tbuckley/cabot-search huggingface dataset:
Abstract 17205: Polypharmacy and the Impact of Apixaban on Clinical Events in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial
Authors: Jeroen Jaspers Focks, Marc A Brouwer, Daniel M Wojdyla, Laine Tomas, Renato D Lopes, Michael Hanna, Fernando Lanas, Denis Xavier, Steen Husted, Lars Wallentin, John H Alexander, Christopher B Granger, Freek W Verheugt
Journal: Circulation (2015)

Purpose: Polypharmacy is associated with frailty and adverse clinical events. Compared with warfarin, apixaban is more efficacious in preventing stroke and safer in patients with atrial fibrillation (AF). However, it has not been shown if these benefits are preserved in patients treated with several concomitant drugs. Methods: All patients included in the ARISTOTLE trial (n=18,201) were divided into tertiles according to the number of drugs used at baseline. The treatment effects of apixaban versus warfarin on clinical outcomes were assessed according to the number of concomitant medications. Results: The median number of concomitant drugs was 6 (IQR 5-9). When comparing tertiles, patients using more drugs were older, more often female, and had more comorbidities than patients using less medications. During a median follow-up of 1.8 years, the rates of efficacy and safety outcomes increased across tertiles. The superiority of apixaban when compared with warfarin in reducing stroke and systemic embolism was consistent regardless of the number of concomitant drugs (interaction p-value= 0.8203; Table). In terms of safety, the magnitude of benefit with apixaban decreased with the number of drugs taken (interaction p-value= 0.0173). A similar treatment effect pattern was seen for the net clinical benefit. Conclusions: In ARISTOTLE, both ischemic and hemorrhagic complications occurred more frequently in patients treated with a higher number of concomitant medications. The benefits of apixaban in reducing stroke were preserved, regardless of the number of drugs taken. In terms of safety and net clinical benefit, while the rates were consistently lower with apixaban, the magnitude of benefit with apixaban decreased with the number of concomitant drugs. Thus, apixaban is a more effective and at least as safe alternative to warfarin in patient with AF with polypharmacy.
Abstract P243: Retinal Microvascular Findings and Future Risk of Peripheral Artery Disease: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: CHAO YANG, Lucia Kwak, Shoshana H Ballew, Bernard Jaar, Jennifer A Deal, Aaron R Folsom, Gerardo Heiss, A. Richey Sharrett, Elizabeth Selvin, Charumathi Sabanayagam, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2017)

Introduction: Lower-extremity peripheral artery disease (PAD) is often considered as a subtype of macrovascular disease. For the development of critical limb ischemia (CLI), a severe form of PAD, microvascular disease is indicated to play a crucial role by impairing collateral formation and wound healing. However, the contribution of microvascular disease to the development of PAD has not been systematically evaluated in a large cohort study. Hypothesis: Microvascular disease, as represented by retinal findings, will be associated with future PAD risk, and its association will be stronger for CLI. Methods: Retinal photographs were taken at the 3 rd examination (1993-1995) of the ARIC Study. We investigated 9390 participants free of clinical history of PAD and quantified the associations of each retinal finding with PAD risk using Cox models. PAD was defined as hospitalizations with PAD diagnosis (ICD-9: 440.2x, 440.3, 440.4) or leg revascularization (38.18, 39.25, 39.29, 39.50). Of PAD cases, those with ulcer (707.1), gangrene (785.4) or leg amputation (84.1x) were considered CLI. Results: During a median follow-up of 19 years, 304 participants developed PAD, of which 92 were considered CLI. Retinal hemorrhages, exudates, microaneurysms and any retinopathy demonstrated independent associations with PAD (Table) beyond potential confounders including diabetes, while generalized arteriolar narrowing did not. These significant retinal findings were more strongly associated with CLI than with PAD (HR range 3.1-6.5 vs. 2.2-3.3, with all p-values for difference in HR from seemingly unrelated regression &lt;0.05 except soft exudates). Also, these retinal findings tended to have stronger associations with PAD outcomes among persons with diabetes than those without. Conclusions: Retinal hemorrhages, exudates, microaneurysms and any retinopathy were independently associated with PAD, especially its severe form, CLI. Our results suggest the importance of microvascular wall fragility/permeability in the development of PAD.
Abstract 12413: Haemoglobin and Change in Haemoglobin Status Predict Mortality, Cardiovascular Events and Bleeding in Stable Coronary Artery Disease: A Clarify Registry Analysis of 21,829 Patients From 45 Countries
Authors: Paul R Kalra, Nicola Greenlaw, Roberto Ferrari, Ian Ford, Jean-Claude Tardif, Michal Tendera, Philippe Gabriel Steg, Kim Fox
Journal: Circulation (2015)

