tbuckley/cabot-search huggingface dataset:
Abstract 4439: The urine miRNA transcriptome of prostate cancer is temporally stable and predicts disease aggressivity
Authors: Jouhyun Jeon
Journal: Cancer Research (2017)

Abstract The clinical management of prostate cancer is the most common non-skin male malignancy in the world is hindered by the limitations of current diagnostic and prognostic tests, such as the low specificity of prostate-specific antigen (PSA) testing, low sensitivity of digital rectal examination (DRE) and complications of biopsies. To try to resolve these issues, we evaluated miRNA abundance in the urine of prostate cancer patients. Alterations in miRNA abundance levels have been reported as playing essential roles in the pathogenesis of cancer and is occurred in a tumor phenotype-specific manner (e.g. aggressive and non-aggressive). miRNAs are stable under diverse analytical conditions and can be detected in various types of body fluids including urine. These characteristics make them as promising non-invasive biomarkers. Here, we examined the intra- and inter-individual variance of urine miRNA abundance by investigating longitudinal changes over months to years in a cohort of patients with localized prostate cancer. We observed a large dynamic range of intra-individual variance in miRNA abundances and identified a set of miRNAs that is stable within individuals, and is biased toward specific biological functions including regulation of transmembrane channel activity. We combined this observation with machine-learning techniques to create a predictive model that can identify aggressive prostate cancer. This four miRNAs predictive model was validated in an independent prostate cancer cohort to non-invasively predict high-risk disease. Remarkably it showed comparable performance to the best existing tissue-based prognostic markers. These results demonstrated that non-invasive biomarkers can be developed to precede or supplement tissue-based tests by understanding the intra- and inter-tumoural heterogeneity of the urine miRNA transcriptome. Citation Format: Jouhyun Jeon. The urine miRNA transcriptome of prostate cancer is temporally stable and predicts disease aggressivity [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 4439. doi:10.1158/1538-7445.AM2017-4439
Abstract 776: Acquired platinum resistance enhances tumour angiogenesis through activation of vascular mimicry
Authors: Aya El Helali, Nuala McCabe, Naomi Dickson, Lara Dura Perez, Denis P Harkin, Richard Wilson, Richard Kennedy
Journal: Cancer Research (2017)

Abstract Introduction: Platinum resistant High Grade Serous Ovarian Cancer (HGSOC) has a poor outcome with limited treatment options. Angiogenesis is a key pathological feature of ovarian cancer and anti-angiogenics have dominated the field of drug development in EOC, particularly in the second-line setting (Marachini et al 2013). In this study we asked if platinum resistance could be associated with an improved response to anti-angiogenic agents. Method: A review of phase III anti-angiogenic clinical trials was used to investigate the association between platinum resistance and response to anti-angiogenic agents. To investigate the effect of chemotherapy on predefined ovarian cancer molecular subgroups (Gourley, et al. J Clin Oncol 32:5s, 2014), we analysed 35 matched pre- and post-chemotherapy samples by gene expression. Novel isogenic cisplatin-resistant HGSOC cell lines were established to study the mechanisms of cisplatin section pressure and shift to an angiogenic phenotype. This was further validated in novel ascites-derived primary cell lines from HGSOC patients with known outcomes following platinum-based chemotherapy. Results: Critical review of 22 phase III anti-angiogenic trials suggested that there was a better response to anti-angiogenics following previous platinum-based chemotherapy. Our analysis demonstrated that 67% of treatment naïve tumours that were initially classified as non-angiogenic shifted to an angiogenic biology, which was associated with platinum resistance. Additionally we found that cisplatin resistant cancer cell lines demonstrated hallmarks of vascular mimicry and an associated increase in vessel density using an angiogenesis Matrigel plug assay in Athymic nude mice (p-value=&amp;lt;0.0001). In addition, cell lines established from platinum-resistant patients as well as cell lines made platinum resistant in-vitro, demonstrated overexpression of VEGFa which would be expected to stimulate angiogenesis. Conclusion: We have demonstrated that platinum-resistance in HGSOC is associated with angiogenic biology supporting the use of anti-angiogenic agents in this setting. Citation Format: Aya El Helali, Nuala McCabe, Naomi Dickson, Lara Dura Perez, Denis P Harkin, Richard Wilson, Richard Kennedy. Acquired platinum resistance enhances tumour angiogenesis through activation of vascular mimicry [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 776. doi:10.1158/1538-7445.AM2017-776
Abstract 19420: Selective Relaxin Receptor 1 Agonist (ML290) Attenuates Myocardial Ischemic Injury Through Preservation of Mitochondrial Function
Authors: Chad Cain, Adolfo G Mauro, Jeremy Thompson, Jun He, Stefano Toldo, Anindita Das, Edward J Lesnefsky, Fadi N Salloum
Journal: Circulation (2016)

