
241. Barcoding as a Tool To Predict Integrating Vector Genotoxicity in HSPCs
Authors: Idalia Yabe, Chuanfeng Wu, Marcus Corat, Sandhya Panch, Samson Koelle, Cynthia E. Dunbar
Journal: Molecular Therapy (2015)

Stem cell gene therapy using integrating retroviral vectors to modify hematopoietic stem and progenitor cells (HSPC) has shown great promise to treat patients with a variety of acquired and inherited immune system and hematologic diseases. However activation of proto-oncogenes via insertional mutagenesis related to the presence of enhancers within integrating vectors has resulted in the development of leukemia in some patients. The risk appears lower with enhancer-deleted retroviral or HIV-based lentiviral vectors. However, to date, there is no predictive or quantitative preclinical in vitro or animal model to assess genotoxicity of integrating vectors, given the difficulty in studying HSPCs in vitro and differences between rodent and human hematopoiesis. An approach to predict the risk of genotoxic adverse events is desirable before moving a new vector into clinical trials. We are utilizing cellular "barcoding" technology to investigate the impact of different vector designs on the clonal behavior of HSPC during in vitro and in vivo expansion as a rapid quantitative surrogate assay for genotoxicity. We have begun by studying a standard HIV-derived lentiviral vector backbone now being developed for clinical applications containing one of three promoter/enhancers with a predicted wide range of genotoxicities, from the least genotoxic EF1a promoter, to a predicted medium genotoxic MSCV enhancer, to the most genotoxic very strong viral enhancer termed SFFV, already associated with a high rate of leukemia incidence in human clinical trials targeting HSPC. Each vector has a high diversity "barcode" (a random sequence tag) inserted into the vector LTR, which will uniquely tag each individual transduced HSPC, and can be retrieved via low cycle PCR and high-throughput Illumina sequencing to quantitate the clonal pattern of contributions from each transduced barcoded HSPC. In addition, actual insertion sites can be retrieved and compared with barcode patterns to identify expanded clones. We have used these barcoded vectors to transduce rhesus macaque CD34+ HSPC in vitro, then expanded transduced cells in culture for 2-3 weeks, and currently in process of bioinformatics analysis of the clonal patterns and diversity with each of the three vectors. The same in vitro approach can be applied to human HSPC. By the time of the ASGCT meeting, we will have in vivo data on clonal pattern generated by each vector type from a rhesus macaque transplanted with autologous CD34+ HSPC split into three fractions, transduced with each of the three vectors, and reinfused simultaneously. In summary, this project will investigate whether HSPC genotoxicity due to integrating vectors can be measured and predicted using a barcoding approach, and provide insights into the relative genotoxicity of a number of different integrating vector designs now under development for clinical applications.
Abstract 1032: The acetylcholine signaling pathway: A novel molecular target for lung cancers
Authors: Kathleen C. Brown, Jamie K. Lau, Haley E. Perry, Brent A. Thornhill, Cathryn D. Stevenson, William D. Rollyson, Cody A. Stover, Dennie V. Jones, Joseph F. Pulliam, Piyali Dasgupta
Journal: Cancer Research (2015)

Abstract Cigarette smoking is a major risk factor for all types of lung cancers. Nicotine, the addictive component of cigarettes, accelerates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). We show that both human SCLCs and NSCLCs contain all proteins of the acetylcholine signaling pathway, namely nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). ACh functions as an autocrine growth factor for human lung cancer cells. Lung adenocarcinoma (LAC), squamous cell carcinoma (SCC-L) and invasive mucinous adenocarcinoma (IMA) express a diverse array of nAChRs. In addition, normal human lung cells also express nAChRs and other ACh signaling proteins. Nicotine amplifies the ACh signaling loop in human lung cancer cells. It increases the levels of alpha7-nAChR subunit in human SCC-Ls. The alpha7-nAChR is responsible for the proliferative and pro-angiogenic activity of nicotine in lung cancer. The level of alpha7-nAChR was analyzed in human SCC-L samples isolated from patients. It was found that the level of alpha7-nAChR in SCC-L patients (who are heavy smokers) was much higher than that of moderate smoker suffering from SCC-Ls. Nicotine was also found to elevate the levels of ChAT and VAChT in human lung cancers. The acetylcholine signaling pathway may be a useful molecular target for the diagnosis and therapy of human lung cancers in smokers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes. Citation Format: Kathleen C. Brown, Jamie K. Lau, Haley E. Perry, Brent A. Thornhill, Cathryn D. Stevenson, William D. Rollyson, Cody A. Stover, Dennie V. Jones, Joseph F. Pulliam, Piyali Dasgupta. The acetylcholine signaling pathway: A novel molecular target for lung cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1032. doi:10.1158/1538-7445.AM2015-1032