Anaemia is a predictor of adverse outcome in patients with acute myocardial infarction and those undergoing revascularisation. Little is known regarding the relationship of hemoglobin (Hb) or its change over time on outcomes in patients with CAD. The CLARIFYregistry provides a unique contemporary opportunity to explore this relationship . Methods: 33 283 patients from 45 countries were enrolled in the CLARIFY registry of stable CAD (Nov 2009 -July 2010). Hb values were available for 21,829 patients, who were divided into groups according to Hb quintiles and anaemia status (WHO criteria) at each of baseline and follow-up (anaemic[A]/normal[N]) (status at baseline/follow-up): (i) N/N (ii) A/N (iii) N/A, (iv) A/A. Results: (Table) Whilst patients with lower Hb were less commonly treated with aspirin and ACEIs, they more commonly received thienopyridines, anticoagulants and ARBs. Low Hb was a consistent predictor of mortality, adverse CV event and major bleeds after controlling for various factors at baseline. Anaemia at follow up was independently associated with higher all-cause mortality (p&lt;0.001, HR 1.9 [1.5, 2.3] for A/A and 1.9 [1.5, 2.3] for N/A), non-CV mortality (p&lt;0.001) and CV mortality (p = 0.001). Patients whose baseline anaemia normalised during follow-up (A/N) did not appear to be at increased risk of death (HR 1.0 [0.8, 1.3], although risk of major bleeding was greater (HR 2.1 [1.2, 3.4], p=0.01). Sensitivity analyses were performed after excluding patients with heart failure and chronic kidney disease at baseline and yielded qualitatively similar results. Conclusions: In this large contemporary stable CAD population, low Hb was an independent predictor of mortality, adverse CV event and major bleeds. Persisting or new onset anaemia is a powerful predictor of CV and non-CV mortality. Whilst low Hb may play a pathophysiological role in CV disease progression, the data suggest that it is also likely to be a marker of other co-morbid disease.
AB0076 Warts in patients with systemic lupus erythematosus
Authors: C Korkmaz, S Ürer, I Zubaroglu
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> It is widely accepted that patients with systemic lupus erythematosus (SLE) have an increased susceptibility to infections, and infections have also been considered to be important in triggering SLE. An increased frequency of bacterial and mycotic infections have been reported. SLE is also associated with few viral infections. <h3>Objectives</h3> During their follow-up many patients with SLE were found to have viral warts. We therefore undertook this study to determine the prevalence of warts in patients with SLE. <h3>Methods</h3> Definite SLE and rheumatoid arthritis (RA) were diagnosed on the basis of criteria by the ACR. Study included 44 SLE patients (39 F,5 M; age 36.4 years), 71 RA patients (59 F, 12 M; age 49 years). The prevalence of warts was also determined in healthy madical students and their neighbours. <h3>Results</h3> Warts occured significantly (p &lt; 0.012, p &lt; 0.001) more often in patients with SLE than in the RA patients and healthy control patients respectively. Table shows the prevalence of warts in patients with SLE and control patients. <h3>Conclusion</h3> The findings suggest that some deficiency in the immune mechanisms of patients with SLE predisposes them to develop warts.
Long‐Term Prevention of Bacterial Infection and Enhanced Osteoinductivity of a Hybrid Coating with Selective Silver Toxicity
Authors: Kai Xie, Ziao Zhou, Yu Guo, Lei Wang, Guoyuan Li, Shuang Zhao, Xiangmei Liu, Jun Li, Wenbo Jiang, Shuilin Wu, Yongqiang Hao
Journal: Advanced Healthcare Materials (2019)

