bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer
Authors: Cruz-Collazo Ailed , Ruiz-Calderon Jean F. , Picon Hector , Borrero-Garcia Luis D. , Lopez Irmaris , Castillo-Pichardo Linette , del Mar Maldonado Maria , Duconge Jorge , Medina Julia I. , Bayro Marvin J. , Hernández-O'Farrill Eliud , Vlaar Cornelis P. , Dharmawardhane Suranganie 
Published: October 2021

Abstract
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.
NAP1051, a Lipoxin A4 Biomimetic Analogue, Demonstrates Antitumor Activity Against the Tumor Microenvironment
Authors: Dong Tiange , Dave Priyal , Yoo EunJeong , Ebright Brandon , Ahluwalia Kabir , Zhou Eugene , Asante Isaac , Salimova Malika , Pei Hua , Lin Tracey , Mead Andrew , Li Zeyang , Humayun Mark , Petasis Nicos A. , Epstein Alan L. , Louie Stan G. 
Published: October 2021

Abstract
Resolving tumor-associated inflammation in the tumor microenvironment (TME) may promote antitumor effects. Lipoxin A4 (LXA4) is a short-lived endogenous bioactive lipid with potent anti-inflammatory and pro-resolving properties. Here, a biomimetic of LXA4, NAP1051, was shown to have LXA4-like in vitro properties and antitumor activity in colorectal cancer xenograft models. NAP1051 inhibited neutrophil chemotaxis toward fMLP and dose-dependently promoted dTHP-1 efferocytosis which was equipotent to aspirin-triggered lipoxin A4 (ATLA). In dTHP-1 cells, NAP1051 induced strong phosphorylation on ERK1/2 and AKT similar to formyl peptide receptor 2 (FPR2/ALX) agonists. In two mouse xenograft colorectal cancer models, NAP1051 significantly inhibited tumor growth when given orally at 4.8 to 5 mg/kg/day. Flow cytometric analyses showed that NAP1051 reduced splenic and intratumoral neutrophil and myeloid-derived suppressor cell populations, which correlated to the antitumor effect. In addition, NAP1051 reduced NETosis in the TME while stimulating T-cell recruitment. Overall, these results show that NAP1051 possesses key lipoxin-like properties and has antitumor activity against colorectal cancer via modulation of neutrophils and NETosis in the TME.
Rethinking Cervical Cancer Screening in Brazil Post COVID-19: A Global Opportunity to Adopt Higher Impact Strategies
Authors: Ribeiro Ana , Corrêa Flávia , Migowski Arn , Leal Aline , Martins Sandro , Raiol Tainá , Marques Carla P. , Torres Katia L. , Novetsky Akiva P. , Marcus Jenna Z. , Wentzensen Nicolas , Schiffman Mark , Rodriguez Ana Cecilia , Gage Julia C. 
Published: October 2021

Abstract
The World Health Organization global call to eliminate cervical cancer encourages countries to consider introducing or improving cervical cancer screening programs. Brazil's Unified Health System (SUS) is among the world's largest public health systems offering free cytology testing, follow-up colposcopy, and treatment. Yet, health care networks across the country have unequal infrastructure, human resources, equipment, and supplies resulting in uneven program performance and large disparities in cervical cancer incidence and mortality. An effective screening program needs multiple strategies feasible for each community's reality, facilitating coverage and follow-up adherence. Prioritizing those at highest risk with tests that better stratify risk will limit inefficiencies, improving program impact across different resource settings. Highly sensitive human papillomavirus (HPV)-DNA testing performs better than cytology and, with self-collection closer to homes and workplaces, improves access, even in remote regions. Molecular triage strategies like HPV genotyping can identify from the same self-collected sample, those at highest risk requiring follow-up. If proven acceptable, affordable, cost-effective, and efficient in the Brazilian context, these strategies would increase coverage while removing the need for speculum exams for routine screening and reducing follow-up visits. SUS could implement a nationwide organized program that accommodates heterogenous settings across Brazil, informing a variety of screening programs worldwide.
Performance Metrics for the Comparative Analysis of Clinical Risk Prediction Models Employing Machine Learning
Authors: Huang Chenxi , Li Shu-Xia , Caraballo César , Masoudi Frederick A. , Rumsfeld John S. , Spertus John A. , Normand Sharon-Lise T. , Mortazavi Bobak J. , Krumholz Harlan M. 
Published: October 2021