Abstract 4587: Genome-wide copy number analysis identified a copy number polymorphism at chromosome 8p11 associated with sporadic colorectal cancer risk in Singapore Chinese
Authors: Peh Yean Cheah, Lai Fun Thean, Yik Ying Teo, Woon-Puay Koh, Jian-Min Yuan, Min Hoe Chew, Choong Leong Tang
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is one of the most frequent cancers and leading cause of cancer mortality in the developed world. Twin study has attributed about 35% of the etiology of sporadic CRC to genes. Hitherto, more than 20 single nucleotide polymorphism (SNP) loci have been associated with CRC risk. The role of structural variant in CRC, however, remains unclear. We performed genome-wide association study (GWAS) on 2,000 ethnicity-, age-, and gender-matched Singapore Chinese CRC patients (aged 50 or more and with no dominant family history of CRC) and healthy controls. Genome-wide genotyping was performed using Affymetrix SNP 6 platform. Copy number polymorphism (CNP) was interrogated in 1830 samples that passed quality assurance tests using a multivariate segmentation algorithm. A 150 kb region at chromosome 8p11 was identified to be significantly associated (-log10 p-value = 29) with sporadic CRC risk. This CNP was preferentially amplified in the cases compared to the controls. The amplification was not gender-specific suggesting that it is not involved in gender-limiting pathway. It is now being replicated in an independent panel using digital polymerase chain reaction (dPCR) and multiplex endogenous reference technique. In silico analysis of a 1.5 Mb region encompassing the CNP reveals a candidate gene 300kb 5′ of the CNP previously implicated in cancer progression. The expression of this gene in cases with copy number and metastasis status is being interrogated. Citation Format: Peh Yean Cheah, Lai Fun Thean, Yik Ying Teo, Woon-Puay Koh, Jian-Min Yuan, Min Hoe Chew, Choong Leong Tang. Genome-wide copy number analysis identified a copy number polymorphism at chromosome 8p11 associated with sporadic colorectal cancer risk in Singapore Chinese. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4587. doi:10.1158/1538-7445.AM2015-4587
Abstract 13035: Impact of Ezetimibe on Hospitalization-Related Costs Among Patients With a Recent Acute Coronary Syndrome: Results From the IMPROVE-IT Trial
Authors: Elizabeth A Magnuson, Khaja Chinnakondepalli, Katherine Vilain, Daniel B Mark, Glenn Davies, Robert P Giugliano, Eugene Braunwald, Christopher P Cannon, David J Cohen
Journal: Circulation (2015)

Impact of Ezetimibe on Hospitalization Costs among Patients with a Recent Acute Coronary Syndrome: Results from the IMPROVE-IT Trial Objectives: The IMPROVE-IT Trial demonstrated that in patients with a recent acute coronary syndrome, the combination of ezetimibe 10 mg and simvastatin 40 mg (E+S) significantly reduced the rate of major cardiovascular events relative to simvastatin 40 mg (S) alone. We used patient-level resource data to compare costs associated with hospitalizations (hosps) between E+S and S over the course of the trial (median follow-up 6 years; mean 5.4 years). Methods: Details regarding hosps for all patients (n=18,144) were collected prospectively. MS-DRGs were assigned to all cardiovascular (CV) hosps, to which average 2013 Medicare reimbursement rates were applied. Physician costs associated with hosps were estimated as a % of hospital costs. Hosp rates/costs per patient were compared using Poisson regression/bootstrapping. Results: Over the follow-up period, there were 8612 and 9105 CV hosps for E+S and S, respectively (p=0.03). Treatment with E+S led to a $459/patient reduction in hospitalization-related costs (95% CI -$885 to -$42; p=0.02). Lower costs associated with coronary revascularization accounted for the majority ($392/patient) of the lower hosp costs for E+S. Forty percent of hosps for an adjudicated MI (1106/2769) involved a revascularization procedure and hosp costs for revascularization procedures in the setting of an MI were $314/patient lower with E+S. Lower costs associated with hosp for angina, stroke, and acute MI not requiring revascularization also contributed to the lower costs with E+S vs. S. Conclusions: Over a mean 5.4 year follow-up period, E+S was associated with lower rates of CV hospitalization and associated hospitalization costs compared with S. The extent to which these lower hospitalization costs offset the higher drug costs is expected to be more favorable when ezetimibe becomes generic in 2016.
