tbuckley/cabot-search huggingface dataset:
Synergistic effects of the PARP inhibitor olaparib and pharmacological ascorbate in castration-resistant prostate cancer.
Authors: Nicolas Gordon, Matthew Joseph Schiewer, Peter Gallagher, Amy C Mandigo, Emanuela Dylgjeri, Christopher McNair, Renee De Leeuw, Jennifer K Jones, Neermala Poudel Neupane, Ayesha A Shafi, Lucas Brand, William Kevin Kelly, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2019)

326 Background: The administration of ascorbate has proved lethal to and highly selective for a variety of cancer cell types; however, despite an increasingly impressive body of evidence, there has not been a robust effort to translate the observed in vitro and in vivo outcomes to the clinic. This is partially due to the fact that the mechanism by which ascorbate exerts its anti-cancer effect is still under investigation. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), by inhibiting DNA damage repair, would augment the toxicity of ascorbate. Methods: In vitro and in vivo models systems queried for anti-tumor effects of PARP inhibitors and ascorbate. Results: Two distinct castration-resistant prostate cancer (CRPC) models were sensitive to ascorbate at physiologically attainable concentrations. These in vitro models were then subjected to treatment with three different PARP inhibitors (olaparib, niraparib, and talazoparib) alone and in combination with ascorbate. The addition of a sub-lethal dose of ascorbate significantly increased cell death across a range of doses for all three PARP inhibitors. A combination index was generated for olaparib and ascorbate in both CRPC models; the results suggest a strongly synergistic relationship between olaparib and ascorbate. Use of a CRPC in vivo model demonstrated that the combination of olaparib and ascorbate significantly increased tumor doubling time compared to vehicle controls and monotherapy. This in vivo efficacy was even more profound in an additional model using castrated mice to mimic the effect of hormone therapy. Additional mechanistic studies are in progress to further investigate the potential for ascorbate and olaparib combination therapy. Conclusions: Ultimately, these data suggest the combination of ascorbate and PARP inhibitors could be an effective treatment for CRPC.
Complex 3q26/EVI1 Rearrangements Genocopy Inv(3)/t(3;3) Acute Myeloid Leukemias By Enhancer Hijacking, EVI1 Overexpression, Absent MDS1-EVI1 and Low GATA2 Expression
Authors: Sophie Ottema, Roger Mulet-Lazaro, Berna Beverloo, Marije Havermans, Claudia Erpelinck-Verschueren, Tim Grob, Peter Valk, Eric Bindels, Torsten Haferlach, Claudia Haferlach, Leonie Smeenk, Ruud Delwel
Journal: Blood (2018)
Identification of differentially expressed genes to predict radioresistant prostate carcinomas.
Authors: Tim Nestler, Maike Wittersheim, Martin Hellmich, David J. K. P. Pfister, Margarete Odenthal, Reinhard Büttner, Stephan Schäfer, Axel Heidenreich
Journal: Journal of Clinical Oncology (2019)

57 Background: Although relapses after radiotherapy are common in prostate cancer (PCa) patients, there are no clinical models or markers to identify patients at high risk for radioresistance. So far, only in vitro studies and xenograft models have been performed to identify gene expression patterns associated with radioresistance. However, studies which address the protein pattern to predict radioresistance in humans are completely missing. In order to determine potential biomarkers for radioresistance, we compared protein expression profiles of radioresistant PCa patients with PCa of primary prostatectomized patients. Methods: Two study groups consisting of: I) 30 patients who were treated by salvage prostatectomy and II) 94 patients treated by primary prostatectomy were formed. Tissue microarrays were constructed and immunostained for 15 proteins which are suggested to be associated with radioresistance by in vitro findings. Kruskal-Wallis test was used for multiple group comparison and followed by Dunn-Bonferroni-Test to detect intergroup differences. Cohen’s d was used to calculate the intergroup effect size. Results: Most proteins studied did not show any relevant differences between radioresistant PCa and primary PCa, except for two (AR and AKR1C3). On comparing immunostaining patterns between radioresistant PCa and primary PCa separated by Gleason risk groups, we observed only AR (androgen receptor) to be most expressed in radioresistant PCa (89.7%) and, in 87.8% of primary PCa of the high-risk group ( &gt; 7a) (p = 0.851, Cohen’s d = 0.05), while only 67.3% PCa of the low-risk group (≤7a) (p = 0.017, Cohen’s d = 0.55) were positive. Considering the highest Gleason pattern per patient, only AKR1C3 (Aldo-Keto Reductase Family 1 Member C3) was seen to be similarly expressed in radiation-resistant PCa and patients with Gleason patterns 4 and 5 (p = 0.827, Cohen’s d = 0.05 and p = 0.893, Cohen’s d = 0.10) as compared to Gleason pattern 3 (p = 0.20, Cohen’s d = 0.69) in primary PCa. Conclusions: This is the first study evaluating protein expression profiles to predict radioresistance in PCa, where AR and AKR1C3 were identified to be the most promising protein markers.
Abstract 13118: Predictive Impact of Plasma Aldosterone Levels on the Future Risk of New-Onset Atrial Fibrillation
Authors: Keiji Inoue, Toru Tanigaki, Akira Ueoka, Takashi Shimonaga, Yoshinori Tsubakimoto, Tomohiko Sakatani, Shinzo Kimura, Akiko Matsuo, Hiroshi Fujita, Makoto Kitamura
Journal: Circulation (2011)

