bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR06: An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants
Authors: Zafra Maria Paz , Alonso-Curbelo Direna , Goswami Sukanya , Schatoff Emma M , Han Teng , Wilkinson John E. , Dow Lukas E. 
Published: June 2020

Abstract
KRAS is the most frequently mutated oncogene in cancer. Tumor sequencing has revealed a complex spectrum of KRAS mutations across different cancer types, yet there is little understanding of how specific KRAS alterations impact tumor in initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each mutation in the developing mouse pancreas reveals striking quantitative and qualitative differences in the degree of ductal transformation and premalignant progression. Further, using organoid models we show that KRASG13D mutants respond to EGFR inhibition, while the antiproliferative effect of KRASG12C-selective inhibitors can be overcome by upstream EGFR signaling. Together, these new mouse strains provide an ideal method for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers.
This abstract is also being presented as Poster A41.
Citation Format: Maria Paz Zafra, Direna Alonso-Curbelo, Sukanya Goswami, Emma M Schatoff, Teng Han, John E. Wilkinson, Lukas E. Dow. An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR06.
Novel Mouse Model for Studying Hemostatic Function of Human Platelets
Authors: Paul David S. , Bergmeier Wolfgang 
Published: June 2020

Objective:
Platelets are critical to the formation of a hemostatic plug and the pathogenesis of atherothrombosis. Preclinical animal models, especially the mouse, provide an important platform to assess the efficacy and safety of antiplatelet drugs. However, these studies are limited by inherent differences between human and mouse platelets and the species-selectivity of many drugs. To circumvent these limitations, we developed a new protocol for the adoptive transfer of human platelets into thrombocytopenic nonobese diabetic/severe combined immune deficiency mice, that is, a model where all endogenous platelets are replaced by human platelets in mice accepting xenogeneic tissues.

Approach and Results:

To demonstrate the power of this new model, we visualized and quantified hemostatic plug formation and stability by intravital spinning disk confocal microscopy following laser ablation injury to the saphenous vein. Integrin α
IIb
β
3
-dependent hemostatic platelet plug formation was achieved within ≈30 seconds after laser ablation injury in humanized platelet mice. Pretreatment of mice with standard dual antiplatelet therapy (Aspirin+Ticagrelor) or PAR1 inhibitor, L-003959712 (an analog of vorapaxar), mildly prolonged the bleeding time and significantly reduced platelet adhesion to the site of injury. Consistent with findings from clinical trials, inhibition of PAR1 in combination with dual antiplatelet therapy markedly prolonged bleeding time in humanized platelet mice.

Conclusions:
We propose that this novel mouse model will provide a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs and to characterize the hemostatic function of synthetic, stored and patient platelets.
LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis
Authors: Cedó Lídia , Metso Jari , Santos David , García-León Annabel , Plana Núria , Sabate-Soler Sonia , Rotllan Noemí , Rivas-Urbina Andrea , Méndez-Lara Karen A. , Tondo Mireia , Girona Josefa , Julve Josep , Pallarès Victor , Benitez-Amaro Aleyda , Llorente-Cortes Vicenta , Pérez Antonio , Gómez-Coronado Diego , Ruotsalainen Anna-Kaisa , Levonen Anna-Liisa , Sanchez-Quesada José Luis , Masana Luís , Kovanen Petri T. , Jauhiainen Matti , Lee-Rueckert Miriam , Blanco-Vaca Francisco , Escolà-Gil Joan Carles 
Published: June 2020

Rationale:
The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown.

Objective:
We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice.

Methods and Results:
Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B–containing lipoproteins.

Conclusions:
Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces.

Graphical Abstract:
A graphical abstract is available for this article.
Label Adherence of Direct Oral Anticoagulants Dosing and Clinical Outcomes in Patients With Atrial Fibrillation
Authors: Yu Hee Tae , Yang Pil‐Sung , Jang Eunsun , Kim Tae‐Hoon , Uhm Jae‐Sun , Kim Jong‐Youn , Pak Hui‐Nam , Lee Moon‐Hyoung , Lip Gregory Y. H. , Joung Boyoung 
Published: June 2020

Background

Dose adjustment of non‐vitamin K antagonist oral anticoagulants (
NOAC
s) is indicated in some patients with atrial fibrillation (
AF
), based on selected patient factors or concomitant medications. We assessed the frequency of label adherence of
NOAC
dosing among
AF
patients and the associations between off‐label
NOAC
dosing and clinical outcomes.

