bluuebunny/crossref_metadata_2025_split huggingface dataset:
Miller–Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy
Authors: Wang Liye , Luo Rongzhen , Lu Qianyi , Jiang Kuikui , Hong Ruoxi , Lee Kaping , Zhang Ping , Zhou Danyang , Wang Shusen , Xu Fei 
Published: September 2021

IntroductionHR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and MethodsThe study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.
Statistical Process Control Charts for Monitoring Next-Generation Sequencing and Bioinformatics Turnaround in Precision Medicine Initiatives
Authors: Jain Sneha Rajiv , Sim Wilson , Ng Cheng Han , Chin Yip Han , Lim Wen Hui , Syn Nicholas L. , Kamal Nur Haidah Bte Ahmad , Gupta Mehek , Heong Valerie , Lee Xiao Wen , Sapari Nur Sabrina , Koh Xue Qing , Isa Zul Fazreen Adam , Ho Lucius , O’Hara Caitlin , Ulagapan Arvindh , Gu Shi Yu , Shroff Kashyap , Weng Rei Chern , Lim Joey S. Y. , Lim Diana , Pang Brendan , Ng Lai Kuan , Wong Andrea , Soo Ross Andrew , Yong Wei Peng , Chee Cheng Ean , Lee Soo-Chin , Goh Boon-Cher , Soong Richie , Tan David S.P. 
Published: September 2021

PurposePrecision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes.Patients and MethodsTrends in NGS and bioinformatics TAT were analyzed using simple regression models with TAT as the dependent variable and chronologically-ordered case number as the independent variable. The M-estimator “robust” regression and negative binomial regression were chosen to serve as sensitivity analyses to each other. Next, two popular statistical process control (SPC) approaches which are CUSUM and EWMA were utilized and the CUSUM log-likelihood ratio (LLR) charts were also generated. All statistical analyses were done in Stata version 16.0 (StataCorp), and nominal P &lt; 0.05 was considered to be statistically significant.ResultsA total of 365 patients underwent successful molecular profiling. Both the robust linear model and negative binomial model showed statistically significant reductions in TAT with accumulating experience. The EWMA and CUSUM charts of overall TAT largely corresponded except that the EWMA chart consistently decreased while the CUSUM analyses indicated improvement only after a nadir at the 82nd case. CUSUM analysis found that the bioinformatics team took a lower number of cases (54 cases) to overcome the learning curve compared to the NGS team (85 cases).ConclusionAs NGS and bioinformatics lead precision oncology into the forefront of cancer management, characterizing the TAT of NGS and bioinformatics processes improves the timeliness of data output by potentially spotlighting problems early for rectification, thereby improving care delivery.
Targeting PI3K, FGFR, CDK4/6 Signaling Pathways Together With Cytostatics and Radiotherapy in Two Medulloblastoma Cell Lines
Authors: Lukoseviciute Monika , Maier Henrietta , Poulou-Sidiropoulou Eleni , Rosendahl Erika , Holzhauser Stefan , Dalianis Tina , Kostopoulou Ourania N. 
Published: September 2021

ObjectivesMedulloblastoma (MB) is treated with surgery and chemotherapy, with or without irradiation, but unfortunately &gt;20% of the patients are not cured, and treatment comes with serious long-term side effects, so novel treatments are urgently needed. Phosphoinositide 3-kinases (PI3K), fibroblast growth factor receptors (FGFR), and cyclin-D kinases (CDK) play critical roles in cancer, and especially PI3K is crucial in MB, so here targeted therapies against them were explored.MethodsMB cell lines DAOY and UW228-3 were exposed to PI3K (BYL719), FGFR (JNJ-42756493), and CDK4/6 (PD-0332991) inhibitors, as single or combined treatments, and their viability, cell confluence, apoptosis, and cytotoxicity were examined. Moreover, the inhibitors were combined with cisplatin, vincristine, or irradiation.ResultsSingle treatments with FGFR, PI3K, or CDK4/6 inhibitors decreased viability and proliferation slightly; however, when combining two inhibitors, or the inhibitors with irradiation, sensitivity was enhanced and lower doses could be used. A more complex pattern was obtained when combining the inhibitors with cisplatin and vincristine.ConclusionsThe data suggest that combination treatments with PI3K, FGFR, and CDK4/6 inhibitors for MB could be beneficial and their use should be pursued further. Likewise, their combination with irradiation gave positive effects, while the addition of cisplatin and vincristine resulted in more complex patterns, which need to be investigated further.
End-of-Life Care Related Distress in the PICU and NICU: A Cross-Sectional Survey in a German Tertiary Center
Authors: Garten Lars , Danke Andrea , Reindl Tobias , Prass Anja , Bührer Christoph 
Published: September 2021

