bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 848: Taming numerous information on variants for better treatment decisions
Authors: Glocker Katrin , Knurr Alexander , Al-Hmad Janine , Czogalla Dennis-Immanuel , Izzo Marvin , Koch Christian , Roth Benjamin , Ückert Frank 
Published: September 2020

Abstract
The developments in the field of genetic screening make high throughput sequencing of patient samples not only technically, but also financially feasible. However, this confronts physicians with a vast amount of information for one patient. Additionally, as more research is done on single variants, the knowledge about predictive biomarkers is also extensive and increasing steadily. To make information like the clinical relevance of single variants available to physicians, multiple databases are available. This adds to the enormous load of data physicians in a molecular Tumor Board (MTB) have to review on top of clinical data to find a suitable therapy for a specific patient.
To support a MTB in making informed therapy decisions based on genomic data, relevant clinical data like the diagnosis and previous therapies is extracted from the electronic health record used by the physicians to document the patients and their course of disease. After sequencing, the variants get pre-filtered by bioinformaticians and their characteristic features like the specific amino acid exchange for SNVs or total copy number for CNVs are presented. With these data, knowledge bases are queried in the background and relevant information is displayed in the Knowledge Connector. For each variant, information about effect of the mutation on the protein, an assessment of oncogeneity, drugs targeting the specific variation or the gene and pathways the gene is involved in, are summarized in one view to grasp all important facts at a glance. Furthermore, the tool offers the opportunity to manually assess the variants according to evidences and automatically generates a report upon this curation, which can be sent to treating physicians.
With this, physicians are supported in managing the huge amount of information referring to one patient in the whole process of a MTB. Additionally, the number of patients benefiting from this comprehensive analysis of specific characteristics can be increased by not only saving time of experienced specialists, but also by enabling physicians with less extensive knowledge about genetics to find therapies based on genetic variants.
Citation Format: Katrin Glocker, Alexander Knurr, Janine Al-Hmad, Dennis-Immanuel Czogalla, Marvin Izzo, Christian Koch, Benjamin Roth, Frank Ückert. Taming numerous information on variants for better treatment decisions [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 848.
Abstract 944: Quantitative cell-based reporter bioassays for functional characterization of immunotherapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors
Authors: Grailer Jamison , Gilden Julia , Stecha Pete , Garvin Denise , Wang Jun , Beck Michael , Hartnett Jim , Krishnan Gopal , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: September 2020

Abstract
The human immune system is regulated by a complex network of inhibitory and stimulatory immune checkpoint receptors that regulate T Cell function. These receptors are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. Novel therapies employing a variety of strategies have been developed that rely on releasing the brakes on the immune system, with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3, TIGIT) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors, individually and in combination. A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These bioassays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals from TCR and immune checkpoint receptors. Thus, these bioassays reflect mechanisms of action for drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. The bioassays are prequalified according to ICH guidelines and show the precision, accuracy and linearity required for routine use in potency and stability studies. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies.
Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based reporter bioassays for functional characterization of immunotherapeutic biologics targeting co-stimulatory and co-inhibitory immune checkpoint receptors [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 944.
Abstract CT250: A Phase 1a/1b, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors
Authors: Cristea Mihaela , Chmielowski Bartosz , Funke Roel , Stallings-Schmitt Todd , Denker Mitch , Frohlich Mark , Franzusoff Alex , Abedi Mehrdad , Ejadi Samuel 
Published: September 2020

Abstract
Introduction: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients' autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Study Design: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors.
Citation Format: Mihaela Cristea, Bartosz Chmielowski, Roel Funke, Todd Stallings-Schmitt, Mitch Denker, Mark Frohlich, Alex Franzusoff, Mehrdad Abedi, Samuel Ejadi. A Phase 1a/1b, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic 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 CT250.
Abstract LB-100: Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines
Authors: Shibue Tsukasa , Krill-Burger John M. , Paolella Brenton R. , Gaeta Benjamin , Asfaw Adhana , Dempster Joshua M. , McFarland James M. , Root David E. , Boehm Jesse S. , Tsherniak Aviad , Hahn William C. , Vazquez Francisca 
Published: September 2020

