tbuckley/cabot-search huggingface dataset:
PWE-026 An audit of inflammatory bowel disease patients' knowledge of surveillance colonoscopy
Authors: N C Bosanko, K F Kane
Journal: Gut (2010)

<h3>Introduction</h3> The BSG advocates discussion with patients regarding surveillance colonoscopy for chronic inflammatory bowel disease (IBD). The 2009 IBD standards document, which carries support from multidisciplinary organisations as well as patient groups, recommends clear, written information for patients. We have not previously provided this for patients prior to surveillance colonoscopy. <h3>Methods</h3> We prospectively audited understanding of the surveillance colonoscopy programme in patients with a diagnosis of extensive colonic IBD for &gt;8 years. A questionnaire was conducted by a single interviewer in clinic or by telephone to determine knowledge of colorectal cancer (CRC) risk, significance of dysplasia and potential clinical advice should dysplasia be identified. An information leaflet was written and sent to a cohort of patients who subsequently had surveillance colonoscopy in the study period and their knowledge was reassessed. <h3>Result</h3> 55 patients were recruited. 71% identified an increased risk of CRC. 22% recognised that surveillance was undertaken to assess for dysplasia/pre-cancerous changes (44% stated, “check up”, 25% responded, “check for cancer” and 9% answered, “check for flare”). 11% identified that colectomy would be advised if dysplasia was found (31% stated, “remove affected part”, 18% responed, “medications” and 40% answered, “don9t know”). 16/55 patients received an information leaflet prior to surveillance colonoscopy and were re-interviewed on the day of their procedure. 88% understood the dysplasia concept and 75% understood that colectomy would usually be advised if significant dysplasia was identified. <h3>Conclusion</h3> Patient knowledge regarding CRC screening in IBD is poor but is significantly improved following the supply of written information. By improving knowledge of the indication for the procedure, the validity of consent is optimised. IBD standards allow patients to demand quality information and we now supply patients with an information leaflet at the time of discussion in clinic and with colonoscopy appointment letters and have scheduled to re-audit in 1 year.
2-Chlorodeoxyadenosine (2-CdA) and Cyclophosphamide (Cy) Alone or in Combination with Rituximab (Rit) for Previously Untreated Waldenstrom’s Macroglobulinemia (WM).
Authors: Donna M. Weber, Michael Wang, Kay B. Delasalle, Maria Gavino, Raymond Alexanian
Journal: Blood (2004)
Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)
Authors: R Westhovens, P C Taylor, R Alten, D Pavlova, F Enríquez-Sosa, M Mazur, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset, P Harrison
Journal: Annals of the Rheumatic Diseases (2016)

Objectives To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. Methods In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. Results Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100 or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. Conclusions Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. Trial registration number: NCT01888874 .
Abstract A2-18: The challenges of using large-scale genomics data to identify novel drivers of lung cancer
Authors: Andrew M. Hudson, Tim Yates, Chris Wirth, Yaoyong Li, Wendy Trotter, Shameem Fawdar, Crispin Miller, John Brognard
Journal: Cancer Research (2015)

Abstract Lung cancer is one of the major causes of cancer deaths worldwide and only 30% of patients survive the disease for at least one year after diagnosis. Patients are often too frail to receive systemic chemotherapy and there is an urgent need for less toxic, efficacious, targeted therapies. Despite recent efforts with large-scale genomics data we still lack knowledge about driver mutations for the majority of lung cancers. Increasingly, cancer researchers are using online cancer genomic databases to identify novel targets to investigate. A comparison of two prominent databases from different institutes (CCLE and COSMIC) revealed marked discrepancies in the detection of missense mutations in identical cell lines (57.38% conformity). A major reason for this discrepancy is inadequate sequencing of GC-rich areas. This is a significant issue for lung cancer, with a mutation signature predominantly affecting guanine and cytosine nucleotides and therefore preferring GC-rich regions. We have therefore focused on GC-rich regions that next-generation-sequencing struggle to cover and discovered over 400 of these regions (cold-spots) in Cancer Consensus and kinase genes alone. We demonstrate how a PAK4 mutation, found in a GC-rich cold-spot in a lung adenocarcinoma cell line, activates the pERK pathway. This suggests that specific targeting of GC-rich regions may be required to uncover further oncogenes and tumour suppressors in lung cancer. The high mutational burden of lung cancer creates additional challenges in distinguishing driver mutations from a multitude of passenger mutations. One solution is to use siRNA knockdown screens on all genes that are mutated in a cell line and assess cell viability. However we demonstrate that inconsistencies in mutational profiling of cell lines and passaging effects have the potential to influence these types of studies. These limitations also offer new explanations for the discrepancies seen when comparing pharmacogenomics studies. Citation Format: Andrew M. Hudson, Tim Yates, Chris Wirth, Yaoyong Li, Wendy Trotter, Shameem Fawdar, Crispin Miller, John Brognard. The challenges of using large-scale genomics data to identify novel drivers of lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-18.
Abstract 5419: Structure elucidation of G-quadruplex within the mid-region of the kRAS promoter and identification of stabilizing small molecules as promising transcriptional silencers
Authors: Rhianna K. Morgan, Tracy A. Brooks, Khondaker M. Rahman
Journal: Cancer Research (2015)

