bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies
Authors: Goedegebuure Ruben S.A. , Wentink Madelon Q. , van der Vliet Hans J. , Timmerman Peter , Griffioen Arjan W. , de Gruijl Tanja D. , Verheul Henk M.W. 
Published: October 2020

Abstract

Lessons Learned
The novel therapeutic vaccine hVEGF26–104/RFASE was found to be safe and well tolerated in patients with cancer. hVEGF26–104/RFASE failed to induce seroconversion against native hVEGF165 and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF26–104/RFASE induced VEGF165-neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates.

Background
Targeting vascular endothelial growth factor-A (VEGF) is a well-established anticancer therapy. We designed a first-in-human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF26–104/RFASE.

Methods
Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose-escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF26–104, a truncated synthetic three-dimensional (3D)-structured peptide mimic covering the amino acids 26–104 of the human VEGF165 isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF-neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers.

Results
Eighteen of 27 enrolled patients received three immunizations in six different dose-levels up to 1,000 μg hVEGF26–104 and 40 mg RFASE. No dose-limiting toxicity was observed. Although in four patients an antibody titer against hVEGF26–104 was induced (highest titer: 2.77 10log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF165 were detected.

Conclusion
Despite having an attractive safety profile, hVEGF26–104/RFASE was not able to elicit seroconversions against native VEGF165 and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF26–104/RFASE's efficacy in humans.
A Phase I Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors
Authors: Ma Yuxiang , Fang Wenfeng , Zhao Hongyun , Bathena Sai Praneeth , Tendolkar Amol , Sheng Jennifer , Zhang Li 
Published: October 2020

AbstractLessons LearnedThe overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified. The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.BackgroundThis phase I, open-label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3-week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12-week cycle, to a maximum of 3 years or PD. Considering the co-primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose-limiting toxicities during the 42-day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti-ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.
A case report of isolated zygomatic arch fracture by modified towel clip method
Authors: Hayashi Kamichika , Migita Masashi , Iwasaki Takahiro , Onda Takeshi , Takano Masayuki , Takaki Takashi 
Published: October 2020

AbstractFractures of the zygomatic arch may be treated with a variety of techniques. The disadvantages of these methods include the difficulty of reaching the fracture site via the intraoral approach and the high level of surgical invasiveness associated with the extraoral approach. This is a case report. A 20‐year‐old man was banged on the face. He presented at our department complaining of a change in facial shape and difficulty in mouth opening. Modified towel clip method was used to treat the zygomatic fracture which was classified into Yamamoto Class II type, and successful reduction was achieved. We believe that this method is very effective from the standpoint of minimum invasiveness and simplicity.
Distinct contributions of cathelin‐related antimicrobial peptide (CRAMP) derived from epithelial cells and macrophages to colon mucosal homeostasis
Authors: Chen Keqiang , Yoshimura Teizo , Yao Xiaohong , Gong Wanghua , Huang Jiaqiang , Dzutsev Amiran K , McCulloch John , O'hUigin Colm , Bian Xiu‐wu , Trinchieri Giorgio , Wang Ji Ming 
Published: October 2020

AbstractThe cathelin‐related antimicrobial peptide CRAMP protects the mouse colon from inflammation, inflammation‐associated carcinogenesis, and disrupted microbiome balance, as shown in systemic Cnlp−/− mice (also known as Camp−/− mice). However, the mechanistic basis for the role and the cellular source of CRAMP in colon pathophysiology are ill defined. This study, using either epithelial or myeloid conditional Cnlp−/− mice, demonstrated that epithelial cell‐derived CRAMP played a major role in supporting normal development of colon crypts, mucus production, and repair of injured mucosa. On the other hand, myeloid cell‐derived CRAMP potently supported colon epithelial resistance to bacterial invasion during acute inflammation with exacerbated mucosal damage and higher rate of mouse mortality. Therefore, a well concerted cooperation of epithelial‐ and myeloid‐derived CRAMP is essential for colon mucosal homeostasis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Dimensionless squared jerk: An objective differential to assess experienced and novice probe movement in obstetric ultrasound
Authors: Dromey Brian P , Ahmed Shahanaz , Vasconcelos Francisco , Mazomenos Evangelos , Kunpalin Yada , Ourselin Sebastien , Deprest Jan , David Anna L , Stoyanov Danail , Peebles Donald M 
Published: October 2020