Abstract Antibacterial and osteogenic design is required for ideal orthopedic implants. The excellent antimicrobial performance of silver nanoparticles (AgNPs) has attracted interest for the treatment of implant‐related infections. However, the dose‐dependent cytotoxicity of silver and its negative impact on bone implants restrict the further use of AgNPs coatings. Therefore, a hybrid coating containing polydopamine (PDA), hydroxyapatite (HA), AgNPs, and chitosan (CS) is prepared. Organic chelators CS and PDA that have promising biocompatibility are used to prevent the rapid release of silver ions from the AgNPs coating. The double chelating effect of PDA and CS significantly reduces silver ion release from the hybrid coating. The coating exhibits excellent anti‐biofilm efficiency of 91.7%, 89.5%, and 92.0% for Staphylococcus aureus , Staphylococcus epidermidis , and Escherichia coli , respectively. In addition, the coating can significantly stimulate osteogenic differentiation of MC3T3‐E1 cells and promote bone‐implant osseointegration in vivo as compared to that in the control group. The longitudinal biosafety of the coating is confirmed in vivo by histological evaluation and blood tests. The results of this study indicate that the hybrid coating exhibits antibacterial properties as well as allow bone‐implant osseointegration, thereby providing insight into the design of multifunctional implants for long‐term orthopedic applications.
Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines
Authors: Piper Nicolosi, Elisa Ledet, Shan Yang, Scott Michalski, Brandy Freschi, Erin O’Leary, Edward D. Esplin, Robert L. Nussbaum, Oliver Sartor
Journal: JAMA Oncology (2019)

<h3>Importance</h3> Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer. <h3>Objective</h3> To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. <h3>Design, Setting, and Participants</h3> Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists–certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. <h3>Main Outcomes and Measures</h3> The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. <h3>Results</h3> Of 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in<i>BRCA1/2</i>. Positive variants in<i>HOXB13</i>, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. <h3>Conclusions and Relevance</h3> Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.
Abstract 043: Leisure-Time Physical Activity in Adulthood and Region of Interest (ROI) Brain Volumes: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)
Authors: Priya Palta, A R Sharrett, Kelly R Evenson, Clifford R Jack, Pamela L Lutsey, Lynne E Wagenknecht, Thomas H Mosley, Gerardo Heiss
Journal: Circulation (2018)

Introduction: Several studies report late-life physical activity (PA) to be associated with less brain atrophy. Associations of PA and subclinical brain markers evaluated at older ages may be subject to reverse causality due to comorbidity, age-related changes in lifestyle, or incipient cognitive impairment. Therefore, we aimed to compare late-life cross-sectional estimates of PA and ROI brain volumes to those using prospective PA measures from mid- to late-life. Methods: Participants (n=1549, mean age: 75, 39% male, 20% Black) with repeat assessments of PA from visit 1 (1987-1989) and a brain magnetic resonance imaging (MRI) in 2011-2013 were included. Total volume of PA in metabolic equivalent-min/week was estimated using the Baecke Physical Activity Questionnaire and classified as no, low, middle or high at each visit. Based on visit 1 and 3 (1993-1995) PA assessments, a subset of participants (n=663) were further categorized as habitually inactive or having habitually low, middle, or high PA in mid-life. Brain MRI using 3D-1.5T equipment quantified ROI volumes following a standardized protocol. Weighted linear regression adjusted for intracranial volume, demographics, select cardiovascular risk factors and ApoE4 estimated the standardized difference in ROI volumes. Results: Compared to no PA, high PA was associated with larger ROI brain volumes cross-sectionally in late-life (Table). High mid-life PA was only modestly associated with larger frontal cortical and deep gray matter volumes in late-life (Table). Habitually high PA in mid-life was not associated with less atrophy across brain regions in late-life. Conclusions: Our results do not support a causal interpretation of the cross-sectional associations between PA and brain volumes reported in late-life. Drawing on long-term population-based data, this study provides novel information on the associations of PA across life epochs with brain health, which can inform translational and intervention efforts to reduce age-related cognitive impairment.
Abstract 21298: Surveillance Invasive Hemodynamics in Pediatric Heart Transplant Patients: Utility or Futility?
Authors: Kate S Arbon, Yuk M Law, James K Kirklin, Elizabeth Pruitt, Timothy M Hoffman, Kenneth O Schowengerdt, Thomas J L'Ecuyer, Steven J Kindel
Journal: Circulation (2017)