Background:  Treatment with recombinant human relaxin, which binds to its cognate receptor RXFP1, has been shown to attenuate myocardial infarction (MI) in animal models. Whether reperfusion therapy with the first potent and selective small-molecule agonist of RXFP1 (ML290, identified by Probe Reports; NIH Molecular Libraries Program) reduces myocardial infarct size and preserves mitochondrial and cardiac function following MI is unknown.   Methods and Results:  After baseline echocardiography, adult male mice underwent MI by coronary artery ligation for 30 minutes followed by 24 h reperfusion. Mice were treated with ML290 (30 mg/Kg;  ip ) or vehicle (10% DMSO in saline) 5 minutes before reperfusion. ML290 significantly reduced infarct size, measured with TTC staining, and plasma cardiac troponin levels (Figs. A & B); preserved LV ejection fraction and markedly improved segmental contractile function using high sensitivity speckle tracking echocardiography (Fig. C) at 24 h post MI compared to vehicle-treated mice. Mitochondria were isolated from LV free wall at 24 h post MI in both groups to assess oxidative phosphorylation (OXPHOS, nAO/mg/min) and calcium retention capacity (CRC, nmol Ca 2+ /mg). Compared to untreated hearts, ML290 improved the rate of OXPHOS using glutamate (Glu) + malate (Mal) as complex I substrates (493±30 vs. control: 403±21, n=4, P   Conclusion:  Reperfusion therapy with ML290 improves LV function at 24 h post MI and significantly reduces infarct size, possibly by improving OXPHOS and inhibiting MPTP opening. We propose that RXFP1 agonists can be promising therapeutic tools for acute MI.
Abstract 2536: miR-187-5p and miR-219a-1-3p: potential biomarkers associated with chemotherapeutic response and prognosis in ovarian cancer
Authors: Chia-Yen Huang, Hsien-Da Huang
Journal: Cancer Research (2017)

Abstract Background: Epithelial ovarian cancer (EOC) is the fifth-most common cause of female cancer death and is associated with high recurrence and mortality despite recent advancements in therapeutic strategies. Chemoresistance remains the main cause of treatment failure in EOC patients. The aim of this study is to identify specific miRNA markers closely associated with the chemoresponse in EOC patients. Methods: We analyzed 374 serous ovarian cancer patients who receiving combination chemotherapy from The Cancer Genome Atlas (TCGA) and identified the most significantly altered miRNAs between different groups patients of chemotherapy response. We then used Kaplan-Meier and log-rank methods to analyze the relationship between these miRNAs and progression-free and overall survival in TCGA (n = 460) and Bagnoli (n = 130) datasets. In vitro study for response to chemotherapy agents were performed in human ovarian cancer cell lines and their transfectants. The biological relevance of putative miRNA targets was also analyzed using bioinformatics. Results: MiR-187-5p and miR-219a-1-3p were associated with better response to chemotherapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (all p &amp;lt;0.05). These two miRNAs also sensitized ovarian cancer cells to chemotherapy, thus recapitulating the clinical observation. Conclusions: This study showed that miR-187-5p and miR-219a-1-3p could be useful biomarker for prediction of chemotherapy response and survival in serous ovarian cancers. MiR-187-5p and miR-219a-1-3p may be potential molecules in the treatment of EOC for sensitizing cancer cells to chemotherapy. Citation Format: Chia-Yen Huang, Hsien-Da Huang. miR-187-5p and miR-219a-1-3p: potential biomarkers associated with chemotherapeutic response and prognosis in ovarian 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 2536. doi:10.1158/1538-7445.AM2017-2536
Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort
Authors: Clémence Basse, Sébastien Thureau, Suzanna Bota, Eric Dansin, Pascal-Alexandre Thomas, Eric Pichon, Hervé Lena, Carole Massabeau, Christelle Clément-Duchene, Gilbert Massard, Virginie Westeel, Xavier Quantin, Youssef Oulkhouir, Serge Danhier, Delphine Lerouge, Ronan Tanguy, François Thillays, Cécile Le Pechoux, Bernard Dubray, Luc Thiberville, Benjamin Besse, Nicolas Girard
Journal: Journal of Thoracic Oncology (2017)
Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial
Authors: Daisuke Ito, Satoshi Shimizu, Kazuyuki Inoue, Daigo Saito, Morifumi Yanagisawa, Kouichi Inukai, Yuji Akiyama, Yoshihiro Morimoto, Mitsuhiko Noda, Akira Shimada
Journal: Diabetes Care (2017)

