tbuckley/cabot-search huggingface dataset:
Methylation-associated miR193b silencing activates master drivers of aggressive prostate cancer.
Authors: Ying Zhang Mazzu, Goutam Chakraborty, Yuki Yoshikawa, Subhiksha Nandakuma, Joshua Armenia, Lina E. Jehane, Gwo-Shu Mary Lee, Lorelei Mucci, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2019)

240 Background: Epigenetic changes in DNA methylation, histone modifications and miRNA expression have major roles in prostate cancer (PC) initiation and progression. Previous screening for epigenetically regulated miRNAs in PC revealed hypermethylation of the miR-193b promoter, but no related functional studies in PC have been reported. Methods: Methylation was measured by methylation-specific PCR. Quantitative RT-PCR was used to validate the regulation of potential miR-193b targets. Luciferase reporter assays were applied to detect the regulation of miR-193b-targets. The promoter methylation status was modified by DNMT and HDAC inhibitors (5-azacytidine and mocetinostat). Results: miR-193b level is inversely correlated with the degree of its promoter’s methylation in the TCGA cohort. Distinct miR-193b promoter methylation patterns were detected in multiple normal and PC cell lines. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. Previously reported top 150-downregulated genes by miR-193b in liposarcoma showed a high correlation with PC progression in multiple PC cohorts. We further identified FOXM1 and RRM2 as the direct targets of miR-193b. Knockdown of FOXM1 and RRM2 in PC cells phenocopied miR-193b with respect to inhibition of invasion and induction of apoptosis. Furthermore, combination treatment with DNMT and HDAC inhibitors released the methylation-regulated silencing of miR-193b in PC cells, resulting the inhibition of FOXM1 and RRM2 expression. Conclusions: We revealed the tumor suppressive function of miR-193b in PC. Overexpression of miR-193b in PC cells with low miR193b level induced cell growth inhibition, apoptosis, or inhibition of invasion. A gene set identified in liposarcoma cells by overexpression of miR-193b showed a high correlation with PC progression in multiple PC cohorts. FOXM1 and RRM2 may be the key targets of miR-193b in PC. Our findings suggest that methylation-silencing miR-193b in PC may release the inhibition of some key oncogenes to contribute PC progression, which could provide a possible therapeutic mechanism for PC therapy.
Abstract MP17: Comorbidity Type and Risk of Hospitalization and Death in Patients With Atrial Fibrillation
Authors: Alanna M Chamberlain, Alvaro Alonso, Peter Noseworthy, Ruoxiang Jiang, Susan Weston, Pamela Lutsey, Lin Chen, Wesley O’Neal, Lindsay Bengtson, Faye Norby, J’Neka Claxton, Richard MacLehose, Veronique Roger
Journal: Circulation (2019)

Background: Multimorbidity is common in atrial fibrillation (AF); however, the impact of the number and type of comorbid conditions on death and hospitalizations is uncertain. Methods: The prevalence of 17 chronic conditions was obtained in 1430 patients with incident AF from 2000-2010 from Olmsted County, MN. Chronic conditions were ascertained electronically prior to AF and were classified into 3 groups: cardiovascular (CV), other physical, and mental. All hospitalizations and deaths were obtained through 12/31/2014. Associations of the number and type of condition and each individual condition with hospitalizations and death were determined using Andersen-Gill and Cox regression, respectively. Results: Among the 1430 patients with AF (median age 76 years, 48.6% men), the mean (SD) number of chronic conditions was 4.7 (2.7). A total of 4496 hospitalizations and 812 deaths occurred over a mean (SD) follow-up of 5.4 (4.1) years. An increase in the number of conditions of each type was associated with increased risks of death and hospitalizations (Table). Mental conditions (which included depression, anxiety, dementia, schizophrenia, and substance abuse) exhibited the strongest association with death, whereas other physical conditions exhibited the strongest association with hospitalizations. Individual predictors of death included heart failure (HF), hypertension, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), depression, dementia, and substance abuse. Predictors of hospitalizations included HF, coronary artery disease, diabetes, COPD, CKD, arthritis, osteoporosis, and substance abuse. Conclusions: Patients with AF have many comorbid conditions which are associated with death and hospitalizations. Although conditions of each type were associated with outcomes, mental conditions exhibited strongest association with death. These data highlight the importance of management of not only CV comorbidities but other physical and mental comorbidities in patients with AF.
Multifunctional Polypyrrole‐Coated Mesoporous TiO<sub>2</sub> Nanocomposites for Photothermal, Sonodynamic, and Chemotherapeutic Treatments and Dual‐Modal Ultrasound/Photoacoustic Imaging of Tumors
Authors: Yue He, Jingyuan Wan, Yang Yang, Pei Yuan, Cheng Yang, Zhigang Wang, Liangke Zhang
Journal: Advanced Healthcare Materials (2019)