Abstract Over 60% of pancreatic cancers harbor mutations in the kRAS oncogene, whose promoter has three distinct guanine-rich regions (near, mid, and far) capable of forming higher order G-quadruplexes (G4s). These important structures have transcriptional silencing potential and stabilizing compounds cause selective apoptosis in kRAS-addicted cells. Previous works in our laboratory have identified the mid-G4 region as having the highest silencing capacity, with little apparent roles for the near- or far-G4 regions. The structure of this mid-region G4 is being elucidated by electromobility shift assay, DNA polymerase stop assay, DMS footprinting, and circular dichroism (CD). In addition, small molecules are being screened by the Förster Resonance Energy Transfer (FRET) melt assay and confirmed by CD for their stabilization potential. We have identified multiple, equilibrating, intramolecular G4s forming within the mid-region of the kRAS promoter. Varying buffer conditions (cations, dehydration, and molecular crowding) affect these formations; the predominating isoform is a tetra-stacked mixed parallel and antiparallel structure with an 8:15:7 loop configuration. Over 1,600 compounds have been screened and several are being pursued as leads. Several compounds selectively stabilized the mid-G4 and suppress kRAS transcription. Our work highlights the mid-G4-forming region of the kRAS promoter a therapeutic target with the utmost promise for pancreatic cancer, and further features the stabilizing potential of targeted compounds. Studies are ongoing to vet the potential of other “hit” compounds from the FRET screen, as well as to elucidate the structure of the kRAS mid-G4 in chromosomal DNA. Brooks Lab startup funds, DoD, Rhianna Morgan GSC Grant, University of Mississippi School of Pharmacy Citation Format: Rhianna K. Morgan, Tracy A. Brooks, Khondaker M. Rahman. Structure elucidation of G-quadruplex within the mid-region of the kRAS promoter and identification of stabilizing small molecules as promising transcriptional silencers. [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 5419. doi:10.1158/1538-7445.AM2015-5419
Graft-Versus-Leukemia Antigen CML66 Elicits Coordinated B and T Cell Immunity After Donor Lymphocyte Infusion.
Authors: Wandi Zhang, Jaewon Choi, Wanyong Zeng, Edwin P Alyea, Christine Canning, Robert J Soiffer, Tetsuro Sasada, Ellis Reinherz, Jerome Ritz, Catherine J Wu
Journal: Blood (2009)
A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects
Authors: Thomas L Hunt, Ming Q. Lu, Yasushi Kawasaki, John P. Hall, Junji Komaba, Masahiro Takeuchi, Takuya Imamura, David J. Kuter
Journal: Blood (2011)
Deciphering the Cis- and Trans-regulatory Roles of KLF6 in Primitive Hematopoiesis
Authors: Qian Xiong, Zhaojun Zhang, Hongzhu Qu, Xiuyan Ruan, Hai Wang, Qian Zhang, Heyuan Qi, Yanming Li, Hongying Sun, Kai-Hsin Chang, George Stamatoyannopoulos, John A. Stamatoyannopoulos, Xiangdong Fang
Journal: Blood (2012)
Neutrophil Recruitment Is Regulated By Adamts-13 in a Murine Model of Invasive Aspergillosis
Authors: Astrid Hasibeder, Steve Prüfer, Katharina Ebner, Sebastian Reuter, Pamela Stein, Inge Scharrer, Fumiaki Banno, Michael Stassen, Hansjörg Schild, Kerstin Jurk, Markus Bosmann, Markus P. Radsak
Journal: Blood (2015)
Abstract 4001: Array profiling identified upregulated miRNAs and target genes and pathways in laryngeal squamous cell carcinoma
Authors: Meng Lian, Xiaoqin Liu, Demin Han, Jugao Fang, Zhong Chen
Journal: Cancer Research (2015)