Background:
New methods such as machine learning techniques have been increasingly used to enhance the performance of risk predictions for clinical decision-making. However, commonly reported performance metrics may not be sufficient to capture the advantages of these newly proposed models for their adoption by health care professionals to improve care. Machine learning models often improve risk estimation for certain subpopulations that may be missed by these metrics.

Methods and Results:
This article addresses the limitations of commonly reported metrics for performance comparison and proposes additional metrics. Our discussions cover metrics related to overall performance, discrimination, calibration, resolution, reclassification, and model implementation. Models for predicting acute kidney injury after percutaneous coronary intervention are used to illustrate the use of these metrics.

Conclusions:
We demonstrate that commonly reported metrics may not have sufficient sensitivity to identify improvement of machine learning models and propose the use of a comprehensive list of performance metrics for reporting and comparing clinical risk prediction models.
Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity
Authors: Basehore Sarah E. , Bohlman Samantha , Weber Callie , Swaminathan Swathi , Zhang Yuji , Jang Cholsoon , Arany Zoltan , Clyne Alisa Morss 
Published: October 2021

Rationale:
In diabetic animals as well as high glucose cell culture conditions, eNOS (endothelial NO synthase) is heavily O-linked-N-acetylglucosaminylated (O-GlcNAcylated), which inhibits its phosphorylation and NO production. It is unknown, however, whether varied blood flow conditions, which affect eNOS phosphorylation, modulate eNOS activity via O-GlcNAcylation-dependent mechanisms.

Objective:
The goal of this study was to test if steady laminar flow, but not oscillating disturbed flow, decreases eNOS O-GlcNAcylation, thereby elevating eNOS phosphorylation and NO production.

Methods and Results:

Human umbilical vein endothelial cells were exposed to either laminar flow (20 dynes/cm
2
shear stress) or oscillating disturbed flow (4±6 dynes/cm
2
shear stress) for 24 hours in a cone-and-plate device. eNOS O-GlcNAcylation was almost completely abolished in cells exposed to steady laminar but not oscillating disturbed flow. Interestingly, there was no change in protein level or activity of key O-GlcNAcylation enzymes (OGT [O-GlcNAc transferase], OGA [O-GlcNAcase], or GFAT [glucosamine-fructose-6-phosphate aminotransferase]). Instead, metabolomics data suggest that steady laminar flow decreases glycolysis and hexosamine biosynthetic pathway activity, thereby reducing UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) pool size and consequent O-GlcNAcylation. Inhibition of glycolysis via 2-deoxy-2-glucose in cells exposed to disturbed flow efficiently decreased eNOS O-GlcNAcylation, thereby increasing eNOS phosphorylation and NO production. Finally, we detected significantly higher O-GlcNAcylated proteins in endothelium of the inner aortic arch in mice, suggesting that disturbed flow increases protein O-GlcNAcylation in vivo.