Abstract TiO 2 nanoparticles have emerged as satisfactory sonosensitizers in sonodynamic therapy over the years, but shortcomings such as poor drug loading capability and inadequate techniques to construct suitable TiO 2 nanoparticles, limit their broader applications. Hence, in this paper, versatile nanocomposites that combine mesoporous TiO 2 nanoparticles (mTiO 2 s) with the promising photothermal material, polypyrrole (PPY) to exert synergistic therapeutic effects on tumors are fabricated. The PPY‐coated mesoporous TiO 2 nanocomposites (mTiO 2 @PPYs) act as drug delivery vehicles and ultrasonically activated sonosensitizers as well as photothermal agents. Besides, mTiO 2 @PPY may have potential as an ultrasound/photoacoustic (US/PA) imaging contrast agent. The mTiO 2 @PPY shows a favorable drug loading and good photothermal conversion ability. Moreover, intracellular reactive oxygen species generation is verified. The in vitro cell experiments on HepG2 and 4T1 cells demonstrate that honokiol (HNK)‐loaded mTiO 2 @PPY has satisfactory cytotoxicity under laser and US irradiation, and the results are further validated by animal experiments. The ability of mTiO 2 @PPY as a contrast agent for US and PA imaging is investigated both in vitro and in vivo. The results indicate that mTiO 2 @PPY‐HNK has multitherapeutic effects and bimodal imaging property, which shows great prospect as a novel nanosystem in antitumor applications.
Changing physician PSA screening behavior in men 70 years of age and older by use of the electronic medical record.
Authors: Joseph Presti, Stacey Alexeeff, Brandon Horton, Stephanie Prausnitz, Andrew Avins
Journal: Journal of Clinical Oncology (2019)

85 Background: Since 2013, both the United States Preventive Services Task Force and the Kaiser Permanente National Prostate Cancer Guidelines have recommended against PSA-based screening for prostate cancer in men ≥70 years of age. Adherence to these guidelines has been variable. A “Best Practice Alert” (BPA) was activated in the electronic medical record (EMR) system in October 2015 at Kaiser Permanente Northern California (KPNC). This alerted physicians, in real time, if they attempted to order a PSA test in a man ≥70 years of age with no history of prostate cancer. No additional physician training or education was used. The objective of the present study was to determine the impact of this BPA on the frequency of inappropriate PSA testing. Methods: This was a retrospective study spanning the years 2013 to 2017, in men ≥70 years of age in KPNC with no prior history of prostate cancer. We compared the annual rates of PSA testing between the pre-BPA period, 2013 and 2014; and the post-BPA period , 2016 and 2017 (the post-BPA period began 3 months after the BPA was instituted). The primary outcome was the annual rate of PSA testing. The percent change between the two time periods, the rate ratio and 95% confidence interval (CI) were calculated. Results: The annual number of eligible men (men ≥70 years of age and no history of prostate cancer) and annual number of these men undergoing PSA testing are shown in the Table. Annual screening rates declined from 34.3% in the pre-BPA era to 13.5% in the post BPA era. The rate ratio was 0.394 (95% CI, 0.390-0.398). Conclusions: Following the activation of a simple and inexpensive BPA within the EMR, the rate of inappropriate PSA testing decreased 61% in men ≥70 years of age. This change was durable over the study period, demonstrating that well-conceived, straightforward interventions can have a marked effect on physician behavior. [Table: see text]
The role of ventricular–arterial coupling in cardiac disease and heart failure: assessment, clinical implications and therapeutic interventions. A consensus document of the European Society of Cardiology Working Group on Aorta &amp; Peripheral Vascular Diseases, European Association of Cardiovascular Imaging, and Heart Failure Association
Authors: Ignatios Ikonomidis, Victor Aboyans, Jacque Blacher, Marianne Brodmann, Dirk L. Brutsaert, Julio A. Chirinos, Marco De Carlo, Victoria Delgado, Patrizio Lancellotti, John Lekakis, Dania Mohty, Petros Nihoyannopoulos, John Parissis, Damiano Rizzoni, Frank Ruschitzka, Petar Seferovic, Eugenio Stabile, Dimitrios Tousoulis, Dragos Vinereanu, Charalambos Vlachopoulos, Dimitrios Vlastos, Panagiotis Xaplanteris, Reuven Zimlichman, Marco Metra
Journal: European Journal of Heart Failure (2019)
Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus
Authors: Thea Anine Strøm Halden, Kine Eide Kvitne, Karsten Midtvedt, Laavanyaah Rajakumar, Ida Robertsen, Jan Brox, Jens Bollerslev, Anders Hartmann, Anders Åsberg, Trond Jenssen
Journal: Diabetes Care (2019)