AbstractObjectiveWidely accepted, validated and objective measures of ultrasound competency have not been established for clinical practice. Outcomes of training curricula are often based on arbitrary thresholds, such as the number of clinical cases completed. We aimed to define metrics against which competency could be measured.MethodWe undertook a prospective, observational study of obstetric sonographers at a UK University Teaching Hospital. Participants were either experienced in fetal ultrasound (n = 10, >200 ultrasound examinations) or novice operators (n = 10, <25 ultrasound examinations). We recorded probe motion data during the performance of biometry on a commercially available mid‐trimester phantom.ResultsWe report that Dimensionless squared jerk, an assessment of deliberate hand movements, independent of movement duration, extent, spurious peaks and dimension differed significantly different between groups, 19.26 (SD 3.02) for experienced and 22.08 (SD 1.05, p = 0.01) for novice operators, respectively. Experienced operator performance, was associated with a shorter time to task completion of 176.46 s (SD 47.31) compared to 666.94 s (SD 490.36, p = 0.0004) for novice operators. Probe travel was also shorter for experienced operators 521.23 mm (SD 27.41) versus 2234.82 mm (SD 188.50, p = 0.007) when compared to novice operators.ConclusionOur results represent progress toward an objective assessment of technical skill in obstetric ultrasound. Repeating this methodology in a clinical environment may develop insight into the generalisability of these findings into ultrasound education.
Development of novel frog‐skin peptide scaffolds with selectivity towards melanocortin receptor subtypes
Authors: Malik Uru , Chan Lai Yue , Cai Minying , Hruby Victor J. , Kaas Quentin , Daly Norelle L. , Craik David J. 
Published: October 2020

AbstractMelanocortin receptors are pharmaceutically important receptors that are involved in complex physiological functions. They have been associated with various diseases including obesity, erectile dysfunction, acne, and skin cancer. It has been challenging to transform nonselective endogenous agonist and antagonist ligands into selective and potent ligands. In this study, we investigated naturally occurring peptides derived from frog skin secretions for selectivity and activity toward melanocortin receptors. Three peptides (ORB, ORB2K and ranacyclin‐T) were found to have selectivity towards the melanocortin receptor 5 (MC5R). ORB and ORB2K had partial binding affinity at nanomolar concentrations, whereas ranacyclin‐T had 57% binding efficiency at 1.6 μM. Backbone cyclization of ORB and ORB2K altered the binding efficiency to melanocortin receptors. Our results suggest that these frog‐skin peptides could be modified for developing melanocortin‐specific ligands and potentially future therapeutics.
Different physiotherapy protocols after coronary artery bypass graft surgery: A randomized controlled trial
Authors: Ribeiro Breno Caldas , Poça Jadson José Guimarães da , Rocha Amanda Martins Cavalcante , Cunha Clícia Naeli Silva da , Cunha Katiane da Costa , Falcão Luiz Fábio Magno , Torres Daniel da Costa , Rocha Larissa Salgado de Oliveira , Rocha Rodrigo Santiago Barbosa 
Published: October 2020

AbstractBackground and purposeThe aim of this study was to investigate the influence of different physiotherapy protocols on heart rate variability (HRV) and hospital length of stay in older adults undergoing coronary artery bypass graft (CABG).MethodsRandomized controlled trial with allocation and researcher blinding and intention‐to‐treat analysis. Forty‐eight patients undergoing CABG were randomly assigned to a control group (CG), early mobilization group (EMG), or virtual reality group (VRG). CG performed respiratory physiotherapy and metabolic exercises, the EMG performed cycle ergometer exercises and ambulation, and the VRG performed the same activities as the EMG, with the addition of two Nintendo Wii games during 3 postoperative days. The variables of heart rate variability on preoperative and fourth postoperative day, and time of discharge of hospital was analyzed.ResultsThe VRG presented a shorter hospital length of stay (p = 0.03). The CG showed a decline in HRV from the preoperative period to fourth postoperative day on square root of the mean of the squared differences between successive RR intervals (33.18 ± 9.89–9.74 ± 6.88, p < 0.05), standard deviation of all RR intervals (25.48 ± 7.50–15.23 ± 11.27, p < 0.05), and dispersion of points perpendicular to identity line (28.26 ± 21.6–2.73 ± 1.31, p < 0.05). The EMG and VRG presented a higher cardiac autonomic modulation compared to the CG (p < 0.05), with improved parasympathetic activity.ConclusionsDifferent protocols of physiotherapy intervention affected autonomic modulation of the heart rate and hospital length of stay in patients undergoing CABG.
Resampling‐based stepwise multiple testing procedures with applications to clinical trial data
Authors: He Jiwei , Li Feng , Gao Yan , Rothmann Mark 
Published: October 2020

