bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-216: Frequent oncogenic tyrosine kinase gene fusions in supratentorial glioblastomas of young children
Authors: Pietsch Torsten , Vokuhl Christian , Gielen Gerrit H. , von Bueren Andre O. , Dörner Evelyn , Kristiansen Glen , Waha Andreas , Kramm Christof 
Published: September 2020

Abstract
Glioblastoma in infancy and early childhood is characterized by a more favorable outcome compared to older children. We have shown in previous studies that these tumors are characterized by a stable genome. The occurrence of tyrosine kinase gene fusions in glioblastomas of infancy may represent therapeutic targets. 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn, Germany. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified on the DNA level by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET and Molecular Inversion Probe (MIP) methodology. For the detection of fusions on the RNA level, targeted RNA sequencing was performed as well as Nanostring-based detection with probes specific for recurrent fusions. 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different fusion partners; all occurred in the first year of life (18/37 cases, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two novel fusions. The different methods led to comparable results. Only recurrent fusions with known fusion partners were detectable with probes designed for the fusion sequence, and library construction for targeted RNA sequencing was not successful in a fraction of cases. Break-apart FISH led to reliable results on the next day, and MIP technology represented the most sensitive method for analysis of FFPE samples. Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of children younger than four years; the most frequent were ALK fusions occurring in infant GBM. DNA based MIP technology represented the most robust and sensitive assay.
Citation Format: Torsten Pietsch, Christian Vokuhl, Gerrit H. Gielen, Andre O. von Bueren, Evelyn Dörner, Glen Kristiansen, Andreas Waha, Christof Kramm. Frequent oncogenic tyrosine kinase gene fusions in supratentorial glioblastomas of young children [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-216.
Abstract LB-301: Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia
Authors: ZHANG CHUJING , Amanda Stella , Wang Cheng , Tan Tze King , Muhammad Zulfaqar Ali , Leong Wei Zhong , Ng Ley Moy , Kitajima Shojiro , Li Zhenhua , Yeoh Allen Eng Juh , Tan Shi Hao , Sanda Takaomi 
Published: September 2020

Abstract
Aldehyde dehydrogenases (ALDHs) have been implicated as a stem cell marker both in normal and malignant cells. Elevated ALDH activity is associated with the stemness capability as well as the drug resistance in various cancers. As a notable example, ALDH1A2, one of ALDH family genes, is ectopically overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological disease that results from malignant transformation of T-cell progenitors. However, its roles and molecular functions in T-ALL pathogenesis are poorly understood. In our study, we demonstrated that the oncogenic transcription factor TAL1 directly induces an expression of ALDH1A2 in T-ALL cells, while normal T-cells do not express this gene. The TAL1 transcriptional complex binds to an intragenic regulatory element of ALDH1A2 and aberrantly activates the alternative promoter of the short isoform, which is specific to T-ALL cells. Using in vitro enzymatic assay, we found that the short isoform still retain enzymatic activity in catalyzing the oxidation of aldehydes. Importantly, ALDH1A2 promotes the viability and survival of T-ALL cells. Unbiased gene expression and metabolome profiling demonstrated that ALDH1A2 promotes glycolysis and mitochondria respiration, thereby supporting energy production. Additionally, expression of the short ALDH1A2 attenuated the amount of reactive oxygen species (ROS) both in vitro and in vivo. Furthermore, forced expression of short ALDH1A2 in T-cells increased overall penetrance of T-cell malignancy induced by the AKT2 oncogene in a zebrafish model. Taken together, our data suggests that ALDH1A2 is crucial and advantageous for T-ALL cell viability and survival by mediating energy production and by protecting cancer cells from oxidative stresses, thus serving as a requisite to maintain the hyperproliferative state of T-ALL cells (“onco-requisite”).
Citation Format: CHUJING ZHANG, Stella Amanda, Cheng Wang, Tze King Tan, Zulfaqar Ali Muhammad, Wei Zhong Leong, Ley Moy Ng, Shojiro Kitajima, Zhenhua Li, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda. Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-301.
Abstract LB-381: Mitigating on-target off-tumor cytotoxicity of EpCAM CAR-T by affinity tuning
Authors: Yang Huan , Puc Janusz , Yang Yanping , McCloskey Jaclyn E. , Vedvyas Yogindra , Li Hongtao , Min Irene M. , Jin Moonsoo M. , Hofe Eric v. 
Published: September 2020

Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown robust anti-cancer responses in hematologic malignancies. However, application of this therapeutic approach to solid tumors has been hindered by multiple challenges, one of which is on-target/off-tumor cytotoxicity to normal tissues. Tumor-specific antigens exclusively present on tumor cells are rare. Most CAR-T cells are designed to target tumor associated antigens (TAAs) expressed in high levels on tumor cells. Yet, normal tissues express these antigens as well, albeit at much lower densities.To mitigate the on-target/off-tumor cytotoxicity, we developed a strategy for fine tuning the affinity of CARs to selectively target tumor cells.
Epithelial cell adhesion molecule (EpCAM) is highly expressed in epithelial cells and overexpressed in tumor cells in a variety of epithelial carcinomas. High-affinity (nM range) EpCAM-targeting CAR-T cells kill both normal human epithelial cells and EpCAM-high tumor cells in vitro. To develop CAR-T cells specific to EpCAM-high cancers, we identified low-affinity scFv variants by rational design of amino acid substitutions. The affinities of these scFvs were measured by Surface Plasmon Resonance (SPR). CAR-T cells equipped with low-affinity scFvs showed antigen-dependent activation, proliferation and Th1-like cytokine secretion when co-cultured with target cells having varied levels of EpCAM. Importantly, low-affinity CAR-T cells still lysed EpCAM-high tumor cells but spared normal human epithelial cells in vitro. Treatment of MKN28 xenograft mice with low-affinity CAR-T cells resulted in tumor regression and prolonged survival. Moreover, transcriptomic profiling of CAR-T cells revealed significant differences in gene expression levels between high- and low- affinity CARs, particularly as they relate to the functional state of these CAR-T cells, and their resistance to exhaustion.
Our results show that rational design of scFv can aid in the identification of CARs that are minimally reactive toward normal tissues while effectively eliminating tumors. Furthermore, affinity-tuned CARs demonstrate better overall fitness and antitumor activity in vivo. This affinity fine-tuning approach shows promise as a general strategy for identifying a therapeutic window for CAR-T cells targeting novel TAAs that may have been overlooked because of basal expression levels in normal tissues.
Citation Format: Huan Yang, Janusz Puc, Yanping Yang, Jaclyn E. McCloskey, Yogindra Vedvyas, Hongtao Li, Irene M. Min, Moonsoo M. Jin, Eric v. Hofe. Mitigating on-target off-tumor cytotoxicity of EpCAM CAR-T by affinity tuning [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-381.
Abstract LB-383: An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors
Authors: Reinhard Katharina , Rengstl Benjamin , Oehm Petra , Türeci Özlem , Sahin Ugur 
Published: September 2020

Abstract
Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet, their application for solid tumors has challenges that include limited cancer-specific targets and nonpersistence of adoptively transferred CAR-T cells. Here, we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident antigen-presenting cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at subtherapeutic CAR-T cell doses.
Citation Format: Katharina Reinhard, Benjamin Rengstl, Petra Oehm, Özlem Türeci, Ugur Sahin. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-383.
Abstract NG14: Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer
Authors: Sahni Nidhi , McGrail Daniel J. , Garnett Jeannine , Yin Jun , Dai Hui , Shih David J. H. , Peng Guang , Menter David , Yates Melinda S. , Kopetz Scott , Lu Karen , Broaddus Russell , Mills Gordon B. , Lin Shiaw Y. 
Published: September 2020

Abstract
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype, leaving a genomic scar known as microsatellite instability (MSI). MSI is observed in approximately 30% of endometrial cancers, 20% of gastric cancers, 15% of colorectal cancers, and in a smaller fraction of other tumor types. This hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens, leading to the approval of MSI status as a clinical biomarker for immunotherapy. However, more than 60% of patients with MSI tumors fail to respond to immune checkpoint therapy. To uncover alternative therapeutic vulnerabilities for these patients, we used transcriptome signature-guided approaches to identify MLN4924 (pevonedistat), a Nedd8-activating enzyme inhibitor, as a potential therapy for dMMR/MSI cancers. We discover that destabilizing mutations from the dMMR mutation process lead to rampant proteome instability in MSI tumors, resulting in an abundance of misfolded protein aggregates. To compensate, MSI cancer cells activate a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins, which is blocked by treatment with MLN4924. The accumulation of misfolded proteins in MSI cancer cells following MLN4924 treatment activated the unfolded protein response, promoted immune cell migration, and induced immunogenic cell death. Antitumor vaccination with MLN4924-treated cells stimulated the generation of endogenous tumor antibodies and prevented tumor incidence upon re-challenge. Based on this immunostimulation, we combined MLN4924 with PD1 blockade, finding that the combination increased recruitment of CD8+ lymphocytes and improved therapeutic efficacy beyond either treatment alone. Taken together, our results indicate that targeting proteome instability is a novel therapeutic avenue for MSI patients and may potentiate immune checkpoint blockade, potentially increasing the depth and duration of response, as well as the fraction of dMMR/MSI patients who can benefit.
Citation Format: Nidhi Sahni, Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J. H. Shih, Guang Peng, David Menter, Melinda S. Yates, Scott Kopetz, Karen Lu, Russell Broaddus, Gordon B. Mills, Shiaw Y. Lin. Proteome instability is an immunogenic therapeutic vulnerability in mismatch repair deficient cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG14.
Abstract PL01-01: Personal regulome navigation of cancer
Authors: Chang Howard Y. 
Published: September 2020

