bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA06: A urine assay to triage patients with hematuria for cystoscopy
Authors: van Kessel Kim E.M. , de Jong Joep J. , Ziel-van der Made Angelique C.J. , Roshani Hossain , Haensel Stefan M. , Wolterbeek Josien H. , Boevé Egbert R. , Oomens Eric H.G.M. , van Casteren Niels J. , Krispin Manuel , Boormans Joost L. , Steyerberg Ewout W. , van Criekinge Wim , Zwarthoff Ellen C. 
Published: August 2020

Abstract
Objectives: To assess the accuracy of a previously developed molecular assay to detect bladder cancer in a large prospective cohort of patients referred for hematuria.
Design, Setting and Participants: A urine sample was collected prior to cystoscopy and mutation/methylation status of 6 genes was determined in DNA from urinary cells and combined with age. This existing diagnostic model was validated on this cohort and optimized using logistic regression. Clinical usefulness was determined by the net benefit approach. Main outcome measures: Primary endpoint was the model performance to detect the presence of urothelial cancer, as indicated by the area under the receiver operating characteristic (ROC) curve (AUC). Secondary endpoints were the sensitivity, specificity, and negative predictive value (NPV) of the optimal diagnostic model.
Results: In 838 patients, the mutation/methylation status could be determined for all genes. Urothelial cancer was observed in 112 patients (98/457 in the gross and 14/381 in the microscopic hematuria group). Application of the existing model resulted in an AUC of 0.93. Combining the assay with the type of hematuria resulted in the final optimal model with an AUC of 0.96 (96% sensitivity, 73% specificity, 99% negative predictive value). The assay also detected all six upper tract urothelial tumors that are not visible by cystoscopy. Net benefit analysis showed that the urine test should be preferred over “cystoscopy for all.” Application of the optimal model on patients whose biomarker status was incomplete resulted in the identification of 5 additional tumors. Implementing the urine test as a triage tool could lead to a 53% reduction in cystoscopies.
Conclusions: The urine test detects urothelial cancer with a very high accuracy and is ready for clinical implementation.
Citation Format: Kim E.M. van Kessel, Joep J. de Jong, Angelique C.J. Ziel-van der Made, Hossain Roshani, Stefan M. Haensel, Josien H. Wolterbeek, Egbert R. Boevé, Eric H.G.M. Oomens, Niels J. van Casteren, Manuel Krispin, Joost L. Boormans, Ewout W. Steyerberg, Wim van Criekinge, Ellen C. Zwarthoff. A urine assay to triage patients with hematuria for cystoscopy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA06.
Abstract IA10: Developing rational combination therapy with checkpoint inhibitors
Authors: Tu Megan M. , Lee Francis Y. F. , Jones Robert T. , Kimball Abigail K. , Saravia Elizabeth , Graziano Robert F. , Coleman Brianne , Menard Krista , Yan Jun , Michaud Erin , Chang Han , Abdel-Hafiz Hany A. , Rozhok Andrii I. , Duex Jason E. , Agarwal Neeraj , Chauca-Diaz Ana , Johnson Linda K. , Ng Terry L. , Cambier John C. , Clambey Eric T. , Costello James C. , Korman Alan J. , Theodorescu Dan 
Published: August 2020