SUMMARYEndpoints in clinical trials are often highly correlated. However, the commonly used multiple testing procedures in clinical trials either do not take into consideration the correlations among test statistics or can only exploit known correlations. Westfall and Young constructed a resampling‐based stepdown method that implicitly utilizes the correlation structure of test statistics in situations with unknown correlations. However, their method requires a “subset pivotality” assumption. Romano and Wolf proposed a more general stepdown method, which does not require such an assumption. There is at present little experience with the application of such methods in analyzing clinical trial data. We advocate the application of resampling‐based multiple testing procedures to clinical trials data when appropriate. We have conjectured that the resampling‐based stepdown methods can be extended to a stepup procedure under appropriate assumptions and examined the performance of both stepdown and stepup methods under a variety of correlation structures and distribution types. Results from our simulation studies support the use of the resampling‐based methods under various scenarios, including binary data and small samples, with strong control of Family wise type I error rate (FWER). Under positive dependence and for binary data even under independence, the resampling‐based methods are more powerful than the Holm and Hochberg methods. Last, we illustrate the advantage of the resampling‐based stepwise methods with two clinical trial data examples: a cardiovascular outcome trial and an oncology trial.
Insight into the X‐ray absorption spectra of Cu‐porphyrazines from electronic structure theory
Authors: Boydas Esma Birsen , Winter Bernd , Batchelor David , Roemelt Michael 
Published: October 2020

AbstractTransition metal porphyrazines are a widely used class of compounds with applications in catalysis, organic solar cells, photodynamic therapy, and nonlinear optics. The most prominent members of that family of compounds are metallophtalocyanines, which have been the subject of numerous spectroscopic and theoretical studies. In this work, the electronic structure and X‐ray absorption characteristics of three Cu‐porphyrazine derivatives are investigated by means of modern electronic structure theory. More precisely, the experimentally observed N K‐edge and Cu L‐edge features are presented and reproduced by time‐dependent density functional theory, restricted open‐shell configuration interaction, and a restricted active space approach. Where possible, the calculations are used to interpret the observed spectroscopic features in terms of electronic transitions and, furthermore, to connect spectral differences to chemical variations. Part of the discussion of the computational results concerns the impact of various parameters and approximations that are used for the calculations, for example, the choice of active space.
Simultaneous screening of dietary supplements for 25 anti‐hyperlipidemic substances using ultra‐performance liquid chromatography and liquid chromatography/electrospray ionization tandem mass spectrometry
Authors: Kim Nam Sook , Lim Na Young , Choi Hwan Seong , Lee Ji Hyun , Moon Sun Hee , Kim Hyungil , Baek Sun Young 
Published: October 2020

RationaleRecently, illegal dietary supplements containing unauthorized compounds have been seized and internationally publicized with a warning to avoid their consumption. This adulteration can be a serious threat to public health because of insufficient and reliable safety data as well as their undesirable side effects. It is, therefore, essential to rapidly and accurately develop and simultaneously validate analytical methods for these unauthorized anti‐hyperlipidemic substances.MethodsDietary supplements were screened simultaneously for 25 anti‐hyperlipidemic drugs using an ultra‐high‐performance liquid chromatography (UPLC) system with a photodiode array (PDA) detector and LC/electrospray ionization tandem mass spectrometry (LC/ESI‐MS/MS). The method validation, according to ICH guidelines, considered specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, matrix effects, and stability for solid and liquid blank samples. The established UPLC‐PDA and LC/ESI‐MS/MS methods were applied to screen 103 dietary supplements for 25 anti‐hyperlipidemic substances.ResultsUsing the validated methods, the screened samples were found to contain peaks with similar retention times and PDA spectra. By comparing the calculated precursor‐product ion ratios with those of standards, lovastatin and lovastatin acid were detected at concentrations from LOQ to 4.12 mg/g and LOQ to 9.65 mg/g, respectively.ConclusionsThe developed UPLC‐PDA and LC/ESI‐MS/MS analytical methods were applied to 103 real samples, of which 13 samples were found to contain lovastatin and lovastatin acid. In view of the increasing demand for dietary supplements in the treatment of hyperlipidemic diseases, widespread use of these methods will contribute to consumer health by ensuring the safety of dietary supplements.
Widespread pulmonary invasion by malignant pleural mesothelioma: an important diagnostic consideration
Authors: MacMillan Mia , Roy Bapti , McLaren Sally , Nowak Anna K. , Thomas Rajesh , Lee Y. C. Gary 
Published: October 2020