Abstract
Cancer is a disease of genes. Yet the elucidation of cancer genomes does not mean we have conquered cancer; the central challenge is in their interpretation. In every human cell, two meters of DNA is packed into a ~10 micron nucleus. The genome is extensively compacted, except for the active regulatory DNA elements that remain accessible. I will describe new technologies based on DNA transposition that reveals the epigenomic profiles of single cells or from clinical biopsies of disease states. The landscape of active DNA regulatory elements are further linked to 3D genome architecture, mutational profiles, and RNA output to reveal the targets of disease associated DNA elements, such as inherited genetic variants or those modified by environmental stimuli. Our analysis of 23 human cancer types reveal nearly half a million active DNA elements across human cancers, disclose oncogenic extrachromosomal DNA, and identify gene-regulatory interactions underlying cancer immune evasion. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy.
Citation Format: Howard Y. Chang. Personal regulome navigation of cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr PL01-01.
Optical repeater for indoor visible light communication using amplify-forward method
Authors: Darlis Arsyad Ramadhan , Jambola Lucia , Lidyawati Lita , Asri Adisty Hanny 
Published: September 2020

<p><span>In this paper, the implementation of an optical repeater for indoor visible light communication using the amplify-forward method was proposed. In indoor, Visible Light Communication (VLC) can occur by transmitting information signals from Lamps as a VLC transmitter toward the VLC receiver as Line-of-Sight (LOS) that is located with only a few meters. In the Non-LOS (NLOS) Communication, the signal will be attenuated, so it needs to amplify to improve good signal quality in a VLC receiver. The optical repeater could be used to improve the signal quality that attenuating due to distance. The audio signal was generated and sent using VLC Transmitter toward the Light Emitting Diode (LED). Then, the electrical signal was converted to become visible light, and it was amplified using an optical amplifier with an amplify-forward method. The signal in the form of visible light that had been amplified would be received by the Photodiode (PD), and the VLC Receiver processed it. The measurement results showed the system that used the optical repeater could improving the distance until 9.5 m with frequency 6000 Hz, where the best signal quality at a frequency of 3000 Hz. The measurement result showed that the use of repeater components with the amplify forward method for VLC systems, especially in the room, can increase the range until 4.5 m compare without an optical repeater. This result exceeds the minimum distance of an indoor visible light communication system, with an average distance of the roof to the floor is 3.5 m.</span></p>
Laser measured rate equations with various transmission coders for optimum of data transmission error rates
Authors: El-Hageen Hazem M. , Alatwi Aadel M. , Zaki Rashed Ahmed Nabih 
Published: September 2020

<p> </p><p>The present study has outlined laser-measured rate equations with various transmission coders for optimum data transmission error rates. Various modulation transmission coders are employed, such as a pulse position modulation coder, a differential pulse intensity modulation coder, and a four band/five band modulation transmission coder, in order to create optimized data rates of up to 40 GB/s for a fiber extension length of up to 100 km. This study has emphasized the important role of pulse position modulation transmission coders, which exhibit superior performance in max. Q parameter and min. data error rates, even for high data rate transmission. </p>
Real-time switching thirteen-level modified CHB-Multilevel inverter using artificial neural network technique based on selective harmonic elimination
Authors: M.A. Alakkad Moataz , Rasin Zulhani , Rasheed Mohammed , Abd Halim Wahidah , Omar Rosli 
Published: September 2020