Background : Upstream therapy may have the potential to decrease the incidence of atrial fibrillation (Af). Renin-angiotensin-aldosterone system has been reported as one of the risk factors of Af. ...
Targeted Locus Amplification (TLA): A Novel Next Generation Sequencing (NGS) Technology to Detect New Molecular Markers and Monitoring Minimal Residual Disease (MRD) in Mantle Cell and Follicular Lymphoma
Authors: Elisa Genuardi, Petra Klous, Daniela Drandi, Barbara Mantoan, Luigia Monitillo, Barbero Daniela, Mehmet Yilmaz, Fabio Cattellino, Marika Vasta, Federica Furia, Gian Maria Zaccaria, Federica Cavallo, Sergio Cortelazzo, Umberto Vitolo, Stefano Luminari, Massimo Federico, Mario Boccadoro, Erik Splinter, Marco Ladetto, Simone Ferrero
Journal: Blood (2017)
A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma
Authors: Joseph Mikhael, Paul Richardson, Saad Z. Usmani, Noopur Raje, William Bensinger, Chatchada Karanes, Frank Campana, Dheepak Kanagavel, Franck Dubin, Qianying Liu, Dorothée Semiond, Kenneth Anderson
Journal: Blood (2019)
Evaluation of Cardiac Rhythm Abnormalities From Wearable Devices
Authors: James E. Ip
Journal: JAMA (2019)

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Renal cell cancer (RCC) due to Birt-Hogg-Dubé syndrome. Results of initial imaging and follow-up among 164 <i>FLCN</i> mutation carriers and outcome of 22 cases with RCC.
Authors: Pieter Postmus, Paul Johannesma, Irma van Beek, Rinze Reinhard, Edward Leter, Theo Starink, Rence Rozendaal, JanHein van Waesberghe, Simon Horenblas, Marianne Jonker, Fred Menko, Arjan Houweling, Reindert Jeroen A. Van Moorselaar
Journal: Journal of Clinical Oncology (2015)

e15579 Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant inherited disorder caused by mutations in the FLCN gene predisposing for renal cell cancer. Generally, surveillance of the kidneys is advised but the optimal imaging method and interval remain to be defined. Aim of the study: To evaluate the compliance to, and the outcome of, yearly surveillance in patients diagnosed with BHD in two centers. Methods: Detailed informationon follow-up was obtained after a written requestfrom 164 patients patients diagnosed with BHD since 2004. We evaluated adherence to the advice for follow up by imaging, as well as the medical records of 22 of the BHD-patients treated for renal tumours. Results: In 118/164 cases (72%) initial imaging consisted of both a renal MRI and ultrasound, the others 46 had either one of the two. Follow up in 135 cases (82%) was complete and consisted of annual renal ultrasound. The total follow-up period was calculated to be 485 patient years. Full compliance with surveillance was recorded for 108/135 cases (80%). At the initial screening 6 patients had symptomatic tumours, 10 asymptomatic, during follow-up, in 6 patients asymptomatic tumours were found. In total, 35 RCC were detected in these 22 patients. The number of tumours found per patient during the observation period is: 1 in 14 patients, 2 in 4 patients, 3 in 3 patients, 4 in 1 patient. In 5 of the 9 patients with multiple tumours these were bilateral. Both MRI and ultrasound were performed in 20/35 tumours. Four tumours were visible only on MRI, all four were < 3cm. Conclusions: Our data indicate that compliance to renal screening is high and that ultrasound might be a sensitive and widely available imaging modality for detecting clinically relevant renal tumours in BHD patients. Further studies in BHD patient cohorts are required to further determine the optimal screening method and interval in BHD patients.
Treatment results of brachytherapy versus external beam radiation therapy for intermediate risk prostate cancer.
Authors: Barry W. Goy, Margaret S. Soper, Tangel Chang, Harry A. Cosmatos, Jeff M. Slezak, Michael Tome
Journal: Journal of Clinical Oncology (2015)