AbstractWe report a rare case of early and extensive pulmonary invasion of malignant pleural mesothelioma (MPM) in a 70‐year‐old woman. She first presented with a hydropneumothorax and subsequent workup, including video‐assisted thoracoscopy (VAT), confirmed MPM. After VAT, she developed dyspnoea, cough, and widespread pulmonary infiltrates of uncertain aetiology. These infiltrates progressed over the following months, failed to respond to antibiotics, and were strongly fluorodeoxyglucose (FDG)‐avid on positron emission tomography (PET). Bronchoalveolar lavage (BAL) yielded extremely viscous fluid containing mesothelioma cells. These cells were also found in the sputum when nebulized deoxyribonuclease (DNase) was trialled to enhance clearance of the pulmonary fluid. The patient deteriorated rapidly with progressive mediastinal and contralateral MPM involvement and died one month later. This case highlights the importance of including tumour invasion as a differential diagnosis of non‐resolving pulmonary infiltrates in patients with MPM.
A limit inferior ‐dependent average dwell time approach for stability analysis of switched systems
Authors: Yu Qiang , Zhai Guisheng 
Published: October 2020

SummaryA novel concept of limit inferior‐dependent average dwell time (LDADT) is first proposed, which is a generalization of various existing concepts of dwell time. Based on the LDADT scheme and the multiple Lyapunov function approach, some new sufficient conditions for stability and stabilization of switched systems are established by introducing some inequalities. Those criteria acquired contain most of the established ones based on ADT, limiting ADT, mode‐dependent ADT,‐dependent ADT, etc. Specifically, the stability and stabilization criteria for switched linear systems are listed as linear matrix inequalities that can be examined and calculated easily by the LMI toolbox in Matlab. At last, three typical numerical examples are presented for illustrating the effectiveness and validity of the LDADT scheme presented in this paper.
Complementary dimension reduction
Authors: Cui Na , Hu Jianjun , Liang Feng 
Published: October 2020

AbstractThe goal of supervised dimension reduction (SDR) is to find a compact yet informative representation of the feature vector. Most SDR algorithms are formulated to solve sequential optimization problems with objective functions being linear functions of the L2 norm of the data, for example, the well‐known Fisher's discriminant analysis (FDA). A drawback of such objective functions is that they favor directions that result in large between‐class distances; however, if the large between‐class distance is mainly from classes that have already been well separated by prior directions, the new direction leads to a negligible improvement over classification accuracy. To address this issue, we introduce an objective function that directly quantifies classification accuracy, and present an efficient algorithm that retrieves directions sequentially from this nonlinear objective function. A key feature of our algorithm is that each sequentially added direction works complementarily with the previous sequentially‐solved directions to boost the discriminative power of the reduced space as a whole. So we name our new algorithm “Complementary Dimension Analysis” (CDA). We have further generalized CDA to retrieve sparse directions that involve only a small fraction of the features. Finally we demonstrate the utility of our algorithms on several simulated and real datasets.
Assessing consistency in clinical trials with two subgroups and binary endpoints: A new test within the logistic regression model
Authors: Grill Susann , Ring Arne , Brannath Werner , Scharpenberg Martin 
Published: October 2020

AbstractIn late stage drug development, the experimental drug is tested in a diverse study population within the relevant indication. In order to receive marketing authorization, robust evidence for the therapeutic efficacy is crucial requiring investigation of treatment effects in well‐defined subgroups. Conventionally, consistency analyses in subgroups have been performed by means of interaction tests. However, the interaction test can only reject the null hypothesis of equivalence and not confirm consistency. Simulation studies suggest that the interaction test has low power but can also be oversensitive depending on sample size—leading in combination with the actually ill‐posed null hypothesis to findings regardless of clinical relevance. In order to overcome these disadvantages in the setup of binary endpoints, we propose to use a consistency test based on the interval inclusion principle, which is able to reject heterogeneity and confirm consistency of subgroup‐specific treatment effects while controlling the type I error. This homogeneity test is based upon the deviation between overall treatment effect and subgroup‐specific effects on the odds ratio scale and is compared with an equivalence test based on the ratio of both subgroup‐specific effects. Performance of these consistency tests is assessed in a simulation study. In addition, the consistency tests are outlined for the relative risk regression. The proposed homogeneity test reaches sufficient power in realistic scenarios with small interactions. As expected, power decreases for unbalanced subgroups, lower sample sizes, and narrower margins. Severe interactions are covered by the null hypothesis and are more likely to be rejected the stronger they are.