bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study
Authors: Lassman Andrew B. , Sepúlveda-Sánchez Juan Manuel , Cloughesy Timothy F. , Gil-Gil Miguel J. , Puduvalli Vinay K. , Raizer Jeffrey J. , De Vos Filip Y.F. , Wen Patrick Y. , Butowski Nicholas A. , Clement Paul M.J. , Groves Morris D. , Belda-Iniesta Cristóbal , Giglio Pierre , Soifer Harris S. , Rowsey Steven , Xu Cindy , Avogadri Francesca , Wei Ge , Moran Susan , Roth Patrick 
Published: March 2022

Abstract

Purpose:
FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1–3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas.

Patients and Methods:
Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy.

Results:
Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0–32.5], median PFS was 1.7 months (95% CI, 1.1–2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors.

Conclusions:
FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.
Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Chung Christine H. , Li Jiannong , Steuer Conor E. , Bhateja Priyanka , Johnson Matthew , Masannat Jude , Poole Maria I. , Song Feifei , Hernandez-Prera Juan C. , Molina Helen , Wenig Bruce M. , Kumar Sunil , Kuperwasser Charlotte , Stephens Philip J. , Farinhas Joaquim M. , Shin Dong M. , Kish Julie A. , Muzaffar Jameel , Kirtane Kedar , Rocco James W. , Schell Michael J. , Saba Nabil F. , Bonomi Marcelo 
Published: March 2022

Abstract

Purpose:
A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with a combination of cetuximab and nivolumab.

Patients and Methods:
Patients with R/M HNSCC were treated with cetuximab 500 mg/m2 i.v. on day 14 as a lead-in followed by cetuximab 500 mg/m2 i.v. and nivolumab 240 mg i.v. on day 1 and day 15 of each 28-day cycle. Expression of p16 and programmed cell death-ligand 1 (PD-L1) in archived tumors were determined. Tumor-tissue–modified human papillomavirus (TTMV) DNA was quantified in plasma.

Results:
Ninety-five patients were enrolled, and 88 patients were evaluable for OS with a median follow-up of 15.9 months. Median OS in the 45 patients who had prior therapy for R/M HNSCC (cohort A) was 11.4 months, with a 1 year OS 50% [90% confidence interval (CI), 0.43–0.57]. Median OS in the 43 patients who had no prior therapy (cohort B) was 20.2 months, with a 1-year OS 66% (90% CI, 0.59–0.71). In the combined cohorts, the p16-negative immunostaining was associated with higher response rate (RR; P = 0.02) but did not impact survival while higher PD-L1 combined positive score was associated with higher RR (P = 0.03) and longer OS (log-rank P = 0.04). In the p16-positive patients, lower median (1,230 copies/mL) TTMV DNA counts were associated with higher RR (P = 0.01) and longer OS compared with higher median (log-rank P = 0.05).

Conclusions:
The combination of cetuximab and nivolumab is effective in patients with both previously treated and untreated R/M HNSCC and warrants further evaluation.
Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication
Authors: Inaba Hiroto , van Oosterwijk Jolieke G. , Panetta John C. , Li Lie , Buelow Daelynn R. , Blachly James S. , Shurtleff Sheila , Pui Ching-Hon , Ribeiro Raul C. , Rubnitz Jeffrey E. , Pounds Stanley , Baker Sharyn D. 
Published: March 2022

Abstract

Purpose:
To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD).

Patients and Methods:
After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1–28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8–28) in 9 pediatric patients with refractory/relapsed FLT3-ITD–positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies.

Results:
The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P &lt; 0.005) and survival (P &lt; 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P &lt; 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug–drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L).