Abstract
Targeting antibodies to programmed cell death protein-1 (PD-1) is an effective treatment across multiple cancer types. While a subset of patients receiving these therapies experience favorable responses, many still show disease progression, highlighting the importance of other mechanisms influencing immune responsiveness in these tumors. Therefore, combining therapies that enhance antitumor immunity has been an area of great interest to the entire cancer community. We have recently tackled this challenge in the rapidly evolving field of cancer immunotherapy by using in vivo functional genomics to identify genes whose inhibition potentiates the response to anti-PD-1 immunotherapy. Using an in vivo screening approach with a customized shRNA pooled library, we identified a number of candidates including DDR2 as promising targets for the enhancement of response to anti-PD-1 immunotherapy. In the case of DDR2, using isogenic in vivo murine models across five different tumor histologies—bladder, breast, colon, sarcoma, and melanoma—we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, also led to tumor load reduction and in some cases, complete clearance. RNAseq and CyTOF analysis revealed higher CD8+ T-cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors. In addition, a number of other potential druggable targets have been identified in our screen that we are currently pursuing.
Citation Format: Megan M. Tu, Francis Y. F. Lee, Robert T. Jones, Abigail K. Kimball, Elizabeth Saravia, Robert F. Graziano, Brianne Coleman, Krista Menard, Jun Yan, Erin Michaud, Han Chang, Hany A. Abdel-Hafiz, Andrii I. Rozhok, Jason E. Duex, Neeraj Agarwal, Ana Chauca-Diaz, Linda K. Johnson, Terry L. Ng, John C. Cambier, Eric T. Clambey, James C. Costello, Alan J. Korman, Dan Theodorescu. Developing rational combination therapy with checkpoint inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA10.
Abstract IA22: Realizing the potential of targeted therapy in non-muscle invasive bladder cancer
Authors: Black Peter C. 
Published: August 2020

Abstract
Targeted therapies have revolutionized the management of most cancers, but the era of targeted therapy has mostly passed by bladder cancer. Ramicurimab (targeting VEGR) and erdafitinib and infigratinib (both targeting FGFR) have recently provided some reason for optimism that targeted therapies with highly potent inhibitors may yet find a role in advanced bladder cancer. Targeting genomic alterations in FGFR3 holds the most promise, but this molecular event is probably even more relevant in non-muscle invasive bladder cancer (NMIBC), and trials in this space are essential. Similarly, KDMT6a appears to be particularly important in NMIBC, and drugs targeting chromatin modification pathways are likely to be relevant in NMIBC. Novel therapies are also under development that are not specific to an individual cancer's genomic makeup, but instead target specific cancer-related pathways. Such agents include oportuzumab monatox and BC-819. Most clinical trial activity has focused on BCG-unresponsive high-risk NMIBC patients, but this is partly due to the pathway for drug registration, and we are likely to see some of the successful drugs in this disease state move forward to earlier disease states, especially to intermediate-risk patients. These therapies will need to be positioned in the treatment landscape along with other nontargeted intravesical agents such as nadofaragene firadenovec (rAd-IFN) and systemic immune checkpoint blockade.
Citation Format: Peter C. Black. Realizing the potential of targeted therapy in non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA22.
Abstract PR01: Novel role of ketone body metabolism in acquired gemcitabine resistance
Authors: Rohena-Rivera Krizia , Bhowmick Neil 
Published: August 2020

Abstract
Urinary bladder cancer accounts for 81,000 new cases per year and 4.7% of the new cancer diagnosis in the US. Even though most of the patients suffer from noninvasive lesions, around 70% will recur following surgical intervention. Chemotherapy with gemcitabine in combination with cisplatin is a common treatment option for recurrent disease; however, 60% of the patients will relapse due to resistance. Gemcitabine is a synthetic pyrimidine nucleoside prodrug, without a known mechanism for resistance. In examining mechanisms of resistance, we identified ketone body metabolism to be important. OXCT1, a rate-limiting enzyme in ketone metabolism, was found to be highly associated with bladder cancer death—Hoglund et al, P = 2.3 × 10-3 and TCGA, P = 6.5 × 10-4. We measured the expression of OXCT1 in RT4, UMUC3, T24, and 5637 bladder cancer cell lines and observed that expression correlated with gemcitabine resistance. The generation of gemcitabine resistance of otherwise sensitive 5637 cells (5637GR) resulted in elevation of OXCT1 expression, as well as PGC1a and SIRT1 involved in mitochondrial biogenesis. Conversely, the CRISPR/Cas9 knockout of OXCT1 was able to sensitize inherently resistant UMUC3 and generated 5637GR lines. Given that OXCT1 is a rate-limiting enzyme in ketone metabolism, we evaluated oxygen consumption rate among parental and resistant cells with Seahorse. Surprisingly, resistant cells were found to be metabolically quiescent. We evaluated the role OXCT1 has on cancer stemness through sphere-forming assays (hanging drop and forced floating methods) to reveal that the OXCT1-KO lines had reduced spheres compared to their parental lines. We identified bone morphogenic protein (BMP) signaling to be induced in promoting SOX9 expression, in OXTC1-dependent manner. Gene expression analysis further corroborated the novel role of ketone metabolism in stemness and therapeutic resistance.
This abstract is also being presented as Poster B28.
Citation Format: Krizia Rohena-Rivera, Neil Bhowmick. Novel role of ketone body metabolism in acquired gemcitabine resistance [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR01.
Abstract PR05: Similarities in molecular subtypes and subtype immune patterns between naturally occurring canine and human invasive bladder cancer
Authors: Dhawan Deepika , Sommer Breann C. , Ramos-Vara José A. , Hahn Noah M. , Knapp Deborah W. 
Published: August 2020