Objective: To investigate and compare nurses' perceived care-related distress and experiences in end-of-life situations in neonatal and pediatric intensive care units.Study design: Single-center, cross-sectional survey. Administration of an anonymous self-report questionnaire survey to nurses of two tertiary neonatal intensive care units (NICUs), and two tertiary pediatric intensive care units (PICUs) in Berlin, Germany.Results: Seventy-three (73/227, response rate 32.2%) nurses completed surveys. Both, NICU (32/49; 65.3%) and PICU (24/24; 100.0%) nurses, reported “staffing shortages” to be the most frequent source of distress in end-of-life situations. However, when asked for the most distressing factor, the most common response by NICU nurses (17/49) was “lack of clearly defined and agreed upon therapeutic goals”, while for PICU nurses (12/24) it was “insufficient time and staffing”. No significant differences were found in reported distress-related symptoms in NICU and PICU nurses. The interventions rated by NICU nurses as most helpful for coping were: “discussion time before the patient's death” (89.6%), “team support” (87.5%), and “discussion time after the patient's death” (87.5%). PICU nurses identified “compassion” (98.8%), “team support”, “personal/private life (family, friends, hobbies)”, and “discussion time after the patient's death” (all 87.5%) as most helpful.Conclusions: Distress-related symptoms as a result of end-of-life care were commonly reported by NICU and PICU nurses. The most frequent and distressing factors in end-of-life situations might be reduced by improving institutional/organizational factors. Addressing the consequences of redirection of care, however, seems to be a more relevant issue for the relief of distress associated with end-of-life situations in NICU, as compared to PICU nurses.
Vascular Endothelial Function Assessed by Flow-Mediated Vasodilatation in Young Adults Born Very Preterm or With Extremely Low Birthweight: A Regional Cohort Study
Authors: Engan Britt , Engan Mette , Greve Gottfried , Vollsæter Maria , Hufthammer Karl Ove , Leirgul Elisabeth 
Published: September 2021

Background: Preterm birth and low birthweight have been associated with increased risk of cardiovascular disease in young adults. Endothelial dysfunction is established as an early marker for development of atherosclerotic cardiovascular disease. Previous studies of endothelial function in young adults born very preterm or with extremely low birthweight have, however, shown diverging results.Objective: We aimed to evaluate the risk of cardiovascular disease as measured by vascular endothelial function in young adults born very preterm (&lt;29 weeks of gestation) or with extremely low birthweight (&lt;1,000 g), compared with term-born controls.Methods: This study included 50 young adults born very preterm or with extremely low birthweight and 49 term-born controls born in Norway in the periods 1982–1985, 1991–1992, and 1999–2000 at mean age 28 (±6) years. The endothelial function was assessed by ultrasound measured flow-mediated dilatation (FMD) of the right brachial artery. The arterial diameter was measured at baseline, after release of 5 min of occlusion, and after sublingual administration of nitroglycerine. FMD was reported as absolute and percentage diameter change from baseline and relative to nitroglycerine-induced dilatation.Results: The participants were mainly normal weight non-smokers, without hypertension, diabetes, or established cardiovascular disease. The cases and controls had mean blood pressure 112/71 (SD 12/9) and 112/69 (SD 11/8) mmHg, body mass index 24.0 (SD 4.2) and 24.4 (SD 4.5) kg/m2, and HbA1c 32.7 (SD 2.5) and 33.0 (SD 2.6) mmol/mol, respectively. For both groups, 4 (8%) were smokers. Mean FMD for the adults born very preterm or with extremely low birthweight was 0.17 mm (95% CI 0.14, 0.21) vs. 0.24 mm (95% CI 0.20, 0.28) for the controls (p = 0.01), corresponding to a percentage increase of 5.4% (95% CI 4.2, 6.6) and 7.6% (95% CI 6.2, 8.9), respectively (p = 0.02). The FMD relative to maximal nitroglycerine-induced dilatation was 20% and 31%, respectively (p = 0.001).Conclusions: Young adults born very preterm or with extremely low birthweight have significantly lower FMD compared with the term-born controls suggesting an increased risk of cardiovascular disease.
Anti-Inflammatory Properties of Statin-Loaded Biodegradable Lecithin/Chitosan Nanoparticles: A Step Toward Nose-to-Brain Treatment of Neurodegenerative Diseases
Authors: Clementino Adryana Rocha , Marchi Cinzia , Pozzoli Michele , Bernini Franco , Zimetti Francesca , Sonvico Fabio 
Published: September 2021