Introduction: Although first year survival after pediatric heart transplant is improving, late-onset rejection, cardiac allograft vasculopathy (CAV), and graft failure remain significant challenges. Patients routinely undergo endomyocardial biopsy with invasive hemodynamics as the gold standard for rejection surveillance and assessment of long-term graft performance. However, it remains unclear how hemodynamic measures contribute to the monitoring of rejection, CAV, and graft dysfunction. This study aims to assess changes in hemodynamics as the graft ages in patients with or without a history of rejection or CAV. Hypothesis: We hypothesize that abnormal hemodynamics, particularly elevated filling pressures, are associated with CAV, rejection and graft aging. Methods: A total of 2,764 patients from the Pediatric Heart Transplant Study database from 1995-2014 met study criteria of survival to 1 year after transplant with available surveillance biopsy and hemodynamics. Retrospective analyses of 16,489 hemodynamic sets were performed. Results: The median age at transplant was 4.89 years [0.73, 12.95]. Average follow up time was 4.05 years [2.04, 7.17]. Fifty-six percent of patients were male, and 46% had history of congenital heart disease. When comparing hemodynamics collected at the first annual catheterization to 10 years after transplant, those who never had rejection or CAV showed statistically significant increases in right atrial pressure (RAP) (p=&lt;0.001), and pulmonary capillary wedge pressure (PCWP) (p = &lt;0.001) with concomitant decrease in cardiac index (p=0.01). When comparing hemodynamics from patients with a history of CAV or rejection to those without such events, patients with history of CAV or rejection had higher RAP (p=&lt;0.001) and PCWP (p = &lt;0.001), and lower cardiac index (p=0.003) and systemic vascular resistance (p=0.0001). Conclusions: Despite freedom from CAV or rejection, RAP and PCWP increase and cardiac index decreases as the graft ages. Additionally, the diagnosis of CAV or rejection during the life of the graft leads to further derangement in graft performance, which can be detected in hemodynamics. Serial hemodynamic assessment may contribute to the ongoing monitoring of graft function in pediatric recipients.
Inhibition of WIP1 Phosphatase in Multiple Myeloma Overcomes Bortezomib Resistance and Promotes Cell Death Via ER Stress-Induced Apoptotic JNK/c-Jun Signaling and Downregulation of Inhibitors of Apoptosis Proteins (IAPs)
Authors: Katia Beider, Evgenia Rosenberg, Valeria Voevoda, Hanna Bitner, Yaarit Sirovsky, Hila Magen, Olga Ostrovsky, Avichai Shimoni, Michael Milyavsky, Amnon Peled, Arnon Nagler
Journal: Blood (2018)
Abstract A062: Systemic oncolytic virotherapy for prostate cancer
Authors: Tien Nguyen, Michael A. Barry
Journal: Cancer Research (2018)