Abstract
Relevant animal models are needed to study treatment strategies related to the molecular subtypes of bladder cancer and the immune response between these subtypes. The purpose of the study was to characterize the molecular subtypes and immune features in naturally occurring canine invasive urothelial carcinoma (InvUC). Canine InvUC is already known to mimic the human condition in pathologic features, metastatic behavior, and chemotherapy response. Molecular subtyping could further increase the utilization of the canine model. RNA-seq data from canine InvUC (n=56) and normal canine bladder mucosa (n=4) were analyzed using Strand NGS (Strand Genomics, San Francisco, CA). Data were normalized (DESeq, TMM), and DEGs selected (2FC, pcorr &lt;0.05) using DESeq2 and edge R, respectively. Following unsupervised clustering that identified two groups of tumors, supervised clustering was performed in which the data were interrogated using a panel of genes known to classify human bladder cancer subtypes (TCGA), as well as multiple gene panels that classify human bladder cancer as immune hot (infiltrated) or immune cold (noninfiltrated, immune-suppressor features). Infiltrating immune cells were observed in histologic sections with CD3 immunohistochemistry. Distinct luminal (n=28) and basal (n=28) subtypes were identified in the canine InvUC samples, with subclassifications emerging in both subtypes. There was anticipated heterogeneity between the samples, but of the 28 basal tumors, all had hot immune features, with 10 being exceptionally hot. Of the luminal tumors, 22 of 28 were notably immune cold. In conclusion, canine InvUC mimics human invasive bladder cancer in regard to molecular subtypes and immune patterns within subtypes. This expands the value of the canine bladder cancer model and offers opportunities to study strategies for individualized therapy and to develop strategies to enhance the tumor immune environment in order to improve treatment outcomes. Support: NIH/NCI P30CA023168 Supp (Knapp, Ratliff).
This abstract is also being presented as Poster A26.
Citation Format: Deepika Dhawan, Breann C. Sommer, José A. Ramos-Vara, Noah M. Hahn, Deborah W. Knapp. Similarities in molecular subtypes and subtype immune patterns between naturally occurring canine and human invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR05.
Reelin Amplifies Glycoprotein VI Activation and AlphaIIb Beta3 Integrin Outside-In Signaling via PLC Gamma 2 and Rho GTPases
Authors: Krueger Irena , Gremer Lothar , Mangels Lena , Klier Meike , Jurk Kerstin , Willbold Dieter , Bock Hans H. , Elvers Margitta 
Published: August 2020

Objective:
Reelin, a secreted glycoprotein, was originally identified in the central nervous system, where it plays an important role in brain development and maintenance. In the cardiovascular system, reelin plays a role in atherosclerosis by enhancing vascular inflammation and in arterial thrombosis by promoting platelet adhesion, activation, and thrombus formation via APP (amyloid precursor protein) and GP (glycoprotein) Ib. However, the role of reelin in hemostasis and arterial thrombosis is not fully understood to date.

Approach and Results:
In the present study, we analyzed the importance of reelin for cytoskeletal reorganization of platelets and thrombus formation in more detail. Platelets release reelin to amplify alphaIIb beta3 integrin outside-in signaling by promoting platelet adhesion, cytoskeletal reorganization, and clot retraction via activation of Rho GTPases RAC1 (Ras-related C3 botulinum toxin substrate) and RhoA (Ras homolog family member A). Reelin interacts with the collagen receptor GP (glycoprotein) VI with subnanomolar affinity, induces tyrosine phosphorylation in a GPVI-dependent manner, and supports platelet binding to collagen and GPVI-dependent RAC1 activation, PLC gamma 2 (1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2) phosphorylation, platelet activation, and aggregation. When GPVI was deleted from the platelet surface by antibody treatment in reelin-deficient mice, thrombus formation was completely abolished after injury of the carotid artery while being only reduced in either GPVI-depleted or reelin-deficient mice.

