bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA21: Intravesical gene therapy for NMIBC
Authors: Mokkapati Sharada , Duplisea Jon , Metcalfe Michael , Lim Amy , Narayan Vikram , Plote Devin , Sundi Debashish , Furguson James E. , Parker Nigel R. , Yla-Herttuala Seppo , McConkey David , Shluns Kimberly S. , Dinney Colin P.N. 
Published: August 2020

Abstract
BCG is our most effective therapy for treating NMIBC, but over time, most patients will eventually recur. Alternative therapies to avoid cystectomy are needed as to date, only valrubicin, with a CR approaching 10% at 12 months in BCG-refractory CIS, has been FDA approved. Significant unmet need thus remains for an effective second-line therapy for patients facing cystectomy. The elucidation of a pathway for registration of new agents for BCG-unresponsive NMIBC has drawn the attention of pharma, and a variety of new approaches are under evaluation. Gene therapy is a promising approach for the management of BCG-unresponsive NMIBC. Effective gene transfer across the urothelium has been accomplished, and several agents are being evaluated in ongoing clinical trials. Coldgenesys reported a 47% CR at 6 months for BCG-unresponsive NMIBC using a replication-competent oncolytic adenovirus. The SUO CTC reported a 35% RFS at 12 months for patients treated with rAd-IFNα2b/Syn3 gene therapy in a phase II trial. The RFS for patients with papillary disease was 50% and the CR for patients with CIS was 30%. The SUO-CTC have recently completed recruitment for the phase III trial and further preclinical work has progressed to elucidate rAd-IFN/Syn3 treatment efficacy via predictive efficacy biomarkers for patient selection, vectors that might improve transduction efficiency and the design of novel therapeutic combination strategies to take advantage of rAd-IFN's immunologic activity.
Citation Format: Sharada Mokkapati, Jon Duplisea, Michael Metcalfe, Amy Lim, Vikram Narayan, Devin Plote, Debashish Sundi, James E. Furguson III, Nigel R. Parker, Seppo Yla-Herttuala, David McConkey, Kimberly S. Shluns, Colin P.N. Dinney. Intravesical gene therapy for NMIBC [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 IA21.
Abstract PR09: Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab
Authors: Choi Woonyoung , McConkey David , Lee I-ling , Currie Graeme , Abella Steve , Kelly William , Siefker-Radtke Arlene 
Published: August 2020

Abstract
Background: FGFR3 mutations (mutFGFR3) are present in up to 20-35% of metastatic bladder (mUC) and upper tract urothelial cancer, respectively. Early data suggest that these tumors respond better to FGFR inhibition as compared with immunotherapy.
Methods: Patients who failed prior treatment for mUC were treated with vofatamab, an antibody targeting both wild-type (wtFGFR3) and mutFGFR3. Patients were treated with a loading dose of vofatamab 25 mg/kg with a biopsy pre- and post-treatment, followed by combination therapy with pembrolizumab to cohorts of patients with and without mutFGFR3. We performed gene expression profiling on paired biopsies from patients enrolled to date.
Results: We performed whole-transcriptome RNAseq on 17 matched tumors. The responses to the therapy were 7 partial responses (PR), 4 stable disease (SD), 5 progressed disease (PD), and 1 unknown. Surprisingly, we did not observe any relationships between FGFR3 mutation status and clinical response (ORR:1/3 mutant and 6/14 wild-type). Unsupervised cluster analysis of 17 matched tumors revealed the presence of two clusters: cluster 1 was enriched for responders (6 PR, 1 SD, and 1 PD), compared with cluster 2 (1 PD, 3 SD, and 4 PD). The significantly differentially expressed genes comparing cluster 1 and 2 were extracted and analyzed by Ingenuity Pathway Analysis (Sigma). Immune cell trafficking pathways, including migration of lymphocytes/T cells and phagocytes, were significantly upregulated in cluster 2 (p&lt;0.001). We then used BASE47 (47 gene signature for basal and luminal subtypes) to assign 17 paired tumors to the molecular subtypes. Of the responding tumors, 6 were luminal and 1 was basal. To further explore sensitivity/resistance mechanisms, the differentially expressed genes between pre- and post-treated PR tumors were extracted and were used to perform IPA analysis. Upstream regulators (CEBPA and RXRA) that control luminal biology were significantly activated after treatment (p&lt;0.001, Z score &gt;2).
Conclusions: Luminal biology may sensitize to combination of vofatamab with pembrolizumab regardless of presence of mutFGFR3, suggesting a role for this combination in wtFGFR3 mUC. Larger cohorts are needed to confirm these results.
This abstract is also being presented as Poster B25.
Citation Format: Woonyoung Choi, David McConkey, I-ling Lee, Graeme Currie, Steve Abella, William Kelly, Arlene Siefker-Radtke. Gene expression profiling in wild-type and mutant FGFR3 metastatic urothelial cancer treated with combination therapy with vofatamab and pembrolizumab [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 PR09.
Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation
Authors: Muramatsu Masashi , Nakagawa Suguru , Osawa Tsuyoshi , Toyono Tetsuya , Uemura Akiyoshi , Kidoya Hiroyasu , Takakura Nobuyuki , Usui Tomohiko , Ryeom Sandra , Minami Takashi 
Published: August 2020