e16041 Background: The role of brachytherapy (BT) using Iodine-125 (I-125) without supplemental external beam radiation (EBRT) is usually limited to patients with low risk prostate cancer (PC). Our objective is to compare long term treatment outcomes of BT vs EBRT with or without neoadjuvant androgen deprivation therapy (NADT) in intermediate risk PC patients. Methods: At our integrated, multi-facility health care system between 2004 and 2007, 690 intermediate risk PC patients were treated with either BT vs EBRT. 93 patients underwent BT using I-125 to a dose of 14,500 centigray (cGy), while 597 patients were treated with EBRT to the prostate and seminal vesicles to a median dose of 7531 cGy. NADT was given in 65.2% of the patients undergoing EBRT (median 6.0 months), but only 17.2% of the BT patients received NADT (p = < 0.0001). None of the BT patients were treated with supplemental EBRT. Multivariate analysis was performed using a Cox proportional hazards model . Kaplan-Meier estimates were calculated at 5 and 10 years, and two-sided p values were used. Results: Median follow up was 7.8 years (0.3-10.9 years). Median age of the BT group was 65.0, and for EBRT was 70.7 years (p < 0.0001). In the BT group, 52% had a Gleason score (GS) of 7, compared to 72% of the EBRT group (p < 0.0001). Median initial PSA (iPSA) was 8.3 for BT, and 9.4 for EBRT (p = 0.01). Percentage of positive biopsy cores > 50% was 9.7% for BT, and 18.4% for EBRT (p = 0.04). The 5 and 10 year biochemical free survival (BFS) for BT was 90.1% and 81.7%, and for EBRT was 84.6% and 54.5%, (p = 0.002). The 5 and 10 year distant metastases free survival (DMFS) for BT was 97.8% and 94%, and for EBRT was 98% and 90.3% (p = 0.76). The 5 and 10 year overall survival (OS) for BT was 97.8% and 75%, and for EBRT was 90.1% and 69.7% (p = 0.02); but on MVA, BT had no impact on OS (p = 0.12). Independent predictors of improved BFS include lower iPSA (p = 0.0004), lower GS (p = 0.007), NADT (p = 0.04), and BT (p = 0.008). Independent predictors of improved DMFS include lower GS (p = 0.04) and lower stage (p = 0.02). The only predictor of improved OS was younger age (p = 0.008). Conclusions: BT using I-125 without supplemental EBRT is a reasonable treatment option for intermediate risk PC patients.
Abstract 9476: Incidence Rates and Risk Factors for Sudden Unexpected Non-Cardiac Death in the Young - A Nationwide Cohort Study in Denmark
Authors: Bjarke Risgaard, Thomas H Lynge, Mads Wissenberg, Reza Jabbari, Charlotte Glinge, Gunnar H Gislason, Stig Haunsø, Bo G Winkel, Jacob Tfelt-Hansen
Journal: Circulation (2014)

Introduction: Upon autopsy of a sudden unexpected death, cause of death can be divided into; 1) those that are sudden cardiac deaths and 2) those that are sudden non-cardiac deaths (SNCDs). Importa...
Combining efficacy and toxicity effect sizes from randomized clinical trials (RCTs) into an interpretable quality-adjusted effect size estimate in patients with multiple myeloma (MM).
Authors: Brittny Major, Angela Dispenzieri, Jeff A. Sloan
Journal: Journal of Clinical Oncology (2015)

e18028 Background: There are a multitude of treatment options for patients with MM, many of which appear to be equivalent in terms of response and others which have superior response but no clear benefit in terms of overall survival. How does one choose the best regimen? We have devised a new quality-adjusted effect size (QASES) method that combines efficacy and toxicity information into a single expression of comparative treatment benefit. Methods: QASES is a weighted combination of the efficacy and toxicity effect sizes based on differences in efficacy and toxicity using the ½ standard deviation method. We applied this method on 13 RCTs in elderly patients and also on 8 Autologous Stem Cell Transplantation (ASCT) RCTs on patients with newly diagnosed myeloma. Results: Eighteen of these trials were published as “positive” trials and four negative trials based on significant differences in PFS/OS. Using our methodology in which equal value could be assigned to differences in toxicity and survival, nine trials would be deemed positive. As an example, a phase III RCT of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with VT in newly diagnosed MM patients ineligible for ASCT found a 15% increase in 3-year PFS rate and 13% more grade 3 or 4 adverse events compared with VMP alone. When equal weights were placed on survival and toxicity, the quality-adjusted PFS difference estimate demonstrated no difference between the treatment and control arms. When survival was weighted as 3 times that of toxicity, the quality-adjusted PFS difference reduces to a 7% difference. Results will be presented for the four possible case combinations of significant/non-significant differences in survival and toxicity data using 21 completed RCTs in patients with newly diagnosed MM. Conclusions: The QASES approach allows for an intuitively appealing and mathematically simple and robust approach to combining efficacy and toxicity data. Clinicians can use QASES to interpret and communicate the findings of clinical trials to patients by weighing both the efficacy and toxicity information into a single quality-adjusted estimate of efficacy.
Abstract 18028: Inclusion of B-type Natriuretic Peptide into Existing Atrial Fibrillation (AF) Risk Scores Improves Identification of Patients with Recurrence of Atrial Fibrillation after Pulmonary Vein Isolation
Authors: Amir Y Shaikh, Nada Esa, Menhel Kinno, William Martin-Doyle, Kevin C Floyd, Clifford Browning, Lawrence S Rosenthal, David D McManus
Journal: Circulation (2014)