OBJECTIVE To compare the efficacy of ipragliflozin versus pioglitazone in patients with type 2 diabetes complicated by nonalcoholic fatty liver disease (NAFLD). RESEARCH DESIGN AND METHODS In this open-label, randomized, active-controlled trial, we randomly assigned 66 patients with type 2 diabetes and NAFLD to receive ipragliflozin 50 mg (n = 32) or pioglitazone 15–30 mg (n = 34) orally once daily. The primary outcome was a change from baseline in the liver-to-spleen attenuation ratio (L/S ratio) on computed tomography at week 24. RESULTS At week 24, the mean ± SD L/S ratio had increased by 0.22 (from 0.80 ± 0.24 to 1.00 ± 0.18) in the ipragliflozin group and 0.21 (from 0.78 ± 0.26 to 0.98 ± 0.16) in the pioglitazone group (P = 0.90). Serum aspartate and alanine aminotransferase levels, HbA1c, and fasting plasma glucose were similarly reduced in the two treatment groups. Nevertheless, body weight and visceral fat area showed significant reductions only in the ipragliflozin group compared with the pioglitazone group (P &amp;lt; 0.0001 and P = 0.0013, respectively). There were no serious adverse events in either group. CONCLUSIONS Compared with pioglitazone, ipragliflozin exerts equally beneficial effects on NAFLD and glycemic control during the treatment of patients with type 2 diabetes complicated by NAFLD. Furthermore, ipragliflozin significantly reduced body weight and abdominal fat area.
The Concept of “Continuing Creation” Will Not Save Us From Difficult Decisions
Authors: Trisha Prentice, Peter G. Davis, Lynn Gillam
Journal: The American Journal of Bioethics (2017)

Distinguishing between “creating” and “saving” is not as morally helpful as Rieder (2017) suggests. In order for this distinction to be morally valid it must have two features: (1) the distinction ...
Changes to the Diagnostic Criteria for Bipolar Disorder in DSM-5 Make Little Difference to Lifetime Diagnosis: Findings From the U.K. Bipolar Disorder Research Network (BDRN) Study
Authors: Katherine Gordon-Smith, Lisa A. Jones, Liz Forty, Nick Craddock, Ian Jones
Journal: American Journal of Psychiatry (2017)

DSM-5 criterion A for manic and hypomanic episodes includes the additional requirement of abnormally and persistently increased activity or energy.This requirement was not present in DSM-IV.This raises the question of whether research groups and consortia with large DSM-IV bipolar disorder cohorts can combine these with DSM-5 cases in ongoing and future analyses.
Minimal Residual Disease in Chronic Lymphocytic Leukemia in the Era of Novel Agents
Authors: Meghan Thompson, Danielle Brander, Chadi Nabhan, Anthony Mato
Journal: JAMA Oncology (2017)