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors have lately become the recommended treatment in patients with type 2 diabetes and high cardiovascular risk. Patients with posttransplant diabetes mellitus (PTDM) also have high cardiovascular risk. The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with PTDM. RESEARCH DESIGN AND METHODS Forty-nine renal transplant recipients were included in an investigator-initiated, single-center, prospective, double-blind study and randomized to receive either 10 mg empagliflozin or placebo once daily for 24 weeks. Patients transplanted &amp;gt;1 year ago, diagnosed with PTDM, with stable renal function (estimated glomerular filtration rate [eGFR] &amp;gt;30 mL/min/1.73 m2), and with stable immunosuppressive therapy were studied. RESULTS Forty-four renal transplant recipients (22 empagliflozin/22 placebo, 34 males) completed the study. Median (interquartile range) change in glycated hemoglobin (HbA1c) was significantly reduced with empagliflozin compared with placebo: −0.2% (−0.6, −0.1) (−2.0 mmol/mol [−6.5, −1.0]) vs. 0.1% (−0.1, 0.4) (1.0 mmol/mol [−0.75, 3.8]) (P = 0.025). The magnitude of glucose reduction was dependent on GFR and baseline HbA1c. The treatment also resulted in a significant reduction in body weight of −2.5 kg (−4.0, −0.05) compared with an increase of 1.0 kg (0.0, 2.0) in the placebo group (P = 0.014). There were no significant differences between the groups in adverse events, immunosuppressive drug levels, or eGFR. CONCLUSIONS Empagliflozin appeared safe and improved glycemic control in renal transplant recipients with PTDM compared with placebo. A concomitant reduction in body weight was seen.
Abstract 017: Impact of Gentrification on Cardiovascular Disease Surveillance Using Data from the Electronic Health Record
Authors: Nrupen A Bhavsar, Megan Shepherd-Banigan, Matthew Phelan, Benjamin A Goldstein, Joseph Lunyera, Clarissa J Diamantidis, Matthew L Maciejewski, Ebony Boulware
Journal: Circulation (2019)

Introduction: Current static approaches of CVD surveillance may not capture the true health of neighborhoods as the influx of younger, healthier, and wealthier individuals (i.e., gentrification) can impact long term residents (LTR) who can be older and of lower socioeconomic status (SES), potentially biasing prevalence estimates. Hypothesis: LTR in gentrifying vs. LTR in non-gentrifying neighborhoods will have a lower prevalence of CVD related conditions. Methods: We quantified the census tract prevalence of diabetes (DM), hypertension (HTN), obesity, and CVD (myocardial infarction or stroke hospitalization) using electronic health record (EHR) data from the Duke Health System and Lincoln Community Health Center from 2008-2010 and 2014-2016. The EHR population was 116,760 patients living in Durham County in 2008 followed until 12/31/16. LTR were patients with the same 2010 and 2015 address; patients moving in/out (i.e., movers) did not have a recorded address in 2010 or 2015. A census tract was defined as gentrifying if 3 of 4 SES indicators (positive z-score for median household income, median rental price, % with bachelor’s degree, or a negative z-score for % living below the poverty line) improved. In difference-in-difference (DiD) analysis, we compared changes in prevalence of CVD health indicators between LTR in gentrifying and non-gentrifying neighborhoods. Results: At baseline, patients had a median age of 43 years, 42% were black and 61% were female. The overall prevalence of DM, HTN, obesity, and CVD was 12%, 32%, 19%, and 5% in 2010 &amp; 14%, 31%, 32%, and 7% in 2016. The prevalence increased in gentrifying and non-gentrifying neighborhoods over time and was higher in LTR than comparable movers. Estimates from DiD models were not statistically significant (Figure 1). Conclusions: LTR vs. movers and not gentrification impacted the surveillance of CVD health indicators. Novel public health informatics methods are needed to address dynamic changes in neighborhoods that may bias the enumeration of CVD health indicators.
Selective sensitization of Ras-mutant (Ras-m) cancer cells to DNA-damaging chemotherapy by Wee1 inhibition with AZD1775.
Authors: Elda Grabocka, Mark Choi, Deirdre Jill Cohen, Robert Godin, Lawrence P. Leichman, Dafna Bar-Sagi
Journal: Journal of Clinical Oncology (2015)