Conclusions:
Our data demonstrate that steady laminar but not oscillating disturbed flow decreases eNOS O-GlcNAcylation by limiting glycolysis and UDP-GlcNAc substrate availability, thus enhancing eNOS phosphorylation and NO production. This research shows for the first time that O-GlcNAcylation is regulated by mechanical stimuli, relates flow-induced glycolytic reductions to macrovascular disease, and highlights targeting hexosamine biosynthetic pathway metabolic enzymes in endothelial cells as a novel therapeutic strategy to restore eNOS activity and prevent endothelial cell dysfunction in cardiovascular disease.
Diagnostic value of cerebrospinal fluid levels of D-lactate, tumour necrosis factor-alpha and interleukin-6, -8, and -17 in suspected nosocomial meningitis
Authors: Goktas Sibel Yorulmaz , Oral Arzu Yılmaztepe , Yılmaz Emel , Akalın Emin Halis , Guvenc Furkan , Ozkaya Guven , Kocaeli Hasan , Dogan Seref , Yılmazlar Selcuk , Oral Haluk Barbaros 
Published: October 2021

Abstract

Introduction:
This study aimed to determine the diagnostic value of interleukin (IL)-6, IL-8, IL-17, tumour necrosis factor-alpha (TNF-α) and D-lactate levels in the cerebrospinal fluid (CSF) of nosocomial meningitis patients.

Methods:
The CSF levels of cytokines and D-lactate were compared across 29 episodes of nosocomial meningitis, 38 episodes of pleocytosis (without meningitis) and 54 control subjects.

Results:
The CSF levels of IL-6, IL-8, and D-lactate were higher in the group with nosocomial meningitis compared to the control group and the group with pleocytosis without meningitis (P < 0.05). For IL-6 levels (threshold: >440 pg/mL), the sensitivity and specificity were 55.17% and 94.74%, respectively. For IL-8 levels (threshold: >1,249 pg/mL), the sensitivity and specificity were 44.83% and 84.21%, respectively. In patients with nosocomial meningitis, when the threshold of D-lactate levels was >1.05 μmol/mL, the sensitivity and specificity were 75.86% and 63.16%, respectively. In pleocytosis (without meningitis) CSF samples and in nosocomial meningitis CSF samples, the highest area under the receiver operating characteristic curve (AUC) was calculated for triple combination model of IL-6, IL-8 and D-lactate levels (AUC 0.801, P < 0.001) and double combination model of IL-6 and IL-8 (AUC 0.790, P < 0.001).

Conclusion:
Our study findings suggest that IL-6, IL-8 and D-lactate levels could be diagnostic markers for nosocomial meningitis.
Comparison of the safety and efficacy between minimally invasive cardiac surgery and median sternotomy in a low-risk mixed Asian population in Singapore
Authors: Ong Zhi Xian , Wu Duoduo , Luo Haidong , Chang Guohao , Sazzad Faizus , Sule Jai Ajitchandra , Hu Peggy , Kofidis Theo 
Published: October 2021

Introduction:
Minimally invasive cardiac surgery (MICS) has attracted increasing attention, with institutions increasingly adopting this approach over conventional median sternotomy (MS). This study aimed to describe the outcomes of minimally invasive cardiac surgery in our institution as the only centre with an established MICS programme in Singapore.

Methods:
Patients who had undergone cardiac procedures such as heart valve replacement or repair, coronary artery bypass grafting or atrial septal defect repair were included in the study. We analysed 4063 patients who had undergone MS and 390 patients who had undergone MICS between January 2009 and February 2020.

Results:
Over the years, the number of MICS procedures performed increased, along with an increase in MICS operations with two or more concomitant cardiac procedures and a decrease in postoperative length of stay. Compared with patients who underwent MS, those who underwent MICS had shorter length of postoperative hospital stay (P < 0.001). On multivariate analysis, patients who underwent MICS had lower rates of atrial fibrillation (P = 0.021), reoperation (P = 0.028) and prolonged ventilation (P < 0.001). However, the rates of other postoperative complications were comparable between patients who underwent MICS and those who underwent MS.