Abstract
Despite its increasing success and revolutionary impact on clinical oncology, Precision Cancer Medicine still has major roadblocks before it becomes applicable to a large proportion of patients. One such roadblock is the limited number of therapeutic targets available. Indeed, for the vast majority of cancer patients, we either do not know what their specific vulnerabilities are or do not have strategies to precisely target their vulnerabilities. In the Cancer Dependency Map Project (DepMap) at the Broad Institute, we aim to overcome these limitations through the use of genome-scale loss-of-function screens in a large panel of cancer cell lines combined with systematic molecular characterization of these cell lines. To date, we have conducted viability screens with genome-wide RNAi and CRISPR/Cas9 libraries on &gt; 800 cell lines, all of which have also been comprehensively profiled with various omics approaches. In order to systematically identify and prioritize potential therapeutic targets, we created an analytical framework that uses a multifaceted approach to score gene dependencies based on the information extracted from screening outcomes, predictive models of sensitivity from all the genetic and molecular information, and the use of priors. To reproducibly validate the nominated targets, we also developed a toolbox of standardized assays that include confirmation of cell viability effects with orthogonal reagents/read-outs and efficient testing for in vivo efficacy across multiple cancer models. Using this approach, we have identified and validated several promising targets, including the WRN DNA helicase that is selectively essential in cancers with microsatellite instability (MSI). The data, framework, and toolbox developed here can inform the nomination and advancement of promising targets for drug development for Precision Cancer Medicine.
Citation Format: Tsukasa Shibue, John M. Krill-Burger, Brenton R. Paolella, Benjamin Gaeta, Adhana Asfaw, Joshua M. Dempster, James M. McFarland, David E. Root, Jesse S. Boehm, Aviad Tsherniak, William C. Hahn, Francisca Vazquez. Systematic target prioritization and validation from genome-scale loss-of-function screens in large panels of human cancer cell lines [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-100.
Harmonic spectra of BLDC motor supplied by a solar PV multilevel inverter
Authors: Anwer Abbood Afaneen 
Published: September 2020

<p>The multilevel inverters have been used especially in renewable energy aspects in order to assess total harmonic distortion (THD). THD is considered to produce a good quality of current signal of BLDC motor drive. In this paper, a solar PV inveter fed brushless DC (BLDC) motor drive is discussed considering two topologies of three phase multilevel inverters. These topologies are flying capacitor and clamped diode inverters. The inverter efficiency and output power have an effectiveness on THD values. A boost dc to dc converter using incremental conductance maximum power point tracking (INC-MPPT) is implemented with a solar PV. The mathematical model of the proposed systems ares tudied via simulation using Matlab/Simulink. The simulation results of a BLDC motor based on two multilevel inverters are compared with each other considering the THD and the utilization of the dc-bus voltage, the comparition verified that the clamped diode inverter has a better harmonic spectra.still the overshoot is a little bit high in the two types of inverter that are proposed. </p>
Implications of Genetic Testing in Dilated Cardiomyopathy
Authors: Verdonschot Job A.J. , Hazebroek Mark R. , Krapels Ingrid P.C. , Henkens Michiel T.H.M. , Raafs Anne , Wang Ping , Merken Jort J. , Claes Godelieve R.F. , Vanhoutte Els K. , van den Wijngaard Arthur , Heymans Stephane R.B. , Brunner Han G. 
Published: September 2020

Background:
Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome.

Methods:
This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias.

Results:

A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (
P
<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM (
P
=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM (
P
<0.001).

Conclusions:
One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.
Economic Systems of Muslims in History
Authors: Çizakça Murat 
Published: September 2020

Abstract
During its long history, the Islamic world experienced three different economic systems. The original Islamic economy introduced by the Qurʾān and other classical sources of Islam, was a form of sui generis, commercial, pre-industrial and ethical capitalism. Evidence for this will be presented from the classical sources of Islam as well as from the history of Islamic economic thought. In later centuries it is possible to observe a transition from this unique capitalism towards more centralised structures, which reached its zenith with the Ottoman proto quasi-socialism. Most recently, after the Second World War, newly independent Muslims re-invented Islamic finance. Although an almost three trillion USD industry, so far this has been basically an imitation of conventional finance. Whether a truly modern and Islamic capitalism or another system will emerge from this, remains to be seen. Ample historical evidence across the Islamic world from West Africa to Indonesia is provided.
Internal Tide Nonstationarity and Wave–Mesoscale Interactions in the Tasman Sea
Authors: Savage Anna C. , Waterhouse Amy F. , Kelly Samuel M. 
Published: September 2020

AbstractInternal tides, generated by barotropic tides flowing over rough topography, are a primary source of energy into the internal wave field. As internal tides propagate away from generation sites, they can dephase from the equilibrium tide, becoming nonstationary. Here, we examine how low-frequency quasigeostrophic background flows scatter and dephase internal tides in the Tasman Sea. We demonstrate that a semi-idealized internal tide model [the Coupled-Mode Shallow Water model (CSW)] must include two background flow effects to replicate the in situ internal tide energy fluxes observed during the Tasmanian Internal Tide Beam Experiment (TBeam). The first effect is internal tide advection by the background flow, which strongly depends on the spatial scale of the background flow and is largest at the smaller scales resolved in the background flow model (i.e., 50–400 km). Internal tide advection is also shown to scatter internal tides from vertical mode-1 to mode-2 at a rate of about 1 mW m−2. The second effect is internal tide refraction due to background flow perturbations to the mode-1 eigenspeed. This effect primarily dephases the internal tide, attenuating stationary energy at a rate of up to 5 mW m−2. Detailed analysis of the stationary internal tide momentum and energy balances indicate that background flow effects on the stationary internal tide can be accurately parameterized using an eddy diffusivity derived from a 1D random walk model. In summary, the results identify an efficient way to model the stationary internal tide and quantify its loss of stationarity.
Global Calculations of Local and Remote Near-Inertial-Wave Dissipation
Authors: Alford Matthew H. 
Published: September 2020