Abstract Background: Laryngeal squamous cell carcinoma (LSCC) is prevalent in the Chinese population, where smoking is a major carcinogen. MicroRNAs (miRNAs) and their gene targets potentially contribute to the multistep regulatory processes of LSCC development. Objective: The purpose of this study is to investigate and validate aberrant expressed miRNAs in LSCC, and analyze the putative target genes of the screened miRNAs. Methods: Six pairs of primary Stage II-IV LSCC and adjacent non-neoplastic tissues were surgically removed for miRNA array analysis using the Affymetrix GeneChip miRNA Array 3.0, containing probes for 5683 miRNAs, and the significantly altered miRNAs were validated by the qRT-PCR in an independent cohort of 36 LSCC patients. MiRNA gene targets were predicted using TargetScan, PITA and microRNAorg in GeneSpring 12.5 software. The functional categories and pathways of the target genes were analyzed by GO category and KEGG pathway database. Results: MiRNAs arrays identified seven up-regulated miRNAs, including hsa-miR-224, hsa-miR-183, hsa-miR-23a, hsa-miR-675, hsa-miR-27a, hsa-miR-503 and hsa-miR-4800-3p in LSCC by the SAM method, and qRT-PCR was performed to validate the screened miRNAs. 72 putative target genes were identified by GeneSpring 12.5 software. These putative target genes are involved in biological processes, such as metabolic, biological regulation, membrane, protein binding, ion binding by GO category analysis, and are the molecular components in MAPK signaling, adherence, and junction pathways by KEGG pathway database analysis. Conclusions: Seven upregulated miRNAs were identified in LSCC tissues by microarrays, and validated by qRT-PCR. The putative target genes were also identified. These up-regulated miRNAs could serve as potential biomarkers for LSCC diagnosis and therapy. Citation Format: Meng Lian, Xiaoqin Liu, Demin Han, Jugao Fang, Zhong Chen. Array profiling identified upregulated miRNAs and target genes and pathways in laryngeal squamous cell carcinoma. [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 4001. doi:10.1158/1538-7445.AM2015-4001
Vitamin D Receptor Genotype, Vitamin D<sub>3</sub> Supplementation, and Risk of Colorectal Adenomas
Authors: Elizabeth L. Barry, Janet L. Peacock, Judy R. Rees, Roberd M. Bostick, Douglas J. Robertson, Robert S. Bresalier, John A. Baron
Journal: JAMA Oncology (2016)

Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial.To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence.We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016.Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither.The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing.Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation.Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype.clinicaltrials.gov Identifier: NCT00153816.
Flow Cytometric Score Correlates with Clinical Response to Azacitidine In Intermediate-2 and High Risk Myelodysplastic Syndrome Patients
Authors: Canan Alhan, Theresia M. Westers, Corien Eeltink, Claudia Cali, Gert J. Ossenkoppele, Arjan A. Van de Loosdrecht
Journal: Blood (2010)
Abstract 5258: Expression analysis of STEAP1 in breast cancer patients as therapeutic target
Authors: Chidananda Mudalagiriyappa, Sreeraj Pillai, Mark Watson, Rebecca Aft
Journal: Cancer Research (2015)