Objective:
The calcineurin-NFAT (nuclear factor for activated T cells)-DSCR (Down syndrome critical region)-1 pathway plays a crucial role as the downstream effector of VEGF (vascular endothelial growth factor)-mediated tumor angiogenesis in endothelial cells. A role for DSCR-1 in different organ microenvironment such as the cornea and its role in ocular diseases is not well understood. Corneal changes can be indicators of various disease states and are easily detected through ocular examinations.

Approach and Results:

The presentation of a corneal arcus or a corneal opacity due to lipid deposition in the cornea often indicates hyperlipidemia and in most cases, hypercholesterolemia. Although the loss of Apo (apolipoprotein) E has been well characterized and is known to lead to elevated serum cholesterol levels, there are few corneal changes observed in
ApoE
−/−
mice. In this study, we show that the combined loss of ApoE and DSCR-1 leads to a dramatic increase in serum cholesterol levels and severe corneal opacity with complete penetrance. The cornea is normally maintained in an avascular state; however, loss of
Dscr-1
is sufficient to induce hyper-inflammatory and -oxidative condition, increased corneal neovascularization, and lymphangiogenesis. Furthermore, immunohistological analysis and genome-wide screening revealed that loss of
Dscr-1
in mice triggers increased immune cell infiltration and upregulation of SDF (stromal derived factor)-1 and its receptor, CXCR4 (C-X-C motif chemokine ligand receptor-4), potentiating this signaling axis in the cornea, thereby contributing to pathological corneal angiogenesis and opacity.

Conclusions:
This study is the first demonstration of the critical role for the endogenous inhibitor of calcineurin, DSCR-1, and pathological corneal angiogenesis in hypercholesterolemia induced corneal opacity.
Greater Neurobiological Resilience to Chronic Socioeconomic or Environmental Stressors Associates With Lower Risk for Cardiovascular Disease Events
Authors: Dar Tawseef , Osborne Michael T. , Abohashem Shady , Abbasi Taimur , Choi Karmel W. , Ghoneem Ahmed , Naddaf Nicki , Smoller Jordan W. , Pitman Roger K. , Denninger John W. , Shin Lisa M. , Fricchione Gregory , Tawakol Ahmed 
Published: August 2020

Background:
Chronic exposure to socioeconomic or environmental stressors associates with greater stress-related neurobiological activity (ie, higher amygdalar activity [AmygA]) and higher risk of major adverse cardiovascular events (MACE). However, among individuals exposed to such stressors, it is unknown whether neurobiological resilience (NBResilience, defined as lower AmygA despite stress exposure) lowers MACE risk. We tested the hypotheses that NBResilience protects against MACE, and that it does so through decreased bone marrow activity and arterial inflammation.