<p>Recently, global research is giving more attention to the renewable energy sources due to its sustainability and environmentally friendly nature. The necessity of DC to AC conversion to integrate these sources to the well established AC power system create a significant development of multi-level inverter with its advantages of operating at higher rating system with lower component rating as well as better harmonics performance at it output voltage and current. In this research paper, a modified topology of CHB-MLI to provide 13-level output AC waveform is proposed based on the SHE-PWM strategy using the ANN optimization technique. The system modeling is done with Matlab Simulink software and verification are carried out by both simulation and experiment. Results show that the ANN technique able to reduce the THD significantly as the level of waveform is increased as low as 5.16% THD for the 13-level output voltage. Results from the experiment shows a good agreement with the simulation, thus verifying the effectiveness of the proposed ANN technique as an optimization method. </p>
Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction
Authors: Docherty Kieran F. , Jhund Pardeep S. , Anand Inder , Bengtsson Olof , Böhm Michael , de Boer Rudolf A. , DeMets David L. , Desai Akshay S. , Drozdz Jaroslaw , Howlett Jonathan , Inzucchi Silvio E. , Johanson Per , Katova Tzvetana , Køber Lars , Kosiborod Mikhail N. , Langkilde Anna Maria , Lindholm Daniel , Martinez Felipe A. , Merkely Béla , Nicolau Jose C. , O’Meara Eileen , Ponikowski Piotr , Sabatine Marc S. , Sjöstrand Mikaela , Solomon Scott D. , Tereshchenko Sergey , Verma Subodh , McMurray John J.V. 
Published: September 2020

Background:
In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events.

Methods:
Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction ≤40% and elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide), were eligible. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or an urgent HF visit requiring intravenous therapy) or cardiovascular death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to the initiation of new, or the augmentation of existing, oral treatment.

Results:

Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65–0.82];
P
<0.0001). Each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat with dapagliflozin to prevent 1 experiencing an episode of fatal or nonfatal worsening was 16. Among the 4744 randomly assigned patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with intravenous therapy in 20 (0.4%), HF hospitalization in 489 (10.3%), and cardiovascular death in 295 (6.2%). The adjusted risk of death from any cause (in comparison with no event) after an outpatient worsening was hazard ratio, 2.67 (95% CI, 2.03–3.52); after an urgent HF visit, the adjusted risk of death was hazard ratio, 3.00 (95% CI, 1.39–6.48); and after a HF hospitalization, the adjusted risk of death was hazard ratio, 6.21 (95% CI, 5.07–7.62).

Conclusion:
In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT03036124.
Platelet Reactivity in Hepatitis C Virus–Infected Patients on Dual Antiplatelet Therapy for Acute Coronary Syndrome
Authors: Scudiero Fernando , Valenti Renato , Marcucci Rossella , Sanna Giuseppe D. , Gori Anna Maria , Migliorini Angela , Vitale Raffaele , Giusti Betti , De Vito Elena , Corda Giulia , Paniccia Rita , Zirolia Davide , Canonico Mario E. , Parodi Guido 
Published: September 2020

Background
Coronary artery disease (CAD) has been recognized as a serious and potentially life‐threatening complication of Hepatitis C Virus (HCV) infection. High on‐treatment platelet reactivity has been associated with high risk of ischemic events in patients with CAD, but data regarding the association with HCV infection are still lacking. This post hoc analysis aims to assess high on‐treatment platelet reactivity, severity of CAD, and long‐term outcomes of patients with acute coronary syndrome (ACS) who were infected with HCV.

Methods and Results

Patients with ACS who were infected with HCV (n=47) were matched to patients with ACS and without HCV (n=137) for age, sex, diabetes mellitus, hypertension, and renal function. HCV‐infected patients with ACS had higher levels of platelet reactivity (ADP
10
–light transmittance aggregometry, 56±18% versus 44±22% [
P
=0.002]; arachidonic acid–light transmittance aggregometry, 25±21% versus 16±15% [
P
=0.011]) and higher rates of high on‐treatment platelet reactivity on clopidogrel and aspirin compared with patients without HCV. Moreover, HCV‐infected patients with ACS had higher rates of multivessel disease (53% versus 30%;
P
=0.004) and 3‐vessel disease (32% versus 7%;
P
<0.001) compared with patients without HCV. At long‐term follow‐up, estimated rates of major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, and ischemia‐driven revascularization) were 57% versus 34% (
P
=0.005) in HCV‐ and non–HCV‐infected patients with ACS, respectively. In addition, thrombolysis In Myocardial Infarction (TIMI) major bleeding rates were higher in HCV‐infected patients (11% versus 3%;
P
=0.043) compared with noninfected patients. Multivariable analysis demonstrated that HCV infection was an independent predictor of high on‐treatment platelet reactivity, severity of CAD, and long‐term outcome.

Conclusions
In this hypothesis‐generating study, patients with ACS and HCV infection showed increased on‐treatment platelet reactivity, more severe CAD, and worse prognosis compared with patients without HCV.