e13517 Background: Human cancers harboring Ras-mutated (m) oncogenes are resistant to current EGFR-targeted therapies. Given the many patients with Ras-m cancers, limited treatment options available, and their poor outcomes, there is a great need to develop treatment modalities that effectively target these tumor types. We previously reported that Ras-m tumors activate the ATR/Chk1 DNA damage checkpoint through signaling from wild-type (wt) Ras proteins, thus conferring resistance to DNA damaging chemotherapeutic agents in vitro and in vivo.1 Consequently, we hypothesized that abrogating the ATR/Chk1 DNA damage checkpoint by downstream Wee1 kinase inhibition would selectively sensitize Ras-m and BRaf-m tumors to DNA damaging chemotherapy. Methods: Toassess whether a Wee1 kinase inhibitor (KI) enhanced the cytotoxicity of DNA damaging agents in Ras-m and Raf-m cells, we utilized a selected panel of colon cancer cell lines with the following mutational backgrounds (2-3 cell lines/group): 1) Ras-m/p53-m; 2) Ras wt/p53-m; 3) Ras-m/p53 wt and 4) BRaf-m/p53-m. 4 log dose response cell viability assays were used to determine the single agent IC50 for the topoisomerase 1 inhibitor, SN38, and the Wee 1 KI AZD1775. Cells were then treated with the two agents at doses ranging in a 5-fold difference below each individual IC50 (0.04X, 0.2X). For all viability assays, cells were plated in 96-well plates in triplicate; viability was determined by MTT assay. Results: AZD1775 treated Ras-m/p53-m cells were ~10-100 fold more sensitive to SN38. Notably, Wee1 inhibition did not sensitize Ras wt/p53-m or Ras-m/p53 wt cells to SN38. Wee1 inhibition in BRaf-m/p53-m cells led to a modest ~3-5 fold sensitization to SN38, with the exception of one cell line which showed ~ 270 fold sensitization. Conclusions: The Wee1 KI AZD1775 strongly enhances the antitumor effect of SN38 in this panel of Ras-m/p53-m cancer cells but not in cancer cells where either p53 alone or Ras alone were mutated. Although this is a limited panel of cell lines, our findings support further testing of this combination in human tumors harboring concomitant Ras and p53 mutations. Supported by NYU GI Cancer Fund. 1. Cancer Cell. 2014 Feb 10;25(2):243-56
Avelumab treatment in metastatic urothelial carcinoma: Association between early response and durable outcomes in the phase Ib JAVELIN Solid Tumor Study.
Authors: Manish R. Patel, James L. Gulley, Keun-Wook Lee, Jeffrey R. Infante, Juliane Manitz, Vijay Kasturi, Hao Zhang, Galit Rosen, Andrea B. Apolo
Journal: Journal of Clinical Oncology (2019)