Methods:

Individuals underwent
18
F-fluorodeoxyglucose positron emission tomography/computed tomography; AmygA, bone marrow activity, and arterial inflammation were quantified. Chronic socioeconomic and environmental stressors known to associate with AmygA and MACE (ie, transportation noise exposure, neighborhood median household income, and crime rate) were quantified. Heightened stress exposure was defined as exposure to at least one chronic stressor (ie, the highest tertile of noise exposure or crime or lowest tertile of income). MACE within 5 years of imaging was adjudicated. Relationships were evaluated using linear and Cox regression, Kaplan-Meier survival, and mediation analyses.

Results:

Of 254 individuals studied (median age [interquartile range]: 57 years [46–67], 36.7% male), 166 were exposed to at least one chronic stressor. Among stress-exposed individuals, 12 experienced MACE over a median follow-up of 3.75 years. Among this group, higher AmygA (ie, lower resilience) associated with higher bone marrow activity (standardized β [95% CI]: 0.192 [0.030–0.353],
P
=0.020), arterial inflammation (0.203 [0.055–0.351],
P
=0.007), and MACE risk (standardized hazard ratio [95% CI]: 1.927 [1.370–2.711],
P
=0.001). The effect of NBResilience on MACE risk was significantly mediated by lower arterial inflammation (
P
<0.05).

Conclusions:
Among individuals who are chronically exposed to socioeconomic or environmental stressors, NBResilience (AmygA <1 SD above the mean) associates with a >50% reduction in MACE risk, potentially via reduced arterial inflammation. These data raise the possibility that enhancing NBResilience may decrease the burden of cardiovascular disease.
Clinical Predictive Models of Sudden Cardiac Arrest: A Survey of the Current Science and Analysis of Model Performances
Authors: Carrick Richard T. , Park Jinny G. , McGinnes Hannah L. , Lundquist Christine , Brown Kristen D. , Janes W. Adam , Wessler Benjamin S. , Kent David M. 
Published: August 2020

Background
More than 500 000 sudden cardiac arrests (SCAs) occur annually in the United States. Clinical predictive models (CPMs) may be helpful tools to differentiate between patients who are likely to survive or have good neurologic recovery and those who are not. However, which CPMs are most reliable for discriminating between outcomes in SCA is not known.

Methods and Results
We performed a systematic review of the literature using the Tufts PACE (Predictive Analytics and Comparative Effectiveness) CPM Registry through February 1, 2020, and identified 81 unique CPMs of SCA and 62 subsequent external validation studies. Initial cardiac rhythm, age, and duration of cardiopulmonary resuscitation were the 3 most commonly used predictive variables. Only 33 of the 81 novel SCA CPMs (41%) were validated at least once. Of 81 novel SCA CPMs, 56 (69%) and 61 of 62 validation studies (98%) reported discrimination, with median c‐statistics of 0.84 and 0.81, respectively. Calibration was reported in only 29 of 62 validation studies (41.9%). For those novel models that both reported discrimination and were validated (26 models), the median percentage change in discrimination was −1.6%. We identified 3 CPMs that had undergone at least 3 external validation studies: the out‐of‐hospital cardiac arrest score (9 validations; median c‐statistic, 0.79), the cardiac arrest hospital prognosis score (6 validations; median c‐statistic, 0.83), and the good outcome following attempted resuscitation score (6 validations; median c‐statistic, 0.76).

Conclusions
Although only a small number of SCA CPMs have been rigorously validated, the ones that have been demonstrate good discrimination.
Use of Cultured Hepatoma Cell Lines in the Assessment of Aldehyde Metabolism
Authors: Ferro Margherita , Bassi Anna Maria , Penco Susanna , Piana Sandra , Ravera Giambattista , Nanni Giorgio 
Published: August 2020