Conclusions:
The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.
eSPA+: Scalable Entropy-Optimal Machine Learning Classification for Small Data Problems
Authors: Vecchi Edoardo , Pospíšil Lukáš , Albrecht Steffen , O'Kane Terence J. , Horenko Illia 
Published: March 2022

Abstract
Classification problems in the small data regime (with small data statistic T and relatively large feature space dimension D) impose challenges for the common machine learning (ML) and deep learning (DL) tools. The standard learning methods from these areas tend to show a lack of robustness when applied to data sets with significantly fewer data points than dimensions and quickly reach the overfitting bound, thus leading to poor performance beyond the training set. To tackle this issue, we propose eSPA+, a significant extension of the recently formulated entropy-optimal scalable probabilistic approximation algorithm (eSPA). Specifically, we propose to change the order of the optimization steps and replace the most computationally expensive subproblem of eSPA with its closed-form solution. We prove that with these two enhancements, eSPA+ moves from the polynomial to the linear class of complexity scaling algorithms. On several small data learning benchmarks, we show that the eSPA+ algorithm achieves a many-fold speed-up with respect to eSPA and even better performance results when compared to a wide array of ML and DL tools. In particular, we benchmark eSPA+ against the standard eSPA and the main classes of common learning algorithms in the small data regime: various forms of support vector machines, random forests, and long short-term memory algorithms. In all the considered applications, the common learning methods and eSPA are markedly outperformed by eSPA+, which achieves significantly higher prediction accuracy with an orders-of-magnitude lower computational cost.
Circ_0041732 regulates tumor properties of triple-negative breast cancer cells by the miR-149-5p/FGF5 pathway
Authors: Li Hongyang , Yin Hailin , Yan Yao 
Published: March 2022

Background Triple-negative breast cancer (TNBC) is a subtype of breast cancers with a high recurrence and mortality. The important factors promoting the TNBC process have not been fully identified. In this research, the role of a TNBC-related circular RNA (circRNA), circ_0041732, was revealed in TNBC cell tumor properties. Methods The expression levels of circ_0041732, microRNA-149-5p (miR-149-5p) and fibroblast growth factor 5 ( FGF5) were detected by quantitative real-time polymerase chain reaction. The protein expression was determined by Western blot analysis or immunohistochemistry assay. Cell proliferation was detected by cell counting kit-8 and cell colony formation assays. Cell apoptosis was analyzed by flow cytometry and caspase-3 activity assays. Cell migration and invasion were evaluated by wound-healing and transwell invasion assays. Cell angiogenic capacity was investigated by a tube formation assay. The targeting relationship between miR-149-5p and circ_0041732 or FGF5 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. The impacts of circ_0041732 knockdown on tumor formation were determined by an in vivo assay. Results Circ_0041732 and FGF5 expression were significantly upregulated, whereas miR-149-5p was downregulated in TNBC tissues and cells compared with normal breast tissues and cells, respectively. Circ_0041732 silencing inhibited TNBC cell proliferation, migration, invasion, and tube formation, but induced apoptosis. Additionally, circ_0041732 regulated TNBC cell tumor properties by binding to miR-149-5p. MiR-149-5p also modulated TNBC cell tumor properties by targeting FGF5. Furthermore, circ_0041732 knockdown hindered tumor formation in vivo. Conclusion Circ_0041732 silencing suppressed TNBC cell tumor properties by decreasing FGF5 expression through miR-149-5p. This finding demonstrated that circ_0041732 had the potential as a therapeutic target for TNBC.
Design and analysis of the mechanical properties of controllable porous scaffolds for bone tissue engineering
Authors: Wang Xiaokang , Chen Jigang , Kang Yongxing , Sun Li 
Published: March 2022

The porous scaffold – a substitute for artificial bone – is vital to bone defect repair and bone tissue regeneration in tissue engineering. In consideration of the limitations of few existing design methods, the significant difference between the internal pore structure of porous scaffolds and natural bone microstructure, and the low controllability of design methods. Based on Voronoi-Tessellation (VT) and random function theory, this paper proposed a design method with controllable pore density, adjustable pore shape and size, and heterogeneous pore distribution. The stress change law of porous scaffolds under compression was analyzed using finite element simulation experiments; the relationship between the porosity and the structural strength of porous scaffolds was obtained. Furthermore, the anisotropy of porous scaffolds was studied, and the change law of the macroscopic equivalent elastic modulus with the change in porosity of porous scaffolds was acquired. Under the same porosity, the mechanical properties of the porous scaffold with a uniform pore distribution and the porous scaffold designed in this paper were analyzed and compared; the damage extension laws of two different porous scaffolds were obtained. The results demonstrate that the design method proposed in this paper has high controllability, and the parametric modeling process is both random and controllable. The internal pore structures of porous scaffolds generated by the design method are closer to the microstructure of natural bone tissue – the structural strength satisfies the requirements of artificial implants. Graphical abstract [Formula: see text]
The use of patient-reported outcome measures to classify type 1 and 2 systemic lupus erythematosus activity
Authors: Eudy Amanda M , Reeve Bryce B , Coles Theresa , Lin Li , Rogers Jennifer L , Pisetsky David S , Criscione-Schreiber Lisa G , Doss Jayanth , Sadun Rebecca , Sun Kai , Clowse Megan EB 
Published: March 2022