Abstract Oncolytic viruses hold promise as “self-amplifying” cancer therapies wherein a virally killed cell can produce thousands of new viral “drugs” that can kill more cancer cells. Oncolytic viruses may also serve to reawaken or initiate immune responses against cancers by virtue of their abilities to lyse cells, liberate cancer antigens, and provide viral DNA and proteins as immune adjuvants. Oncolytics can also be armed with cytokine or checkpoint inhibitors to amplify antitumor immune responses. Adenoviruses (Ads) are one family of oncolytic viruses. Most human studies have used human Ad serotype 5 (Ad5). Unfortunately, most patients are already immune to Ad5, increasing the likelihood that the agent will be neutralized if used as a cancer therapy. In this work, low seroprevalence Ad6 and Ad57 oncolytic viruses were tested as intravenous therapies against distant prostate cancer sites. After prostate cell infection in vitro, Ad viruses executed these cells efficiently and generated 10,000 to 100,000 progeny infectious viruses. This genome replication also amplified transgene protein production by 100 to 1,000-fold when compared to nonreplicating Ad vectors. Ad5, Ad6, and Ad57 were injected intravenously a single time in nude mice bearing human prostate tumors, and toxicity and efficacy were assessed. Ad6 and 57 produced 30-fold lower liver damage and less toxicity than Ad5. Ad6 and Ad57 significantly repressed the growth of androgen-resistant human DU145 prostate tumors and androgen-sensitive LNCaP prostate tumors and extended survival after single intravenous injection in mice. Ad6 and Ad57 E1 protein were also modified to protect normal cells from viral oncolysis while allowing the virus to amplify and kill prostate cancer cells having perturbations in p300 and pRB pathways. These and other data suggest that targeted and untargeted low seroprevalent Ad6 and Ad57 have better efficacy and safety than the benchmark oncolytic virus Ad5 for systemic therapy of advanced prostate cancer. Citation Format: Tien Nguyen, Michael A. Barry. Systemic oncolytic virotherapy for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A062.
Abstract P3-06-13: Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T)
Authors: N Walsh, G Gullo, C Quinn, SJ Furney, J Crown
Journal: Cancer Research (2019)

Abstract Background: Trastuzumab (T) has shown clinical efficacy in early-stage and MBC. However, within 1-year 40-50% develop resistance to T. The exact mechanism of the development of T resistance is not completely understood. Anecdotal observations suggest that a small fraction of patients with HER2+ MBC may be "extraordinary durable complete responders (ExdCR)". Indeed, we previously reported that 9% of MBC achieve dCR following T and chemotherapy. Understanding the genomic mechanisms underlying exceptional dCR to T may improve patient selection and treatment rationale to identify HER2+ MBC pts who are more likely to achieve dCR following T treatment. Methods: Genomic DNA was extracted from paraffin embedded formalin fixed (FFPE) tissue. Whole exome sequencing (WES) on primary tumours from 9 MBC ExdCR &amp;gt; 60 mo (5 matched T:N) and 6 non-responders (NR) or PR &amp;lt; 6 mo (3 matched T:N). Tumours were analysed for single nucleotide variants (SNVs) point mutations, insertions/deletions (indels), copy number alterations (CNA), and tumour mutational burden. Detailed clinicopathologic data was collected for each patient and linked to the genomic information. Results: WES of matched tumour:normal samples revealed differences in SNVs and indels between the ExdCR pts compared to NR. Mutations in TP53 were found in 2/5 ExdCR pts and in 0/3 NR. Initial analysis of CNA revealed that HER2 is significantly more amplified in ExdCR pts compared to NR, and this was also shown by IHC and FISH. Conclusions: We present a genomic landscape of extraordinary durable complete responders compared to non-responders using WES. High variability exists in mutation profile of ExdCR pts with few overlapping genes. Further analysis into clinically relevant genomic and molecular alterations will be performed to potential aid in patient selection and choice of therapy, and novel drug targets. Citation Format: Walsh N, Gullo G, Quinn C, Furney SJ, Crown J. Whole exome sequencing of HER2+ metastatic breast cancer (MBC) patients (pts) with extraordinary durable complete responses (ExdCR) to trastuzumab (T) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-13.