PTH-087 Routine duodenal bulb biopsy in coeliac disease: a paradigm shift in our clinical practice?: Abstract PTH-087
Authors: K E Evans, S S Cross, G R Sahota, A D Hopper, M Hadjivassiliou, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Historically Brunner9s glands were thought to interfere with interpretation of duodenal bulb biopsies. Recent reports suggest that the duodenal bulb may be the only site to demonstrate villous atrophy (VA) in coeliac disease (CD). There are few data on the prevalence of lesions in non-coeliac patients. <h3>Methods</h3> We aimed to compare the histological findings in the duodenal bulb and distal duodenum of patients with CD against controls having gastroscopy with duodenal biopsy. Indications included positive coeliac serology, family history, diarrhoea, and iron deficiency anaemia. A total of 215 patients were prospectively accrued. Biopsies were graded using the Marsh criteria by a single pathologist. <h3>Results</h3> 215 patients, (150 female, 65 male) median age 48 years (range 16-89) were analysed. 17 patients demonstrated VA in the bulb only. 1 had VA in distal duodenum only. 1 control patient with HIV enteropathy had VA in the bulb and distal duodenum. Both new diagnosis CD (8%, p&lt;0.05) and CD in remission (15%, p&lt;0.001) were more likely than controls to have VA in the bulb alone. When comparing the Marsh grade score for the bulb and the duodenum, 24/59 of patients in remission had a discrepancy of at least 1 Marsh grade compared with only 8/91 new diagnosis CD (p&lt;0.0001), and 4/65 controls (p&lt;0.0001). 21/24 of the patients in remission with a discrepancy had the more severe lesion in the bulb (Abstract 087). <h3>Conclusion</h3> Villous atrophy may be present only in the duodenal bulb. In this study 7/91 (8%) of new diagnosis CD and 9/59 (15%) of CD in remission demonstrated VA in the bulb alone. When looking at CD in remission, 41% of patients have a discrepancy in severity of the histological lesion between the bulb and the duodenum; in this group the most severe lesion is nearly always in the bulb. This is the first study to demonstrate that optimal assessment of both new diagnosis CD and those in remission requires a duodenal bulb biopsy in addition to distal duodenal biopsies.
Abstract 4979: SIRT1 regulates the function of the KRAB-associated protein 1 (KAP1) in DNA damage response signaling
Authors: Yi-Hui Lin, Zhenkun Lou
Journal: Cancer Research (2015)

Abstract KRAB-Associated Protein 1 (KAP1) is a master regulator for genome stability, heterochromatin formation, and target gene silencing. Many studies have suggested that post-translational modification is required for KAP1 to execute pleiotropic effects. Here, we have identified the physical interaction between KAP1 and SIRT1, which is a widely recognized NAD+-dependent deacetylase in DNA damage response. Therefore, the objective of this study was to characterize the functional significance of KAP1 deacetylation in DNA damage repair signaling. In this study, SIRT1 was identified as a major interacting partner of KAP1 via biochemical approaches. Inhibition of SIRT1 activity by shRNA or selective inhibitor was able to upregulate the total acetylation level on KAP1, suggesting that KAP1 is a novel target of SIRT1. The major SIRT1-regulated KAP1 deacetylation sites (Lys266, Lys377, Lys469, and Lys770) were detected by quantitative mass spectrometric analysis. Next, to explore the functional significance of KAP1 deacetylation in NHEJ-mediated repair, KAP1 depleted cells reconstituted with wild-type KAP1 or 4KR acetylation mutant were used in the in vivo end-joining reporter system. Compare to wild-type KAP1, the 4KR mutant presented higher activity in promoting NHEJ efficiency. Furthermore, 4KR mutant showed stronger binding affinity to 53BP1, a crucial NHEJ promoting factor, and stabilized the 53BP1 foci formation in response to DNA damage. In summary, this study unambiguously established KAP1 as a target of SIRT1 and that the deacetylation of KAP1 on Lys266, Lys377, Lys469, and Lys770 stabilizes the formation of 53BP1 foci on sites of double-strand breaks, thereby promotes NHEJ-mediated repair pathway. Citation Format: Yi-Hui Lin, Zhenkun Lou. SIRT1 regulates the function of the KRAB-associated protein 1 (KAP1) in DNA damage response signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4979. doi:10.1158/1538-7445.AM2015-4979
Class-II Associated Invariant Chain Peptide (CLIP) Expression on AML Blasts Adversely Affects Alloreactive CD4+ T Cell Recognition.