Conclusions:
Our study identified a novel signaling pathway that involves reelin-induced GPVI activation and alphaIIb beta3 integrin outside-in signaling in platelets. Loss of both, GPVI and reelin, completely prevents stable arterial thrombus formation in vivo suggesting that inhibiting reelin-platelet-interaction might represent a novel strategy to avoid arterial thrombosis in cardiovascular disease.
Systematic Interrogation of Angiogenesis in the Ischemic Mouse Hind Limb
Authors: Lee Jason J. , Arpino John-Michael , Yin Hao , Nong Zengxuan , Szpakowski Alexis , Hashi Abdulaziz A. , Chevalier Jacqueline , O’Neil Caroline , Pickering J. Geoffrey 
Published: August 2020

Objective:
There has been little success in translating preclinical studies of mouse hind limb ischemia into benefit for patients with peripheral artery disease. Using systematic strategies, we sought to define the injury and angiogenesis landscapes in mice subjected to hind limb ischemia and ascertain whether published studies to date have used an analysis strategy concordant with these data.

Approach and Results:
Maps of ischemic injury were generated from 22 different hind limb muscles and 33 muscle territories in 12-week-old C57BL/6 mice, based on loss or centralization of myofiber nuclei. Angiogenesis was similarly mapped based on CD (cluster of differentiation) 31–positive capillary content. Only 10 of 33 muscle territories displayed consistent muscle injury, with the distal anterior hind limb muscles most reliably injured. Angiogenesis was patchy and exclusively associated with zones of regenerated muscle (central nuclei). Angiogenesis was not observed in normal appearing muscle, necrotic muscle, or injury border zones. Systematic review of mouse hind limb angiogenesis studies identified 5147 unique publications, of which 509 met eligibility criteria for analysis. Only 7% of these analyzed manuscripts evaluated angiogenesis in distal anterior hind limb muscles and only 15% consistently examined for angiogenesis in zones of muscle regeneration.

Conclusions:
In 12-week C57BL/6 mice, angiogenesis postfemoral artery excision proceeds exclusively in zones of muscle regeneration. Only a minority of studies to date have analyzed angiogenesis in regions of demonstrably regenerating muscle or in high-likelihood territories. Quality assurance standards, informed by the atlas and mapping data herein, could augment data reliability and potentially help translate mouse hind limb ischemia studies to patient care.
Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia
Authors: Trinder Mark , Paquette Martine , Cermakova Lubomira , Ban Matthew R. , Hegele Robert A. , Baass Alexis , Brunham Liam R. 
Published: August 2020

Background:
Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH.

Methods:
We constructed a weighted LDL-C polygenic score, composed of 28 single-nucleotide variants, for individuals with monogenic FH from the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank cohorts (n=306). We assessed the association between LDL-C polygenic score with LDL-C levels and ASCVD risk using linear regression and Cox-proportional hazard models, respectively. ASCVD was defined as myocardial infarction, coronary or carotid revascularization, transient ischemic attack, or stroke. The results from individual cohorts were combined in fixed-effect meta-analyses.

Results:

Levels of LDL-C were significantly associated with LDL-C polygenic score in the Nutrition, Metabolism and Atherosclerosis Clinic cohort, UK Biobank cohort, and in the meta-analysis (β [95% CI]=0.13 [0.072–0.19] per a 20% increase in LDL-C polygenic score percentile,
P
<0.0001). Additionally, an elevated LDL-C polygenic score (≥80th percentile) was associated with a trend towards increased ASCVD risk in all 3 cohorts individually. This association was statistically significant in the meta-analysis (hazard ratio [95% CI]=1.48 [1.02–2.14],
P
=0.04).