<h3>Importance</h3> The landscape of chronic lymphocytic leukemia (CLL) treatment has changed considerably since the first reported assessment of minimal residual disease (MRD) by flow cytometry in 1992. Chemoimmunotherapy (CIT) combinations have become the standard of care for most patients, and novel targeted agents are rapidly being incorporated into the front-line and relapsed settings. Minimal residual disease status has been shown to be a predictor of both progression-free survival (PFS) and overall survival (OS) at the time of response assessment following CIT, but less is known about the relationship between MRD and outcomes after novel oral therapeutics. Herein, we review current methods for MRD testing and present relevant clinical data for MRD for current treatment regimens focusing on novel oral agents as monotherapies and in combination. <h3>Observations</h3> Flow cytometry and polymerase chain reaction are the 2 methods most frequently used to measure MRD, although high-throughput sequencing and more specific assays are being refined. Minimal residual disease status is an independent predictor of PFS and OS for patients receiving CIT, and emerging data for venetoclax suggest a relationship between MRD negativity and outcomes. The prognostic value of MRD status for kinase inhibitors remains unknown. <h3>Conclusions and Relevance</h3> Minimal residual disease as a clinical trial end point must be validated in prospective studies prior to being used as a surrogate for survival. Given the heterogeneity of CLL biology and therapies, this validation must be regimen specific. Minimal residual disease assessments should be performed in clinical trial patients with both partial and complete responses. Following CIT, MRD status has prognostic value in all responders and this observation is important to validate with novel agents because most patients obtain partial remission. Further research is required to validate the use of MRD status as a decision point in guiding therapy in clinical practice.
Abstract 5490: Non-overlapping promoter and super-enhancer-associated dependencies in multiple myeloma
Authors: Mariateresa Fulciniti, Charles Y. Lin, Mehmet K. Samur, Richard Young, Herve Avet-loiseau, Kenneth Anderson, James Bradner, Nikhil Munshi
Journal: Cancer Research (2017)

Abstract The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well-defined. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators to identify their individual contribution to eventual functional effect in multiple myeloma (MM). To better understand how E2F1 and DP1 drive proliferation, we mapped the global occupancy of E2F1/DP1 in MM. Integration of E2F1 and DP1 genomic localization to MM reference epigenome revealed specific co-occupancy of the factors at promoters of active genes marked by H3K4me3, with a strong positive correlation between E2F and RNA Polymerase II (RNA Pol II) binding at transcription start sites. In contrast, active enhancers, as defined by promoter distal Mediator (MED1) peaks and marked by H3K27ac and BRD4, showed virtually no E2F binding. Unbiased hierarchical clustering revealed distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth/proliferation genes and BETs disproportionately at enhancer- regulated tissue specific genes confirming that these factors establish distinct target gene programs. At the extremes, we found less than 10% of genes were among the top 500 in BRD4 enhancer signal (i.e. SE-regulated) and top 500 E2F promoter signal. We hypothesized that the presence of BETs and E2F in distinct regulatory axes divides active genes in MM into those that can be selectively influenced by BET inhibition or E2F perturbation, but not both. In line with this we have observed that dual E2F and BET inhibition is synergistic for MM cell growth, both in vitro and in vivo. In conclusions, our results highlights the existence of distinct regulatory axes controlled by promoter and enhancer driven processes, suggesting a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy. Citation Format: Mariateresa Fulciniti, Charles Y. Lin, Mehmet K. Samur, Richard Young, Herve Avet-loiseau, Kenneth Anderson, James Bradner, Nikhil Munshi. Non-overlapping promoter and super-enhancer-associated dependencies in multiple myeloma [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 5490. doi:10.1158/1538-7445.AM2017-5490
Abstract 833: Alginate hydrogels for three-dimensional culture and real-time monitoring of cancer cell metabolism and radiation response
Authors: Aparna H. Kesarwala, Jenna L. Carter, Graham H. Read, Natsuko Miura, Kazutoshi Yamamoto, James B. Mitchell, Murali C. Krishna
Journal: Cancer Research (2017)