Objective We developed a model that categorizes systemic lupus erythematosus (SLE) activity into two dimensions: Type 1 SLE consists of inflammatory activity, including arthritis, nephritis, and rashes; Type 2 SLE includes fatigue, myalgia, mood disturbance, and cognitive dysfunction. Patient-reported outcome (PRO) measures have received attention as a way to capture symptomatology of SLE. The objective of this study was to explore the use of existing PRO measures to classify Type 1 and 2 SLE activity. Methods Systemic lupus erythematosus patients completed three questionnaires: Systemic Lupus Activity Questionnaire (SLAQ), Polysymptomatic Distress Scale (PSD), and Patient Health Questionnaire (PHQ-2). SLE Disease Activity Index (SLEDAI) and physician global assessments (PGA; 0–3) for Type 1 and Type 2 activity were also recorded. High Type 1 SLE activity was defined as cSLEDAI ≥4 (scored without labs), SLEDAI ≥6, active nephritis, or Type 1 PGA ≥1.0. High Type 2 SLE activity was defined as Type 2 PGA ≥1.0. Patients with both high Type 1 and 2 activity were defined as Mixed SLE, and patients with low Type 1 and 2 activity were defined as Minimal SLE. Data were reduced with a factor analysis. Using a reduced set of 13 variables, multinomial logistic regression models estimated the probability of Minimal, Type 1, Type 2, and Mixed SLE classification. Results The study included 208 patients with SLE. The model accurately predicted the clinician-based Type 1 and 2 SLE classification in 63% of patients; 73% of patients had their Type 1 SLE activity accurately predicted; and 83% had their Type 2 SLE activity accurately predicted. Performance varied by group: 87% of Minimal patients were correctly predicted to be in the Minimal SLE group, yet only about one-third of patients in the Type 1 group were correctly predicted to be in the Type 1 group. Conclusions Our findings indicate Type 2 SLE activity can be identified by patient-reported data. The use of PROs was not as accurate at predicting Type 1 activity. These findings highlight the challenges of using PROs to categorize and classify SLE symptoms since some manifestations of Type 1 activity (e.g., nephritis) may be essentially clinically silent while other Type 1 manifestations may cause severe symptoms.
Bilinguals have more effective executive function: Evidence from an fNIRS study of the neural correlates of cognitive shifting
Authors: Li Hui , Wu Dandan , Yang Jinfeng , Xie Sha , Chang Chunqi , Luo Jiutong 
Published: March 2022

Aims and objectives/purpose/research questions: The bilingual advantage in executive function (EF) has recently been explored with functional near-infrared spectroscopy (fNIRS) technology, but the results are still controversial because of the limited statistical analysis. This study aims to fill the gap by replicating the existing studies and advancing the statistical analysis. Design/methodology/approach: Altogether, 35 preschoolers (aged between 4.1 and 6.3 years, Mage = 5.0 years, SD = 0.59) completed the Peabody Picture Vocabulary Test—Fourth Edition (PPVT-4) and the Dimensional Change Card Sort (DCCS) task. Their behavioral performance and the associated brain activities during the three sessions of the DCCS task were measured using fNIRS. In addition, they were classified into either Bilingual or Monolingual groups based on the PPVT scores. Data and analysis: t-tests and quadratic regression analyses were conducted to examine whether children’s performance in the DCCS was related to their bilingualism and whether the changes in oxygenated hemoglobin (HbO) in the prefrontal regions were related to their bilingualism and performance in the DCCS. Findings/conclusions: The behavioral data analysis indicated no significant differences between the monolinguals and bilinguals. However, the fNIRS evidence indicated that (1) the monolinguals had to recruit 15 channels to complete the cognitive shifting of DCCS tasks, whereas the bilinguals only employed 11; (2) the bilinguals had significantly more brain activation with fewer channels in BA 44 than the monolinguals, demonstrating more effective executive function. Originality: This study has advanced the statistical analysis of the HbO changes for the cognitive shifting in the DCCS by confirming the nonlinear U-shape by quadratic regression a better fit than the linear V-shape by GLM. Significance/implications: This finding implies that early bilingual experience has equipped young children with more effective executive function.
MNB1 gene is involved in regulating the iron-deficiency stress response in Arabidopsis thaliana
Authors: Song Hui , Chen Feng , Wu Xi , Hu Min , Geng Qingliu , Ye Min , Zhang Cheng , Jiang Li , Cao Shuqing 
Published: March 2022