Conclusion:
In our institution, MICS is a safe, reproducible and efficacious technique that yields superior outcomes compared with conventional MS procedures, in some aspects. The results of this study provide further evidence and support towards adopting the minimally invasive approach to cardiac surgery in a carefully selected group of cardiac patients in Singapore.
Contribution to the Glolarnaca Gorochov, 2008 (Orthoptera: Gryllacrididae: Hyperbaeninae) from China
Authors: YANG ZIZHON , LU XIANGYI , BIAN XUN 
Published: October 2021

Herein two new species of Glolarnaca Gorochov, 2008 are reported. Images illustrating the morphology of the two new species are provided. And the type specimens are deposited in the Institute of Entomoceutics Research, Dali University (DUIER) and Guangxi Normal University (GXNU).
Long-Term Effect of Barotropic Instability across the Moat in Double-Eyewall Tropical Cyclone–Like Vortices in Forced and Unforced Shallow-Water Models
Authors: Lai Tsz-Kin , Hendricks Eric A. , Yau M. K. 
Published: October 2021

Abstract
Secondary eyewall formation and the ensuing eyewall replacement cycles may take place in mature tropical cyclones (TCs) during part of their lifetime. A better understanding of the underlying dynamics is beneficial to improving the prediction of TC intensity and structure. Previous studies suggested that the barotropic instability (BI) across the moat (aka type-2 BI) can make a substantial contribution to the inner-eyewall decay through the associated eddy radial transport of absolute angular momentum (AAM). Simultaneously, the type-2 BI can also increase the AAM of the outer eyewall. While the previous studies focused on the early stage of the type-2 BI, this paper explores the long-term effect of the type-2 BI and the underlying processes in forced and unforced shallow-water experiments. Under the long-term effect, it will be shown that the inner eyewalls repeatedly weaken and strengthen (while the order is reversed for the outer eyewalls). Sensitivity tests are conducted to examine the sensitivity of the long-term effect of the type-2 BI to different vortex parameters and the strength of the parameterized diabatic heating. Implication of the long-term effect for the intensity changes of the inner and outer eyewalls of real TCs are also discussed.
A cyclone-centered perspective on the drivers of asymmetric patterns in the atmosphere and sea ice during Arctic cyclones
Authors: Clancy Robin , Bitz Cecilia M. , Blanchard-Wrigglesworth Edward , McGraw Marie C. , Cavallo Steven M. 
Published: October 2021

AbstractArctic cyclones are an extremely common, year-round phenomenon, with substantial influence on sea ice. However, few studies address the heterogeneity in the spatial patterns in the atmosphere and sea ice during Arctic cyclones. We investigate these spatial patterns by compositing on cyclones from 1985-2016 using a novel, cyclone-centered approach that reveals conditions as functions of bearing and distance from cyclone centers. An axisymmetric, cold core model for the structure of Arctic cyclones has previously been proposed, however, we show that the structure of Arctic cyclones is comparable to those in the mid-latitudes, with cyclonic surface winds, a warm, moist sector to the east of cyclones and a cold, dry sector to the west. There is no consensus on the impact of Arctic cyclones on sea ice, as some studies have shown that Arctic cyclones lead to sea ice growth and others to sea ice loss. Instead, we find that sea ice decreases to the east of Arctic cyclones and increases to the west, with the greatest changes occurring in the marginal ice zone. Using a sea ice model forced with prescribed atmospheric reanalysis, we reveal the relative importance of the dynamic and thermodynamic forcing of Arctic cyclones on sea ice. The dynamic and thermodynamic responses of sea ice concentration to cyclones are comparable in magnitude, however dynamic processes dominate the response of sea ice thickness and are the primary driver of the east-west difference in the sea ice response to cyclones.
Machine learning for precipitation forecasts post-processing — Multi-model comparison and experimental investigation
Authors: Zhang Yuhang , Ye Aizhong 
Published: October 2021