Aldehyde dehydrogenases (ALDH) represent a major pathway for the enzymatic removal of many potentially toxic aldehydes. The purpose of this study was to examine the basal levels of ALDH in five hepatoma cell lines chosen as representatives of three different species (man, rat, mouse) and their inducibility by some xenobiotics. Human HepG2, rat MH1C1, HTC, H4IIEC3 and mouse Hepa 1c1c7 cell lines were grown as monolayers. The ALDH activities were determined in cell homogenates from both unexposed control cultures and cells exposed to phenobarbital (PB), 3-methylcholanthrene (MC) and β-naphthoflavone (BNF). The ALDH activity was detected using benzaldehyde (BA) and propionaldehyde (PA) as substrates and both NAD and NADP as co-enzymes. Great variability in basal ALDH levels was found in the five cell lines: BA/NAD and BA/NADP enzyme activities were very high in the HTC cell line, intermediate in MH1C1 cells (near to normal rat hepatocytes) and very low in the remaining three cell lines. In HTC cells only, the PA/NAD activity was slightly induced by PB, but it remained unchanged under all the other experimental conditions. MH1C1 cells showed highly significant increases of all the activities with MC and BNF (up to 10-fold). The low basal activity of the H4IIEC3 cell line was significantly increased by MC and BNF, but only with BA/NADP. The Hepa 1c1c7 cell line responded only to BNF, as inducing compound, whereas the low basal enzyme levels of the human-derived HepG2 cell line were not significantly increased. These results suggest various applications of hepatoma cell cultures in in vitro toxicology.
Technical implementation of percutaneous thrombus aspiration using the AngioVac system
Authors: Haupt Benjamin , Merkle Frank , Dreizler Thomas , Falk Volkmar , Starck Christoph 
Published: August 2020

Objectives: The AngioVac system (AngioDynamics, Latham, NY, USA) provides a method for the minimally invasive, percutaneous aspiration of thrombus formations originating from the central venous system as well as solid matter such as lead vegetations and right atrial thrombi. Methods: This retrospective, observational study describes the initial experience in 52 adult patients with the AngioVac system, focusing mainly on the development of the extracorporeal circuit to improve usability and safety. Results: The mean patient age was 62.9 years (range 23-86 years). 22 patients were female and 30 were male. Indications for percutaneous aspiration were lead vegetations (n = 36; 69.2%), right atrial thrombi (n = 9; 17.3%), central venous thrombi (n = 5; 9.6%) and pulmonary embolisms (n = 2; 3.8%). Successful aspiration was performed in 44 cases (84.6%) and partial success was achieved in five patients (9.6%), while failure to remove thrombi or vegetations occurred in three cases (5.8%). Our practical experience led to the installation of a shunt line for recirculation and the implementation of safety features concerning air handling, which are also employed in minimally invasive extracorporeal bypass circuits. Initial tests monitored the level of negative pressure according to differences in flow and access sites but these still have to be validated on a larger scale. Conclusion: In this initial experience, the AngioVac system appeared to be safe regarding the extracorporeal circulation and the elimination of thrombi and lead vegetations.
Oculocardiac reflex and oculorespiratory reflex during strabismus surgery under general anesthesia using the laryngeal mask airway with maintenance of spontaneous respiration: A retrospective study
Authors: Shin Sun Young , Kim Min Ju , Joo Jin 
Published: August 2020

Objective To determine (1) how the specific muscle undergoing surgical treatment affects the occurrence of the oculocardiac reflex (OCR) and oculorespiratory reflex (ORR) and (2) whether the depth of anesthesia influences the occurrence of the OCR and ORR in patients undergoing strabismus surgery with a laryngeal mask airway with maintenance of spontaneous respiration. Methods The medical records of patients who underwent strabismus surgery on the lateral rectus (LR) and medial rectus (MR) muscles from January 2017 to December 2017 were retrospectively reviewed. Results The incidence of the OCR was not significantly different between LR and MR operations in either pediatric or adult patients. The incidence of the ORR as indexed by the tidal volume (TV) was significantly higher during MR than LR surgery in pediatric patients (29.3% vs. 10.1%, respectively). The change in TV during muscle traction and the bispectral index were significantly correlated in both pediatric and adult patients (r2 = 0.034 and 0.058, respectively). Conclusions The OCR was not influenced by the specific muscle undergoing surgery or the depth of anesthesia. The incidence of the ORR as indexed by the TV was higher during MR surgery in pediatric patients and was positively correlated with the depth of anesthesia.
Impact of anion exchange adsorbents on regional citrate anticoagulation
Authors: Strobl Karin , Harm Stephan , Fichtinger Ute , Schildböck Claudia , Hartmann Jens 
Published: August 2020