Abstract Objective: The six transmembrane epithelial antigen of the prostate (STEAP1) is predominantly overexpressed in human prostate cancer. STEAP1 was first identified as a prostate-specific cell-surface antigen and found to be up-regulated in multiple cancer cell lines and in various cancers, including lung, bladder, colon and ovarian cancers. However no significant expression in normal tissue has been reported suggesting its potential use as a target for anti-STEAP1 immunotherapy. An anti-STEAP1 monoclonal antibody linked to an antimitotic agent is in Phase I clinical trials for prostate cancer patients. Microarray data from our lab suggested that STEAP1 is also highly expressed in human breast cancers. In this study we evaluate expression STEAP1 in primary tumors and the bone marrow from breast cancer patients as a therapeutic target for minimal residual disease. Experimental procedures: RNA was isolated from primary tumor and non-malignant breast tissue. RNA was also isolated from bone marrow of state II and III breast cancer patients, healthy volunteers and breast cancer cell lines. STEAP1 expression was analyzed by nanostring nCounter and real time qRT-PCR using human specific probes. STEAP1 immunohistochemical (IHC) staining of human tissue was performed using standard IHC Protocol. Results: STEAP1 mRNA was up-regulated in 77% of tumors (28/36) compared to the corresponding normal tissue. STEAP1 protein was expressed in 100% of tumors (8/8) and was absent in non-malignant breast tissue (7/7) by IHC staining. STEAP1 mRNA was not expressed normal BM, but was detected in 8% (6/74) of BM from patients with early stage breast cancer. Of patients with STEAP1 positive BM, 50% (3/6) had triple negative disease and 66% (4/6) developed recurrent disease (p = .028). Conclusion: STEAP1 is expressed in human breast tumors and the BM of breast cancer patients. Expression of STEAP1 in the BM is significantly associated with the development of metastatic disease. Our data indicate that STEAP1 could serve as a therapeutic target for the treatment of minimal residual disease in breast cancer. Citation Format: Chidananda Mudalagiriyappa, Sreeraj Pillai, Mark Watson, Rebecca Aft. Expression analysis of STEAP1 in breast cancer patients as therapeutic target. [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 5258. doi:10.1158/1538-7445.AM2015-5258
The Timetree of Prokaryotes: New Insights into Their Evolution and Speciation
Authors: Julie Marin, Fabia U. Battistuzzi, Anais C. Brown, S. Blair Hedges
Journal: Molecular Biology and Evolution (2016)

The increasing size of timetrees in recent years has led to a focus on diversification analyses to better understand patterns of macroevolution. Thus far, nearly all studies have been conducted with eukaryotes primarily because phylogenies have been more difficult to reconstruct and calibrate to geologic time in prokaryotes. Here, we have estimated a timetree of 11,784 'species' of prokaryotes and explored their pattern of diversification. We used data from the small subunit ribosomal RNA along with an evolutionary framework from previous multi-gene studies to produce three alternative timetrees. For each timetree we surprisingly found a constant net diversification rate derived from an exponential increase of lineages and showing no evidence of saturation (rate decline), the same pattern found previously in eukaryotes. The implication is that prokaryote diversification as a whole is the result of the random splitting of lineages and is neither limited by existing diversity (filled niches) nor responsive in any major way to environmental changes.
297. The Influence of ELABELA AAV Gene Therapy on Cardiorenal Function in Rat Models of Salt-Induced Hypertension and Myocardial Infarction
Authors: Claire A. Schreiber, Sara Holditch, Alex Generous, Yasuhiro Ikeda
Journal: Molecular Therapy (2016)

Elabela (ELA) is a recently identified apelin receptor agonist essential for cardiac development, but its biology and therapeutic potential are unclear. The apelin receptor when bound to its original ligand, apelin, exerts peripheral vasodilatory and positive inotropic effects. We initially assessed endogenous ELA expression in normal and diseased rats. ELA was predominantly expressed in kidneys, especially in renal collecting duct cells and was not affected by disease. We then characterized the effects of long-term, adeno-associated virus (AAV)-ELA gene delivery on cardiorenal function in Dahl salt-sensitive rats (DS) on a high-salt diet. We overexpressed codon optimized rat ELA in the heart via AAV9 vector by a single intravenous injection. This led to a delayed onset of blood pressure (BP) elevation, and ELA-treated rats had lower BP than controls starting at 5 weeks post-injection (p.i.). As well, ELA significantly reduced fractional sodium and chloride excretion in treated (4 days p.i.), normotensive DS rats on low-salt diet, suggesting ELA's role in sodium and chloride readsorption. Glomerular architecture was better preserved in rats treated with the AAV9-ELA vector. A decrease in renal fibrosis and the significantly suppressed expression of fibrosis associated genes, including transforming growth factor beta (TGF-β), collagen, type 1, alpha 1 (COL1A1) and fibronectin 1 (FN1), was also seen in the treated group. Since ELA is essential for cardiac development, we additionally assessed the impact of the AAV9-ELA vector on cardiac repair in a rat myocardial infarction (MI) model. When compared with control MI rats, ELA treatment did not significantly improve cardiac function or structure. Thus, long-term ELA gene delivery may offer a potential therapy for hypertension and renal remodeling, but its application for MI may be limited.