AIMS: Pre-procedural identification of patients with atrial fibrillation (AF) who will remain free from AF after pulmonary vein isolation (PVI) remains challenging. Clinical risk scores, including CHADS2, CHA2DS2-VASc, R2CHADS2, and HATCH scores show modest discriminative ability with respect to AF recurrence. B-type natriuretic peptide (BNP) is associated with risk for AF and AF recurrence but is not currently included in existing AF risk scores. We sought to evaluate the incremental benefit of adding pre-operative BNP to existing risk scores in predicting AF recurrence within 6-months after PVI. METHODS AND RESULTS: One hundred and fifty one patients (105 men, age 60 ± 10 years) with paroxysmal or persistent AF underwent an index PVI procedure between 2010-2014. Seventy-seven patients had an AF recurrence (51%) over the 6-month follow-up period. BNP level of &gt;100 units was significantly associated with 6-month AF recurrence in univariate models (p&lt;0.001). A composite risk score including BNP to the existing scores significantly improved their predictive value and net AF recurrence reclassification (net reclassification index, 63.4%; p&lt;0.001) (Table 1). CONCLUSIONS: Addition of BNP to existing AF risk scores enhanced their predictive value and discriminative ability in predicting AF recurrence after PVI. Further research is needed including large and diverse cohorts of patients undergoing ablation and monitored for AF recurrence over extended periods to further validate the performance of this composite score.
Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1
Authors: James V. McCann, Lin Xiao, Dae Joong Kim, Omar F. Khan, Piotr S. Kowalski, Daniel G. Anderson, Chad V. Pecot, Salma H. Azam, Joel S. Parker, Yihsuan S. Tsai, Alisa S. Wolberg, Stephen D. Turner, Kohei Tatsumi, Nigel Mackman, Andrew C. Dudley
Journal: Journal of Clinical Investigation (2019)

In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β-mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1-dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.
Let-7f microRNA expression within established bladder cancer subtypes and upregulation with recombinant interferon-alpha.
Authors: Vikram M Narayan, Amy Lim, Sharada Mokkapati, Ganiraju C. Manyam, Devin Plote, Debasish Sundi, Woonyoung Choi, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2019)

462 Background: Let7f is a microRNA (miR) that may act as a tumor suppressor in multiple human malignancies. In patients with BCG-refractory non-muscle invasive bladder cancer, detectable let7f levels in the urine of patients undergoing treatment with adenoviral vector-mediated IFNα gene therapy (clinical trial setting) were found to be prognostic of treatment response at 12 months. Here we sought to define the association of let7f with clinical bladder cancer phenotypes within The Cancer Genome Atlas (TCGA) cohort and characterize the role of let7f in preclinical models. Methods: Using miRNA sequencing data from the published TCGA 2018 bladder cohort (n = 412), let7f miR expression was characterized and stratified by molecular subtype (basal-squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal). Kaplan-Meier analyses were performed to compare survival (upper vs lower median, by let7f expression level). The murine urothelial carcinoma cell line MB49 was cultured in colonies of 10 5 and in vitro administrations of 100U/mL of recombinant mu-IFNα were performed with cells harvested at 0, 2, 8, 12, and 24 hours. Let7f miR expression levels were then determined by qRT-PCR. Results: Within the TCGA cohort, let7f expression levels were found to be lower in the more aggressive basal-squamous (median = 12.8), luminal-infiltrated (median = 12.9), and neuronal (median = 12.4) subtypes relative to the luminal (median = 13.2) and luminal-papillary (median = 13.3) subtypes (p &lt; 0.001). Survival analysis demonstrated a trend towards improved survival in the high let7f expressers, but this did not reach statistical significance. In MB49 cells treated with mu-IFNα, there was a time-dependent increase in let7f miR expression suggesting that IFNα may play a role in upregulation of this potential tumor suppressor. Conclusions: Let7f miR is downregulated in more aggressive subtypes of MIBC. IFNα upregulates let7f expression in MB49 cells, and the inability to do so may comprise an escape mechanism for IFNα-treated tumors. Let7f miR may serve as a novel biomarker to identify aggressive phenotypes and treatment failures for bladder tumors treated with IFNα-based gene therapy.