Introduction: Heparin and citrate are commonly used anticoagulants in membrane/adsorption based extracorporeal liver support systems. However, anion exchange resins employed for the removal of negatively charged target molecules including bilirubin may also deplete these anticoagulants due to their negative charge. The aim of this study was to evaluate the adsorption of citrate by anion exchange resins and the impact on extracorporeal Ca2+ concentrations. Methods: Liver support treatments were simulated in vitro. Citrate and Ca2+ concentrations were measured pre and post albumin filter as well as pre and post adsorbents. In addition, batch experiments were performed to quantify citrate adsorption. Results: Pre albumin filter target Ca2+ concentrations were reached well with only minor deviations. Citrate was adsorbed by anion exchange resins, resulting in a higher Ca2+ concentration downstream of the adsorbent cartridges during the first hour of treatment. Conclusions: The anion exchange resin depletes citrate, leading to an increased Ca2+ concentration in the extracorporeal circuit, which may cause an increased risk of clotting during the first hour of treatment. An increase of citrate infusion during the first hour of treatment should therefore be considered to compensate for the adsorption of citrate.
Neurological Assessment Using a Physical-Virtual Patient (PVP)
Authors: Gonzalez Laura , Daher Salam , Welch Greg 
Published: August 2020

Background. Simulation has revolutionized teaching and learning. However, traditional manikins are limited in their ability to exhibit emotions, movements, and interactive eye gaze. As a result, students struggle with immersion and may be unable to authentically relate to the patient. Intervention. We developed a new type of patient simulator called the Physical-Virtual Patients (PVP) which combines the physicality of manikins with the richness of dynamic visuals. The PVP uses spatial Augmented Reality to rear project dynamic imagery (e.g., facial expressions, ptosis, pupil reactions) on a semi-transparent physical shell. The shell occupies space and matches the dimensions of a human head. Methods. We compared two groups of third semester nursing students (N=59) from a baccalaureate program using a between-participant design, one group interacting with a traditional high-fidelity manikin versus a more realistic PVP head. The learners had to perform a neurological assessment. We measured authenticity, urgency, and learning. Results. Learners had a more realistic encounter with the PVP patient (p=0.046), they were more engaged with the PVP condition compared to the manikin in terms of authenticity of encounter and cognitive strategies. The PVP provoked a higher sense of urgency (p=0.002). There was increased learning for the PVP group compared to the manikin group on the pre and post-simulation scores (p=0.027). Conclusion. The realism of the visuals in the PVP increases authenticity and engagement which results in a greater sense of urgency and overall learning.
Effect of operative time on complications following primary total hip arthroplasty: analysis of the NSQIP database
Authors: Sikov Mark , Sloan Matthew , Sheth Neil P 
Published: August 2020

Background: Long operative times in total hip arthroplasty (THA) have been shown to be associated with increased risk of revision as well as perioperative morbidity. This study assesses the effect of extended operative times on complication rates following primary THA using the most recent national data. Methods: The National Surgical Quality Improvement Program (NSQIP) database (2008–2016) was queried for primary THA. Groups were defined by operative time 1 standard deviation (1 SD) above the mean. Univariate, propensity score-matched, and multivariate logistic regression analyses were performed to evaluate outcomes. Results: Data was available for 135,013 THA patients. Among these groups, mean operative time in the extended operative time group was 166 minutes (compared with 82 minutes). Patients undergoing longer operative times were 3.8 years younger, had a 1.5 kg/m2 higher body mass index and had a 0.5 day longer mean length of stay. Propensity matching identified 16,123 pairs for analysis in the 1 SD group. Longer operative time led to 173% increased risk of major medical morbidity, 140% increased likelihood of length of stay greater than 5 days, 59% increased risk of reoperation, 45% increased risk of readmission, and a 30% decreased likelihood of return to home postoperatively. There was no increased risk of death within 30 days. Conclusion: Long operative times were associated with increases in multiple postoperative complications, but not mortality. Surgeons should be advised to take steps to minimise operative time by adequate preoperative planning and optimal team communication.