Abstract
Background
Iron (Fe) is an essential mineral element that involves in many biological processes important for most plants growth and development. Fe-deficiency induces a complex series of responses in plants, involving physiological and developmental changes, to increase Fe uptake from soil. However, the molecular mechanism involved in plant Fe-deficiency is not well understood.

Results
Here, we found that the MNB1 (mannose-binding-lectin 1) gene is involved in the regulation of Fe-deficiency stress response in Arabidopsis thaliana. The expression abundance of MNB1 was inhibited by Fe-deficiency stress. Knockout of MNB1 led to enhanced Fe accumulation and tolerance, whereas the MNB1-overexpressing plants were sensitive to Fe-deficiency stress. Under conditions of normal and Fe-deficiency, lower H2O2 concentrations were detected in mnb1 mutant plants compared to wild type. On the contrary, higher H2O2 concentrations were found in MNB1-overexpressing plants, which was negatively correlated with malondialdehyde (MDA) levels. Furthermore, in mnb1 mutants, the transcription level of the Fe uptake- and translocation-related genes, FIT, IRT1, FRO2, ZIF, FRD3, NAS4, PYE and MYB72, were considerably elevated during Fe-deficiency stress, resulting in enhanced Fe uptake and translocation, thereby increasing Fe accumulation.

Conclusions
Together, our findings show that the MNB1 gene negatively controls the Fe-deficiency response in Arabidopsis via modulating reactive oxygen species (ROS) levels and the ROS-mediated signaling pathway, thereby affecting the expression of Fe uptake- and translocation-related genes.
Designing and describing an electronic referral system to facilitate direct hospital admissions
Authors: Montellier Marion , Delpech Raphaëlle , Mion Mathieu , Boué François , Metzger Marie-Hélène 
Published: March 2022

Abstract
Background
In France, the progressive use of emergency departments (EDs) by primary care providers (PCPs) as a point of access to hospitalization for nonurgent patients is one of the many causes of their overcrowding. To increase the proportion of direct hospital admissions, it is necessary to improve coordination between PCPs and hospital specialists. The objective of our work was to describe the design and implementation of an electronic referral system aimed at facilitating direct hospital admissions.

Methods
This initiative was conducted in a French area (Hauts-de-Seine Sud) through a partnership between the Antoine-Béclère University Hospital, the Paris-Saclay University Department of General Medicine and the local health care network. The implementation was carried out in 3 stages, namely, conducting a survey of PCPs in the territory about their communication methods with the hospital, designing and implementing a web-based application called “SIPILINK” (Système d'Information de la Plateforme d’Intermédiation Link) and an innovative organization for hospital management of the requests, and analysing through descriptive statistics the platform use 9 months after launch.

Results
The e-referral platform was launched in November 2019. First, a PCP filled out an electronic form describing the reason for his or her request. Then, a hospital specialist worked to respond within 72 h. Nine months after the launch, 132 PCPs had registered for the SIPILINK platform, which represented 36.6% of PCPs in this area. Of the 124 requests made, 46.8% corresponded to a hospitalization request (conventional or day hospitalization). The most requested specialty was internal medicine (48.4% of requests). The median time to first response was 43 min, and 43.5% of these requests resulted in direct admission (conventional or day hospitalization).

Conclusions
This type of system responds to a need for coordination in the primary-secondary care direction, which is less often addressed than in the secondary-primary care direction. The first results show the potential of the system to facilitate direct admissions within a short time frame. To make the system sustainable, the next step is to extend its use to other hospitals in the territory.