Nasal delivery has been indicated as one of the most interesting alternative routes for the brain delivery of neuroprotective drugs. Nanocarriers have emerged as a promising strategy for the delivery of neurotherapeutics across the nasal epithelia. In this work, hybrid lecithin/chitosan nanoparticles (LCNs) were proposed as a drug delivery platform for the nasal administration of simvastatin (SVT) for the treatment of neuroinflammatory diseases. The impact of SVT nanoencapsulation on its transport across the nasal epithelium was investigated, as well as the efficacy of SVT-LCNs in suppressing cytokines release in a cellular model of neuroinflammation. Drug release studies were performed in simulated nasal fluids to investigate SVT release from the nanoparticles under conditions mimicking the physiological environment present in the nasal cavity. It was observed that interaction of nanoparticles with a simulated nasal mucus decreased nanoparticle drug release and/or slowed drug diffusion. On the other hand, it was demonstrated that two antibacterial enzymes commonly present in the nasal secretions, lysozyme and phospholipase A2, promoted drug release from the nanocarrier. Indeed, an enzyme-triggered drug release was observed even in the presence of mucus, with a 5-fold increase in drug release from LCNs. Moreover, chitosan-coated nanoparticles enhanced SVT permeation across a human cell model of the nasal epithelium (×11). The nanoformulation pharmacological activity was assessed using an accepted model of microglia, obtained by activating the human macrophage cell line THP-1 with the Escherichia coli–derived lipopolysaccharide (LPS) as the pro-inflammatory stimulus. SVT-LCNs were demonstrated to suppress the pro-inflammatory signaling more efficiently than the simple drug solution (−75% for IL-6 and −27% for TNF-α vs. −47% and −15% at 10 µM concentration for SVT-LCNs and SVT solution, respectively). Moreover, neither cellular toxicity nor pro-inflammatory responses were evidenced for the treatment with the blank nanoparticles even after 36 h of incubation, indicating a good biocompatibility of the nanomedicine components in vitro. Due to their biocompatibility and ability to promote drug release and absorption at the biointerface, hybrid LCNs appear to be an ideal carrier for achieving nose-to-brain delivery of poorly water-soluble drugs such as SVT.
Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth
Authors: Cruz Flores Valerie A. , Menghani Hemant , Mukherjee Pranab K. , Marrero Luis , Obenaus Andre , Dang Quan , Khoutorova Larissa , Reid Madigan M. , Belayev Ludmila , Bazan Nicolas G. 
Published: September 2021

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.
Effects of Extreme Weight Loss on Cardiometabolic Health in Children With Metabolic Syndrome: A Metabolomic Study
Authors: Liu Jingxin , Zhu Lin , Liao Jing , Liu Xiaoguang 
Published: September 2021

Objectives: To evaluate the effect of extreme weight loss programs on circulating metabolites and their relationship with cardiometabolic health in children with metabolic syndrome.Methods: This study was a quasi-experimental design with a pretest and post-test. Thirty children with metabolic syndrome and aged 10–17years were recruited to an extreme weight loss program (i.e., exercise combined with diet control). The primary outcomes included plasma metabolites, body composition, and cardiometabolic risk factors. A total of 324 metabolites were quantitatively detected by an ultra-performance liquid chromatography coupled to tandem mass spectrometry system, and the variable importance in the projection (VIP) value of each metabolite was calculated by the orthogonal projection to latent structures discriminant analysis. The fold change (FC) and p value of each metabolite were used to screen differential metabolites with the following values: VIP&gt;1, p value&lt;0.05, and |log2FC|&gt;0.25. Pathway enrichment and correlation analyses between metabolites and cardiometabolic risk factors were also performed.Result: A large effect size was observed, presenting a weight loss of −8.9kg (Cohen’s d=1.00, p&lt;0.001), body mass index reduction of −3.3kg/m2 (Cohen’s d=1.47, p&lt;0.001), and body fat percent reduction of −4.1 (%) (Cohen’s d=1.22, p&lt;0.001) after the intervention. Similar improvements were found in total cholesterol (Cohen’s d=2.65, p&lt;0.001), triglycerides (Cohen’s d=2.59, p&lt;0.001), low-density lipoprotein cholesterol (Cohen’s d=2.81, p&lt;0.001), glucose metabolism, and blood pressure. A total of 59 metabolites were changed after the intervention (e.g., aminoacyl-tRNA biosynthesis, glycine, serine, and threonine metabolism; nitrogen metabolism, tricarboxylic acid cycle, and phenylalanine, tyrosine, and tryptophan biosynthesis). The changes in metabolites (e.g., amino acids, fatty acids, organic acids, and carnitine) were related to lipid metabolism improvement (p&lt;0.05). Organic acids and carnitines were associated with changes in the body composition (p&lt;0.05).Conclusion: Exercise combined with dietary control improved the body composition and cardiometabolic health in children with metabolic syndrome, and these changes may be related to plasma metabolites.
High-Intensity Interval Training for Heart Failure Patients With Preserved Ejection Fraction (HIT-HF)-Rational and Design of a Prospective, Randomized, Controlled Trial
Authors: Gasser Benedikt A. , Boesing Maria , Schoch Raphael , Brighenti-Zogg Stefanie , Kröpfl Julia M. , Thesenvitz Elke , Hanssen Henner , Leuppi Jörg D. , Schmidt-Trucksäss Arno , Dieterle Thomas 
Published: September 2021