Authors: Marvin M. van Luijn, Martine E.D. Chamuleau, Theresia M. Westers, James A. Thompson, Suzanne Ostrand-Rosenberg, Gert J. Ossenkoppele, S. Marieke van Ham, Arjan A. Van de Loosdrecht
Journal: Blood (2007)
BCR/ABL Kinase Elevates ROS-Mediated Oxidative DNA Damage in CML Stem/Progenitor Cells and Affects the Efficiency and Fidelity of DNA Repair To Induce Genetic Instability.
Authors: Margaret Nieborowska-Skorska, Artur Slupianek, Tomasz Stoklosa, Tomasz Poplawski, Kimberly Cramer, Tomasz Skorski
Journal: Blood (2007)
Serum C<sub>18</sub>-ceramide as a biomarker for response: Phase II trial of gemcitabine plus doxorubicin in patients with HNSCC.
Authors: K. Shirai, S. Saddoughi, P. E. O'Brien, L. Afrin, E. Garrett-Mayer, G. R. Simon, U. B. Chaudhary, B. Ogretmen
Journal: Journal of Clinical Oncology (2011)

5590 Background: Our previous studies showed the combination of gemcitabine (GEM) and doxorubicin (DOX) significantly inhibited the growth of human head and neck squamous cell carcinoma (HNSCC) both in culture and in pre-clinical studies via reconstitution of C18 ceramide, a tumor suppressor sphingolipid. A single-center, phase II clinical trial to determine the toxicity profile and treatment responses with GEM/DOX treatment was developed. Methods: Patients with HNSCC previously treated with platinum-based therapy received a combination of GEM 1000mg/m2 and DOX 25 mg/m2 on days 1 and 8 every 21 days. After every 2 cycles of treatment, patients were assessed radiographically, and serum samples were taken from patients for lipidomics analyses using high performance liquid chromatography/mass spectrometry to measure sphingolipid levels including C18 ceramide tumor suppressor signaling. With null and alternative response rates of 20% and 45%, power of 81% and alpha of 0.09, the Simon Optimal two-stage design enrolls 7 patients in stage 1 (continuing to stage 2 if >1 responses are observed) and 10 in stage 2. 6 or more responses in 17 patients allow the null to be rejected. Results: 17 patients were enrolled on this trial. Overall response rate was 29% (24% complete response (CR) 4/17) and 6% partial response (PR) 1/17). Stable disease (SD) was observed in the majority of patients (47%), while 29% of patients had progressive disease (PD). The median time-to-failure was 1.6 months and median survival was 5.6 months. Treatment was well tolerated with neutropenia being the most commonly observed side effect (9/17 patients). Sphingolipid analysis showed patients with CR+PR and SD had statistically significant increase in serum C18 ceramide levels in comparison to patients who had progressed (SD vs. PD p=0.05 and CR+PR vs. PD p=0.05). Conclusions: The GEM/DOX combination might be an effective treatment option for patients with recurrent or metastatic HNSCC. Additionally, Serum C18 ceramide elevations statistically significantly correlate with response. Serum C18 ceramide levels could serve as a predictive biomarker of response to chemotherapy in patients with HNSCC.
Changes in the worldwide epidemiology of peritoneal dialysis
Authors: Philip Kam-Tao Li, Kai Ming Chow, Moniek W.M. Van de Luijtgaarden, David W. Johnson, Kitty J. Jager, Rajnish Mehrotra, Sarala Naicker, Roberto Pecoits-Filho, Xue Qing Yu, Norbert Lameire
Journal: Nature Reviews Nephrology (2016)