Methods and Results

We evaluated 53 649
AF
patients treated with an
NOAC
using Korean National Health Insurance Service database during the period from 2013 to 2016.
NOAC
doses were classified as either underdosed or overdosed, consistent with Korea Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all‐cause mortality. Overall, 16 757
NOAC
‐treated patients (31.2%) were underdosed, 4492 were overdosed (8.4%), and 32 400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (aged 71±8 and 75±7 years versus 70±9 years, respectively;
P
<0.001) and had higher
CHA
2
DS
2
‐
VAS
c scores (4.6±1.7 and 5.3±1.7 versus 4.5±1.8, respectively;
P
<0.001).
NOAC
overdosing was associated with increased risk for stroke or systemic embolism (5.76 versus 4.03 events/100 patient‐years,
P
<0.001), major bleeding (4.77 versus 2.94 events/100 patient‐years,
P
<0.001), and all‐cause mortality (5.43 versus 3.05 events/100 patient‐years,
P
<0.001) compared with label‐adherent use.

Conclusions

In real‐world practice, a significant proportion (almost 2 in 5) of
AF
patients received
NOAC
doses inconsistent with drug labeling.
NOAC
overdosing is associated with worse clinical outcomes in Asian
AF
patients.
Antepartum Aspirin Administration Reduces Activin A and Cardiac Global Longitudinal Strain in Preeclamptic Women
Authors: Naseem Heba , Dreixler John , Mueller Ariel , Tung Avery , Dhir Rohin , Chibber Rachna , Fazal Abid , Granger Joey P. , Bakrania Bhavisha A. , deMartelly Victoria , Rana Sarosh , Shahul Sajid 
Published: June 2020

Background

Approximately 60% of women have Stage B heart failure 1 year after a preeclamptic delivery. Emerging evidence suggests that the profibrotic growth factor activin A, which has been shown to induce cardiac fibrosis and hypertrophy, is elevated in preeclampsia and may be inhibited by aspirin therapy. We hypothesized that preeclamptic women receiving aspirin would have lower activin A levels and reduced global longitudinal strain (
GLS
), a sensitive measure of cardiac dysfunction, than women who do not receive aspirin. To test our hypothesis, we performed a cohort study of women with preeclampsia or superimposed preeclampsia and compared activin A levels and
GLS
in parturients who did or did not receive aspirin.

Methods and Results

Ninety‐two parturients were enrolled, of whom 25 (27%) received aspirin (81 mg/day) therapy.
GLS
, plasma activin A, and follistatin, which inactivates activin A, were measured. Women receiving aspirin therapy had lower median (interquartile range) levels of activin A (8.17 [3.70, 10.36] versus 12.77 [8.37, 31.25] ng/mL;
P
=0.001) and lower activin/follistatin ratio (0.59 [0.31, 0.93] versus 1.01 [0.64, 2.60]
P
=0.002) than women who did not receive aspirin, which also remained significant after multivariable analysis. Furthermore,
GLS
was worse in patients who did not receive aspirin (−19.84±2.50 versus −17.77±2.60%;
P
=0.03) despite no differences in blood pressure between groups.

Conclusions

Our study suggests that antepartum aspirin therapy reduced serum activin A levels and improved
GLS
in preeclamptic patients, suggesting that aspirin may mitigate the postpartum cardiac dysfunction seen in women with preeclampsia.
From Kings to Monsters: Jewish Perspectives on the Hellenistic and Roman Empires in Sibylline Oracles 3 and 5
Authors: McBay Susannah 
Published: June 2020

Abstract
Both the third and fifth books of the Sibylline Oracles engage with the threat and challenges of the political powers of their day, the Hellenistic and Roman respectively (Sib. Or. 3:657-714; 5:28-34, 155-161, 342-359). Both books also construe these powers as part of the reason for the arrival of God as Divine Warrior to execute judgement. In contrast to Alexandria Frisch, who argued that the Hellenistic Empire was the cause of greater Jewish critique, this article demonstrates that within the Sibylline tradition, the development in use of Jewish combat myth of the Divine Warrior across the two books actually shows the reverse. The texts from Sibylline Oracles 5 escalate the threat of the political enemy, not only depicting the Roman Empire and emperor within the cosmic drama, but as a force of chaos and agent of evil.
Constraints in Dvorak Wind Speed Estimates: How Quickly Can Hurricanes Intensify?
Authors: Sangster Samuel J. , Landsea Christopher W. 
Published: June 2020