AbstractObtaining high-quality quantitative precipitation forecasts is a key precondition for hydrological forecast systems. Due to multisource uncertainties (e.g., initial conditions, model structures and parameters), raw forecasts are subject to systematic biases; hence, statistical post-processing is often required to reduce these errors before the forecasts can proceed to hydrological applications. Machine learning (ML) algorithms are canonical statistical models, and they are diverse in type and variation. It is important to verify and compare their performance in the same scenario (e.g., precipitation post-processing). In this paper, we conduct a large-scale comparison study for the major ML models with diverse model structures and regularization strategies as post-processors for improving the quality of precipitation forecasts. Specifically, we compare the efficiency and effectiveness of 21 ML algorithms on solving this task. Daily reforecast precipitation with lead times up to 8 days from the Global Ensemble Forecast System and corresponding observations are employed to determine the usability of different models in the Yalong River basin in China. The performance of each model is validated by a group of carefully designed experiments and statistical metrics. The results reveal that improvements in model structures are more effective than regularization strategies. Among these algorithms, the optimized extra-trees regressor exhibit the best performance, effectively reduce overestimation and achieve the best skill in forecasting precipitation. Eleven ensemble members and a 2-day time window can be used as predictors to obtain the best model performance. The systematic experiments and findings also offer useful guidelines for other related studies.
Probabilistic fire-danger forecasting: A framework for week-two forecasts using statistical post-processing techniques and the Global ECMWF Fire Forecast System (GEFF)
Authors: Worsnop Rochelle P. , Scheuerer Michael , Di Giuseppe Francesca , Barnard Christopher , Hamill Thomas M. , Vitolo Claudia 
Published: October 2021

AbstractWildfire guidance two weeks ahead is needed for strategic planning of fire mitigation and suppression. However, fire forecasts driven by meteorological forecasts from numerical weather prediction models inherently suffer from systematic biases. This study uses several statistical-postprocessing methods to correct these biases and increase the skill of ensemble fire forecasts over the contiguous United States 8–14 days ahead. We train and validate the post-processing models on 20 years of European Centre for Medium-range Weather Forecast (ECMWF) reforecasts and ERA5 reanalysis data for 11 meteorological variables related to fire, such as surface temperature, wind speed, relative humidity, cloud cover, and precipitation. The calibrated variables are then input to the Global ECMWF Fire Forecast (GEFF) system to produce probabilistic forecasts of daily fire-indicators which characterize the relationships between fuels, weather, and topography. Skill scores show that the post-processed forecasts overall have greater positive skill at Days 8–14 relative to raw and climatological forecasts. It is shown that the post-processed forecasts are more reliable at predicting above- and below-normal probabilities of various fire indicators than the raw forecasts and that the greatest skill for Days 8–14 is achieved by aggregating forecast days together.
Object-Process Methodology as an Alternative to Human Factors Task Analysis
Authors: Dori Dov , Jbara Ahmad , Yang Yongkai E. , Liu Andrew M. , Oman Charles M. 
Published: October 2021

Objective We define and demonstrate the use of OPM-TA—a model-based task analysis (TA) framework that uses object-process methodology (OPM) ISO 19450 as a viable alternative to traditional TA techniques. Background A variety of different TA methods exist in human factors engineering, and several of them are often applied successively for a broad task representation, making it difficult to follow. Method Using OPM-TA, we modeled how an International Space Station (ISS) astronaut would support extravehicular activities using the existing robotic arm workstation with a new control panel and an electronic procedure system. The modeling employed traditional TA methods and the new OPM-TA approach, enabling a comparison between them. Results While the initial stages of modeling with OPM-TA follow those of traditional TA, OPM-TA modeling yields an executable and logically verifiable model of the entire human–robot system. Both OPM’s hierarchical set of diagrams and the equivalent, automatically generated statements in a subset of natural language text specify how objects and processes relate to each other at increasingly detailed levels. The graphic and textual OPM modalities specify the system’s architecture, which enables its function and benefits its users. To verify the model logical correctness model, we executed it using OPM’s simulation capability. Conclusion OPM-TA was able to unify traditional TA methods and expand their capabilities. The formal yet intuitive OPM-TA approach fuses and extends traditional TA methods, which are not amenable to simulation. It therefore can potentially become a widely used means for TA and human–machine procedure development and testing.