Background: The pathophysiology of HF with preserved ejection fraction (HFpEF) has not yet been fully understood and HFpEF is often misdiagnosed. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. In contrast to patients with HF with reduced ejection fraction, medical treatment in HFpEF is limited to relieving HF symptoms. Since mortality in HFpEF patients remains unacceptably high with a 5-year survival rate of only 30%, new treatment strategies are urgently needed. Exercise seems to be a valid option. However, the optimal training regime still has to be elucidated. Therefore, the aim of the study is to investigate the effects of a high-intensity interval (HIT) training vs. a moderate continuous training (MCT) on exercise capacity and disease-specific mechanisms in a cohort of patients with HFpEF.Methods: The proposed study will be a prospective, randomized controlled trial in a primary care setting including 86 patients with stable HFpEF. Patients will undergo measurements of exercise capacity, disease-specific blood biomarkers, cardiac and arterial vessel structure and function, total hemoglobin mass, metabolic requirements, habitual physical activity, and quality of life (QoL) at baseline and follow-up. After the baseline visit, patients will be randomized to the intervention or control group. The intervention group (n = 43) will attend a supervised 12-week HIT on a bicycle ergometer combined with strength training. The control group (n = 43) will receive an isocaloric supervised MCT combined with strength training. After 12 weeks, study measurements will be repeated in all patients to quantify the effects of the intervention. In addition, telephone interviews will be performed at 6 months, 1, 2, and 3 years after the last visit to assess clinical outcomes and QoL.Discussion: We anticipate clinically significant changes in exercise capacity, expressed as VO2peak, as well as in disease-specific mechanisms following HIT compared to MCT. Moreover, the study is expected to add important knowledge on the pathophysiology of HFpEF and the clinical benefits of a training intervention as a novel treatment strategy in HFpEF patients, which may help to improve both QoL and functional status in affected patients.Trial registration:ClinicalTrials.gov, identifier: NCT03184311, Registered 9 June 2017.
Validity and Reliability of a Phone App and Stopwatch for the Measurement of 505 Change of Direction Performance: A Test-Retest Study Design
Authors: Chen Zhili , Bian Chao , Liao Kaifang , Bishop Chris , Li Yongming 
Published: September 2021

Purpose: The aim of this study was to explore the validity and reliability of a phone app [named: change of direction (COD) timer] and stopwatches for the measurement of COD performance.Methods: Sixty-two youth basketball players (age: 15.9±1.4yrs., height: 178.8±11.0cm, and body mass: 70.0±14.1kg) performed six trials of 505 COD test (with the left side being the plant leg first, then the right side). The completion time was measured simultaneously via timing gates (with error correction processing algorithms), the phone app, and stopwatches.Results: There was an almost perfect correlation and agreement between timing gates and COD timer (r=0.978; SEE=0.035s; and LoA=−0.08~0.06s), but a lower correlation and agreement between timing gates and stopwatch (r=0.954; SEE=0.050s; and LoA=−0.17~0.04s) with statistical significance in completion time (ES=1.29, 95%CI: 1.15–1.43, p&lt;0.01). The coefficient of variation revealed similar level of dispersion between the three timing devices (timing gates: 6.58%; COD timer: 6.32%; and stopwatch: 6.71%). Inter-observer reliability (ICC=0.991) and test-retest reliability (ICC=0.998) were excellent in COD timer, while the inter-observer reliability was lower (ICC=0.890) in the stopwatches.Conclusion: In the 505 COD test, the COD timer was able to provide a valid and reliable measurement. On the contrary, stopwatch was not recommended because of large error. Thus, if timing gates are unavailable, practitioners can adopt the COD timer app to assess 505 COD speed times.