AbstractThe Dvorak technique is used operationally by meteorological agencies throughout the world for estimating tropical cyclone intensity and position. The technique consists of constraints that put a maximum threshold for which the final T-number, relating directly to intensity, can change during a certain time interval (6, 12, 18, and 24 h). There are cases when these constraints could be broken, especially during rapid intensification. This research tests whether the constraints used for intensity change are warranted or need to be changed. A database of cases with the largest intensity changes for 2000–17 Atlantic tropical cyclones was compiled. A reconnaissance or scatterometer “fix” is required within 3 h of both the beginning and ending of the period for each case to inform the best track and to be included for analysis. Dvorak classifications from the Tropical Analysis and Forecast Branch are noted for each case, which includes the initial and final T-numbers, current intensity numbers, and data T-numbers. Statistical parameters, including correlations, intensity errors, absolute intensity errors, root-mean-square errors, and significance tests are calculated and analyzed for each period. Results suggest that the T-number constraints for the 18- and 24-h periods could be increased to a 2.5 and a 3.0, respectively. However, results also suggest that the constraints for the 6- and 12-h time intervals should remain the same.
Endoscopic Ossiculoplasty for the Management of Isolated Congenital Ossicular Chain Malformation: Surgical Results in 16 Ears
Authors: Zhang Chunlin , Mi Jiaoping , Long Dan , Deng Yuan , Sun Qiang , Liu Zhaohui 
Published: June 2020

Objective: The aim of this study is to describe the clinical characteristics and intraoperative findings and further evaluate the efficacy of endoscopic ossiculoplasty for the management of isolated congenital ossicular chain malformation. Methods: A retrospective study was performed on 16 ears (15 patients) with the isolated congenital ossicular chain malformation who underwent endoscopic ossiculoplasty in our department from May 2017 to January 2019. Endoscopic exploratory tympanotomy was conducted to check the ossicular chain; at the same time, endoscopic ossiculoplasty was performed depending on intraoperative findings. Air-conduction thresholds, bone-conduction thresholds, and air-bone gaps (ABGs) were measured before and after surgery, and the hearing outcome was assessed at 6 months postoperatively. Results: The most common malformations of ossicular chain were the missing of the incus long process and stapes suprastructure. A serial assessment of the hearing status was conducted before and 6 months after surgery. It showed the mean postoperative pure-tone average (PTA) was significantly reduced, and the mean postoperative ABG was obviously closed, respectively ( P < .001). The mean PTA gain was 36.3 ± 8.6 dB, and the ABG closure was 35.1 ± 8.3 dB; ABG closure to 20 dB or less and ABG closure to 10 dB or less were achieved in 14 cases (87.5%) and 5 cases (31.3%), respectively. No differences were observed in postoperative hearing outcome between type Ⅲ cases and type Ⅳ cases; however, cases with partial ossicular replacement prosthesis implantation showed a larger hearing gain ( P = .049) and a higher proportion of postoperative ABG less than 10 dB ( P = .021). No facial palsy and significant sensorineural hearing loss occurred; all patients completed the surgery without the need of canalplasty, and the chorda tympani nerve was preserved in all patients. Conclusions: This research showed endoscopic surgery was effective in the diagnosis and management of isolated congenital ossicular chain malformation; the endoscopic ossiculoplasty provides an alternative method to manage congenital ossicular chain malformation, with comfortable hearing outcome and the advantage of excellent vision and less invasion.
Efficacy of functional magnetic stimulation in improving upper extremity function after stroke: a randomized, single-blind, controlled study
Authors: Chen Xiaowei , Liu Xuncan , Cui Yinxing , Xu Guoxing , Liu Lu , Zhang Xueru , Jiang Kun , Li Zhenlan 
Published: June 2020

Objective To clarify the efficacy of functional magnetic stimulation (FMS) in improving hemiplegic upper extremity function in patients with sub-acute stroke. Methods In this randomized controlled trial, 40 sub-acute stroke patients with hemiplegia were recruited from inpatient wards in the Department of Rehabilitation and randomly assigned to two groups. In the FMS group, magnetic stimulation was applied to extensor muscle groups of the affected upper extremity. In the low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) group, stimulation was applied to the contralesional primary motor cortex. All patients received occupational therapy. Hand and upper extremity motor function was evaluated using the Fugl–Meyer Assessment for upper extremity (FMA-UE), and the Barthel Index (BI) evaluated daily living abilities. Results The FMA-UE and BI scores were significantly increased in both groups following stimulation. Furthermore, a significant between-group difference was observed in both FMA-UE and BI scores after 2 weeks of therapy. In the FMS group, 6 of 19 patients regained wrist and finger extension abilities, but only 2 patients regained equivalent motor skills in the LF-rTMS group Conclusions FMS improves paretic upper extremity function and leads to better recovery of motor activity than LF-rTMS. FMS may be a novel modality to improve motor function.
Trends in bacterial resistance among perioperative infections in patients with primary ovarian cancer: A retrospective 20-year study at an affiliated hospital in South China
Authors: Zhou Yanlin , Zhang Tingting 
Published: June 2020