AbstractGlobal estimates are presented of the fraction q of wind-generated near-inertial wave power available for local turbulent dissipation under the assumption that modes 1–3 propagate “far” and the higher modes remain to eventually break. Using climatological stratification profiles and mixed layer depth, the modal distribution of near-inertial energy flux is computed following Gill's classic 1984 work by projecting a slab flow in the mixed layer onto the dynamical modes. Global maps and zonal-mean profiles are presented, which show a global-mean value of q = 0.63 and 0.75 for winter and summer profiles, respectively. The simplicity of the calculation makes it of potential use in parameterizations of near-inertial breaking in climate simulations.
Trends in pneumonectomy for treatment of small-cell lung cancer
Authors: Zhao Jasmine , Nguyen Alexandra , Ding Li , David Elizabeth A , Atay Scott M , Wightman Sean C , McFadden P Michael , Kim Anthony W 
Published: September 2020

Background According to practice guidelines, patients with clinical stage T1–2 node-negative small-cell lung cancer are candidates for surgical resection. However, the role of pneumonectomy in small-cell lung cancer patients is not well understood. The objective of this study was to assess the extent to which pneumonectomy is used and to evaluate the survival implications for small-cell lung cancer patients who underwent pneumonectomy. Methods A total of 106 small-cell lung cancer patients who underwent pneumonectomy between 2006 and 2016 and met the study criteria were identified in the National Cancer Database. Demographics and treatment regimens are described, and overall survival was assessed using Kaplan-Meier and log-rank tests. Results The most common treatment was surgery with adjuvant chemotherapy, followed by surgery only and surgery with neoadjuvant therapy. The 5-year overall survival for the entire cohort after pneumonectomy was 23%. In subgroup analysis, the 5-year overall survival was 30% for guideline-concordant clinical stage I patients and 28% for clinical stage II/III patients who underwent pneumonectomy. There was no statistical difference in survival according to pathologic N disease. Patients with a right-sided pneumonectomy had higher mortality than patients with a left-sided pneumonectomy. Conclusions This study suggests a role for pneumonectomy in clinical stage I and potentially some clinical stage II and III small-cell lung cancer patients. Right-sided pneumonectomy is associated with higher mortality and should be approached with caution. Despite declining trends over the past decades, pneumonectomy is still an effective treatment that is able to achieve acceptable survival outcomes.
Prevalence of Gluteus Medius Pathology on Magnetic Resonance Imaging in Patients Undergoing Hip Arthroscopy for Femoroacetabular Impingement: Asymptomatic Tears Are Rare, Whereas Tendinosis Is Common
Authors: Meghpara Mitchell B. , Bheem Rishika , Shah Sapan , Shapira Jacob , Maldonado David R. , Rosinsky Philip J. , Lall Ajay C. , Domb Benjamin G. 
Published: September 2020

Background: There is a paucity of literature on asymptomatic gluteus medius pathology. Moreover, no studies have examined the prevalence of asymptomatic gluteus medius pathology. Purpose: To describe the prevalence of asymptomatic gluteus medius pathology in patients undergoing hip arthroscopy for femoroacetabular impingement. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A database search of our institution was performed for patients undergoing hip arthroscopy for labral treatment between February 2008 and January 2019. Patients were included if they had gluteus medius pathology identified through magnetic resonance imaging (MRI). Patients were deemed to be asymptomatic if they lacked greater trochanteric hip tenderness, abductor weakness, a positive Trendelenburg sign, or a positive Trendelenburg gait on physical examination. Patients were excluded if they were unwilling to participate or did not have a documented physical examination or MRI read in the database. Results: A total of 2851 hips (2452 patients) met the inclusion/exclusion criteria. Gluteus medius pathology was found in 871 hips (30.6%) on MRI. Symptomatic gluteus medius pathology was observed in 414 (14.5%) hips, of which 305 (10.7%) had tendinosis, 99 (3.5%) had partial-thickness tears, and 10 (0.4%) had full-thickness tears. Asymptomatic gluteus medius pathology was observed in 457 (16.0%) hips, of which 408 (14.3%) had tendinosis and 49 (1.7%) had partial-thickness tears. No hips with full-thickness tears on MRI were asymptomatic. Patients with asymptomatic partial-thickness tears were significantly older than those with only tendinosis (45.3 vs 39.4 years, respectively; P = .001). Patients aged 40 years or older had a 2.11 (1.80-2.50) ( P < .001) relative risk of asymptomatic pathology compared with patients younger than 40 years. Conclusion: Although there is a meaningful prevalence of asymptomatic gluteus medius tendinosis, the prevalence of asymptomatic gluteus medius tears is low. Treatment of gluteus medius tendinosis should therefore be based not solely on MRI findings but rather on a complete clinical evaluation. In contrast, MRI findings of partial or full-thickness gluteus medius tears may be more likely to have clinical significance.