429 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, avelumab treatment in post-platinum patients (pts) has shown promising and durable antitumor activity and favorable overall survival (OS) outcomes. Here, we report post hoc analyses to assess if early response to avelumab is associated with long-term treatment outcomes. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). A Kaplan-Meier subgroup analysis has been performed for duration of response (DOR); response by week 7 (first tumor scan ± 5 days) define balanced subgroups. A landmark analysis was used to assess the association between time-to-response and OS. The landmark was 3 mo (second tumor assessment; 12 weeks ± 5 days). Results: 242 pts with platinum-treated mUC received avelumab and were followed up for ≥2 years (median, 2.7 years; data cutoff, Apr 2018). No difference in DOR was found between pts who had responded by the first tumor assessment (n=15) and those who responded later (n=25; HR, 0.8 [95% CI: 0.3-2.0]). In a landmark analysis for OS, the median OS was not reached (NR [95% CI: 18.9 mo-NR]) in pts who had responded within 3 mo (n=29) compared with 9.5 mo (95% CI: 6.5-14.4) in pts with late response or stable disease (n=74), and 4.3 mo (95% CI: 2.8-7.1) in other pts (progressive disease [PD] or not evaluable; n=70). Further sensitivity analyses found that survival did not vary between pts who continued treatment beyond investigator-confirmed PD (n=46) vs those that did not (n=24; median survival, 5.0 mo [95% CI: 2.8-8.8] vs 4.3 mo [95% CI: 0.9-8.3], respectively). Conclusions: Responses to avelumab have similar durability irrespective of time to response. Pts with an early response to avelumab tend to survive longer than pts with stable disease, and both groups have longer OS than nonresponders. Clinical trial information: NCT01772004.
An updated analysis evaluating skeletal related events (SREs) in CTRIAL-IE 13-21: Phase II trial of radium-223 (R223) in combination with enzalutamide (ENZA) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: John Patrick Greene, Marvin Chang Jui Lim, Anne-Marie Baird, Olwyn Deignan, John McCaffrey, Lisa Mary Prior, Imelda Parker, Alison Bowes, Ausra Teiserskiene, John Feeney, Pierre Guillame Thirion, Stephen P. Finn, Paul J. Kelly, Ray McDermott
Journal: Journal of Clinical Oncology (2019)

215 Background: This phase II single arm study, previously reported on the safety and tolerability of the combination of R223 and ENZA in pts with mCRPC. R223 in combination with ENZA was well tolerated with acceptable safety and toxicity profiles. Methods: This study enrolled pts with mCRPC to bone with or without visceral/lymph node involvement progressing on ADT. Pts received 6 cycles of R223 (55 kBq/kg IV Q4W) in combination with ENZA (160mg/day), followed by ENZA alone. Bone health agents were initiated as per treating clinician choice. SREs were defined as: a pathologic fracture, spinal cord compression (SCC), necessity for external beam radiation (EBRT) or surgery to bone. SREs during the combination period and after completion of R223 are reported here. An unplanned retrospective analysis of all scans performed on each patient for any fracture was performed and is included. Results: From July 2015 to July 2017, 45 pts were enrolled. 42 pts (93.3%) received all 6 cycles of combination therapy. 16 pts (35.5%) remain on ENZA alone. In total, 6 pts (13.3%) had SREs. 4 developed pathological fractures (femur = 1, vertebrae = 3) while 3 had EBRT for pain. Of these 6 pts, 2 developed SCC requiring EBRT. The average time from starting R223 to SRE was 615 days. 2/6 pts were not receiving bone protection. One pt who developed a pathological fracture has subsequently died related to progressive disease (time to death = 292 days). In the retrospective analysis, 4 pts (8.8%) developed fractures which were associated with a history of trauma (radius = 1, tibia = 1 ribs = 2). 11 pts (24.4%) developed asymptomatic insufficiency fractures (ankle = 1, femur = 1, sacrum = 2, vertebrae = 4, ribs = 4). The average time to insufficiency fracture was 354 days. No interventions were required. The majority of pts (75.5%) on the study were receiving bone health agents. Conclusions: SREs were in keeping with previously published data. In an unplanned retrospective analysis, there was a higher incidence of asymptomatic insufficiency fractures in this cohort of patients, however no interventions were required. Clinical trial information: NCT02225704.
Corrigendum to “Engineering multifunctional bioactive citric acid-based nanovectors for intrinsical targeted tumor imaging and specific siRNA gene delivery in vitro/in vivo” [Biomaterials 199 (2019) 10–21]
Authors: Min Wang, Yi Guo, Yumeng Xue, Wen Niu, Mi Chen, Peter X. Ma, Bo Lei
Journal: Biomaterials (2019)