Background We aimed to analyze the epidemiological and drug-resistance trends among bacterial cultures from perioperative infections in patients with primary ovarian cancer. Methods Medical and bacteriological records for patients with ovarian cancer patients who developed perioperative infections after primary cytoreductive surgery from 1999 to 2018 were reviewed retrospectively. Results The incidence of perioperative infections and the culture-positive percentage among patients in the first 10 years were 20.2% and 29.3%, respectively, and the equivalent rates in the second 10 years were 18.0% and 33.5%. The most commonly isolated pathogens in both year-groups were Escherichia coli and Enterococcus spp., but the respective percentages differed between the groups. Some strains of Staphylococcus aureus and Enterococcus spp. in the second 10-year group were resistant to linezolid and vancomycin, and ciprofloxacin resistance among Gram-negative bacteria isolates also increased in this group. However, resistance of Gram-negative bacteria to imipenem and meropenem was low among in both groups. Conclusion The pathogen distribution in perioperative infections in patients with primary ovarian cancer undergoing cytoreductive changed slightly from 1999 to 2018, and the antibiotic resistance of the main isolated pathogens increased. These results indicate the importance of periodic bacterial surveillance of surgical infections in these patients.
Recurrence of First Afebrile Unprovoked Seizure and Parental Consanguinity: A Hospital-Based Study
Authors: Al Momani Miral A. , Almomani Basima , Hani Salar Bani , Lux Andrew 
Published: June 2020

Purpose: The aim of the current study was to determine the incidence, clinical characteristics, and risk factors associated with the recurrence of first unprovoked seizure in children. Methods: A retrospective, observational study was conducted at King Abdullah University Hospital in Jordan. Children aged from 1 month to 16 years old who attended the hospital between January 2013 to December 2017 were evaluated on the basis of medical records, from the first visit and for a 1-year follow-up period. Results: During the study period, a total of 290 cases with first unprovoked seizure were included. The incidence of first unprovoked seizure was 441 cases per 100 000 patient visits to the pediatric clinic. More than half of the cases developed a second attack (55.3%). Children with parental consanguinity were almost 3 times more likely to develop a second attack of seizure compared to those without parental consanguinity (odds ratio [OR] = 2.785, 95% confidence interval [CI] = 1.216-6.378, P = .015) and patients who had a history of focal type of seizure were almost twice as likely to develop seizure recurrence (OR = 1.798, 95% CI = 1.013-3.193, P = .045). Conclusions: The current results showed a high incidence of first unprovoked seizure among children in Jordan. Parental consanguinity and focal seizure were associated with the increased risk of recurrent attack. This finding highlights the need for public education regarding the outcomes of parental consanguinity to improve the patient’s quality of life.
Transoral Endoscopic Thyroidectomy Vestibular Approach: A Single-institution Experience of the First 50 Cases
Authors: Fernandez-Ranvier Gustavo , Meknat Aryan , Guevara Daniela , Taye Aida , Suh Hyunsuk , Inabnet William B. 
Published: June 2020

Background. Transoral endoscopic thyroidectomy vestibular approach (TOETVA) has evolved from a novel procedure to a cosmetically appealing alternative to the traditional open thyroidectomy. TOETVA is limited to only high-volume centers with the hope to expand and demonstrate the safety, reproducibility, and application for the correct patient with thyroid disease. We present our experience with the first 50 TOETVA procedures performed at our institution. Methods. From September 2016 to June 2018, we performed 50 transoral endoscopic thyroidectomies via the vestibular approach for a variety of thyroid pathologies. Outcomes were analyzed from a prospectively maintained database. Patients were treated for a different range of thyroid pathologies. Results. A total of 12 (24%) patients underwent total thyroidectomy, whereas 38 (76%) patients underwent a subtotal thyroidectomy or thyroid lobectomy. The mean surgical time was 149 ± 40.0 (90-256) minutes for lobectomy and 217.6 ± 33.3 (175-276) minutes for total thyroidectomy. Of our 50 patients, 16 (32%) had postoperative transient lower lip numbness with an average time to recovery of 23.8 (.43-48) weeks, with 1 (2%) patient having persistent, but improving, lower lip numbness beyond the 6-month follow-up. There were 13 (26%) patients with transient chin numbness with an average time to recovery of 15.7 (2-48) weeks. Two (4%) patients had transient recurrent laryngeal nerve (RLN) injury with hoarseness, whereas 1 (2%) patient had permanent injury. Conclusion. The TOETVA is a safe and reproducible procedure. For selected patients, this technique is a viable alternative to conventional thyroidectomy.