Abstract The purpose of this study was to characterize a three-dimensional calcium alginate culture system for real-time monitoring of cancer cell metabolism and radiation response. HCT116 colorectal cancer cells were encapsulated in 2.5% calcium alginate using a custom electrostatic rig adapted from a previously published system. Bead diameter was a function of voltage and alginate concentration: 4 x 107 cells/mL encapsulated at 4 and 8 kV resulted in mean diameters of 880 and 584 µm, respectively. The distribution of bead radii for all voltages showed positive excess kurtosis (4 kV = 1.6, 8 kV = 3.0) and 72.9% of 4 kV and 77.2% of 8 kV bead diameters fell within one standard deviation of the mean. Encapsulated cell viability was assessed by staining with Trypan Blue and clonogenic survival assays (CSAs). The baseline viability of cells immediately after encapsulation was 93.2%, which decreased 2 days after a single 10 Gy dose (90.7%, p&amp;lt;0.05). After two weeks of continuous culturing, 84.1% of non-irradiated and 73.8% of irradiated encapsulated cells remained viable (p&amp;lt;0.003). Pimonidazole staining demonstrated the presence of hypoxic cores proportional to bead size. CSAs of 8 kV beads showed a dose modifying factor (DMF) of 1.06 relative to cells grown in a monolayer, while larger 4 kV beads showed a DMF of 1.58. Mean oxygen consumption rate rose with increasing number of 8 kV beads/well: 1 bead, 35.5; 2 beads, 97.4; 3 beads, 175.5; 4 beads, 209.9; 2.0 x 104 monolayer cells, 92.6 (all pmol/min, ~8.2 x103 cells/bead, p&amp;lt;0.005). Hyperpolarized 13C-NMR spectroscopy of 400 uL of 8 kV beads containing 1.2 x 108 cells/mL showed a detectable conversion of [1-13C]-pyruvate to [1-13C]-lactate; 1 hour after a single 10 Gy dose, the lactate:pyruvate ratio decreased by 25%. Unpaired 2-tailed Student’s t-tests were used to determine significance between and one-way ANOVA was used to determine significance among groups with α set at p≤0.05. These data demonstrate the versatility of alginate hydrogels for real-time metabolic and radiation response studies which are non-invasive, higher throughput, and lower cost compared to in vivo systems. Future directions include additional metabolic flux analysis and hyperpolarized 13C-NMR spectroscopy to further investigate the cancer cell metabolic response to drug and/or radiation therapy. Citation Format: Aparna H. Kesarwala, Jenna L. Carter, Graham H. Read, Natsuko Miura, Kazutoshi Yamamoto, James B. Mitchell, Murali C. Krishna. Alginate hydrogels for three-dimensional culture and real-time monitoring of cancer cell metabolism and radiation response [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 833. doi:10.1158/1538-7445.AM2017-833
Abstract 3744: Office cervicoscopy in the diagnosis of HPV infection
Authors: Atef Darwish
Journal: Cancer Research (2017)

Abstract Introduction: Since the association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Searching for HPV became a basic step in all screening programs. Laboratory HPV testing is costly and unavailable in developing countries. Objective: To compare the diagnostic indices of office cervicoscopy against cytology and punch biopsy for detection of underlying HPV lesions in women with suspicious cervix. Design: An analytic cross-sectional research design Setting: Early cervical cancer Detection Unit of the Women's Health University Hospital. Assiut, Egypt. Patients and methods: A total of 274 non-pregnant women with clinical diagnosis of suspicious cervix were included in this study. After cervical smearing with Ayre's spatula, they were subjected to cervicoscopy utilizing 2.6 mm telescope and a 3.2 mm outer sheath office hysteroscope. Evaluation of the vulva, vagina, ectocervix, endocervical canal and the endometrial cavity were done. The cervix was then painted with saline, acetic acid and Schiller's iodine stains successively as used during colposcopic examination. Abnormal lesions were biopsied using punch biopsy forceps. Cytologic evaluation relied on both classic and non-classic (secondary) criteria for the diagnosis of HPV including "mild koilocytosis," mild dyskeratocytosis," hyperchromatic nuclei, bi- and multinucleation, and cleared cytoplasm. Punch biopsies were taken from every case based on cervicoscopic localization after staining. Results:. The main complaint was abnormal vaginal discharge in 197 cases (71.4%) . Pap smear sampling was negative for HPV in 188 cases (68.6%) and positive in 86 cases (31.4%). Cervicoscopic findings suggestive of HPV infection were positive in 77 cases ( 28.1% ) and negative in 197 cases (71.9% ). Gold stand histopathology diagnosed HPV in 53 cases only (19.3%). All diagnostic indices of cervicoscopy significantly improved after combination with cytology positive results except false positive results.. Conclusions: Cervicoscopy as a simple, cheap and office procedure can be used as a quick screening tool of HPV infection in women with suspicious cervix. It has the advantage of screening of the rest of the genital tract. In the absence of laboratory HPV testing, cervicoscopy in conjunction with cytology screening of high-risk cases should be encouraged. Note: This abstract was not presented at the meeting. Citation Format: Atef Darwish. Office cervicoscopy in the diagnosis of HPV infection [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 3744. doi:10.1158/1538-7445.AM2017-3744