Conclusions:
Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.
Contrast‐Induced Acute Kidney Injury in Patients Undergoing TAVI Compared With Coronary Interventions
Authors: Venturi Gabriele , Pighi Michele , Pesarini Gabriele , Ferrero Valeria , Lunardi Mattia , Castaldi Gianluca , Setti Martina , Benini Annachiara , Scarsini Roberto , Ribichini Flavio L. 
Published: August 2020

Background
Differences in the impact of contrast medium on the development of contrast‐induced acute kidney injury (CI‐AKI) in patients undergoing transcatheter aortic valve implantation (TAVI) or a coronary angiography/percutaneous coronary intervention (CA/PCI) have not been previously investigated.

Methods and Results

Patients treated with TAVI or elective CA/PCI were retrospectively analyzed in terms of baseline and procedural characteristics, including preprocedural and postprocedural kidney function. CI‐AKI was defined as a relative increase in serum creatinine concentration of at least 0.3 mg/dL within 72 hours of contrast‐medium administration compared with baseline. The incidence of CI‐AKI in the TAVI versus CA/PCI group was compared. After the exclusion of patients in dialysis and emergency procedures, 977 patients were analyzed; there were 489 patients who had undergone TAVI (50.1%) and 488 patients who had undergone CA/PCI (49.9%). Patients treated by TAVI were older, presenting a higher rate of anemia and chronic kidney disease (
P
<0.001 for all comparisons). Consistently, they also had a significantly lower glomerular filtration rate and higher serum creatinine concentration (
P
<0.001 for all). However, the occurrence of CI‐AKI was significantly lower in these patients compared with patients treated by a CA/PCI (6.7% versus 14.5%,
P
<0.001). At multivariate analysis, the TAVI procedure had an independent protective effect on CI‐AKI incidence among total population (odds ratio, 0.334; 95% CI, 0.193–0.579;
P
<0.001). This observation was confirmed after propensity score matching among 360 patients (180 by TAVI and 180 by CA/PCI;
P
=0.002).

Conclusions
CI‐AKI occurred less frequently in patients undergoing TAVI than in patients undergoing a CA/PCI, despite a worse‐risk profile. The impact of contrast administration on kidney function in patients who had undergone TAVI may be better tolerated because of the hemodynamic changes following aortic valve replacement.
Reducing ECG Artifact From Left Ventricular Assist Device Electromagnetic Interference
Authors: Loring Zak , Sen Sounok , Black-Maier Eric , Atwater Brett D. , Russell Stuart D. , DeVore Adam D. , Piccini Jonathan P. 
Published: August 2020

Background
Left ventricular assist devices (LVADs) generate electromagnetic interference that causes high‐frequency noise artifacts on 12‐lead ECGs. We describe the causes of this interference and potential solutions to aid ECG interpretation in patients with LVAD.

Methods and Results
Waveform data from ECGs performed before and after LVAD implantation were passed through a fast Fourier transform to identify LVAD‐related changes in the spectral profile. ECGs recorded in 9 patients with HeartMate II, HeartMate 3, and HeartWare LVADs were analyzed to identify the LVAD model‐specific spectral patterns. Waveform data were then passed through digital low‐pass and bandstop filters and redisplayed to evaluate the effect of filtering on LVAD‐related electromagnetic interference. The spectral profile of patients with HeartMate II and HeartMate 3 LVADs demonstrated a prominent signal at the device‐specific frequency of impeller rotation. In patients with the HeartMate 3 LVAD, 2 additional peaks were observed at the frequencies equivalent to the LVAD's artificial pulsatility rotational speeds. Patients with HeartWare devices demonstrated a prominent signal peak at a frequency equal to double their LVAD's set rotational speed. Applying a low‐pass filter to a value below the observed frequency peak from the LVAD significantly improved the waveform tracing and quality of the ECG. Applying a speed‐specific bandstop filter to remove the observed LVAD frequency peak also improved the clarity of the ECG without compromising physiological high‐frequency signal components.

Conclusions
LVADs create impeller rotational speed‐specific electromagnetic interference that can be ameliorated by application of low‐pass or bandstop filters to improve ECG clarity.