bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel In Vitro Assays for the Characterization of EMT in Tumourigenesis
Authors: Koo Vincent , El Mekabaty Amgad , Hamilton Peter , Maxwell Perry , Sharaf Osama , Diamond Jim , Watson Jenny , Williamson Kathleen
Published: January 2021

Background: Two novel assays quantifying Epithelial to Mesenchymal Transition (EMT) were compared to traditional motility and migration assays. TGF-β1 treatment of AY-27 rat bladder cancer cells acted as a model of EMT in tumourigenesis.

Methods: AY-27 rat bladder cancer cells incubated with 3 ng/ml TGF-β1 or control media for 24 or 48 h were assessed using novel and traditional assays. The Spindle Index, a novel measure of spindle phenotype, was derived from the ratio of maximum length to maximum width of cells. The area covered by cells which migrated from a fixed coverslip towards supplemented agarose was measured in a novel chemoattractant assay. Motility, migration and immunoreactivity for E-cadherin, Vimentin and cytokeratin were assessed.

Results: TGF-β1 treated cells had increased “spindle” phenotype together with decreased E-cadherin, decreased Cytokeratin-18 and increased Vimentin immunoreactivity. After 48 h, the mean Spindle Index of TGF-β1 treated cells was significantly higher than Mock (p=0.02, Bonferroni test) and there were significant differences in migration across treatment groups measured using the novel chemoattractant assay (p=0.02, Chi-square). TGF-β1 significantly increased matrigel invasion.

Conclusions: The Spindle Index and the novel chemoattractant assay are valuable adjunctive assays for objective characterization of EMT changes during tumourigenesis.
An Adaptive EEG Feature Extraction Method Based on Stacked Denoising Autoencoder for Mental Fatigue Connectivity
Authors: Yu Zhongliang , Li Lili , Zhang Wenwei , Lv Hangyuan , Liu Yun , Khalique Umair
Published: January 2021

Mental fatigue is a common psychobiological state elected by prolonged cognitive activities. Although, the performance and the disadvantage of the mental fatigue have been well known, its connectivity among the multiareas of the brain has not been thoroughly studied yet. This is important for the clarification of the mental fatigue mechanism. However, the common method of connectivity analysis based on EEG cannot get rid of the interference from strong noise. In this paper, an adaptive feature extraction model based on stacked denoising autoencoder has been proposed. The signal to noise ratio of the extracted feature has been analyzed. Compared with principal component analysis, the proposed method can significantly improve the signal to noise ratio and suppress the noise interference. The proposed method has been applied on the analysis of mental fatigue connectivity. The causal connectivity among the frontal, motor, parietal, and visual areas under the awake, fatigue, and sleep deprivation conditions has been analyzed, and different patterns of connectivity between conditions have been revealed. The connectivity direction under awake condition and sleep deprivation condition is opposite. Moreover, there is a complex and bidirectional connectivity relationship, from the anterior areas to the posterior areas and from the posterior areas to the anterior areas, under fatigue condition. These results imply that there are different brain patterns on the three conditions. This study provides an effective method for EEG analysis. It may be favorable to disclose the underlying mechanism of mental fatigue by connectivity analysis.
GAN‐Holo: Generative Adversarial Networks‐Based Generated Holography Using Deep Learning
Authors: Khan Aamir , Zhijiang Zhang , Yu Yingjie , Khan Muhammad Amir , Yan Ketao , Aziz Khizar
Published: January 2021

Current development in a deep neural network (DNN) has given an opportunity to a novel framework for the reconstruction of a holographic image and a phase recovery method with real‐time performance. There are many deep learning‐based techniques that have been proposed for the holographic image reconstruction, but these deep learning‐based methods can still lack in performance, time complexity, accuracy, and real‐time performance. Due to iterative calculation, the generation of a CGH requires a long computation time. A novel deep generative adversarial network holography (GAN‐Holo) framework is proposed for hologram reconstruction. This novel framework consists of two phases. In phase one, we used the Fresnel‐based method to make the dataset. In the second phase, we trained the raw input image and holographic label image data from phase one acquired images. Our method has the capability of the noniterative process of computer‐generated holograms (CGHs). The experimental results have demonstrated that the proposed method outperforms the existing methods.
Involvement of CD26 in Differentiation and Functions of Th1 and Th17 Subpopulations of T Lymphocytes
Authors: Zhao Xiangli , Wang Wenhan , Zhang Kai , Yang Jingya , Fuchs Hendrik , Fan Hua
Published: January 2021

CD26, acting as a costimulator of T cell activation, plays an important role in the immune system. However, the role of CD26 in the differentiation of T cell subsets, especially of new paradigms of T cells, such as Th17 and Tregs, is not fully clarified. In the present study, the role of CD26 in T cell differentiation was investigated in vitro. CD26 expression was analyzed in the different subsets of human peripheral blood T lymphocytes after solid-phase immobilized specific anti-CD3 mAb stimulation. Here, the percentage of CD4+ cells significantly increased and most of these cells were coexpressed with CD26, suggesting a close correlation of CD26 expression with the proliferation of CD4+ cells. Subsequently, after immobilized anti-CD3 mAb stimulation, CD26 high-expressing cells (CD26high) were separated from CD26 low-expressing cells (CD26low) by magnetic cell sorting. We found that the percentages of cells secreting Th1 typical cytokines (IL-2, IFN-γ) and Th17 typical cytokines (IL-6, IL-17, and IL-22) or expressing Th17 typical biomarkers (IL-23R, CD161, and CD196) in the CD26high group were markedly higher than in those in the CD26low group. In addition, a coexpression of CD26 with IL-2, IFN-γ, IL-17, IL-22, and IL-23R in lymphocytes was demonstrated by fluorescence microscopy. These results provide direct evidence that the high expression of CD26 is accompanied by the differentiation of T lymphocytes into Th1 and Th17, indicating that CD26 plays a crucial role in regulating the immune response.
Common Fixed-Point Theorems of Generalizedψ,φ−Weakly Contractive Mappings inb−Metric-Like Spaces and Application
Authors: Guan Hongyan , Li Jianju
Published: January 2021

In this paper, we prove some common fixed-point theorems of generalizedψ,φ−weakly contractive mappings inb−metric-like spaces. We also give two examples to support our results. Meanwhile, we present an application to the existence of solutions for a system of integral equations by means of our results.
Serum Sickness following Tetanus Toxoid Injection
Authors: alhawal Saja , Aldarwish Manar , Almoosa Zainab
Published: January 2021

Serum sickness is an allergic reaction that frequently occurs in patients after the injection of foreign protein or serum. It is characterized by fever, skin rash, enlarged lymph nodes, and painful joints. In this case, we describe a case of 6-year-old girl who developed a rash and arthralgia after being vaccinated with tetanus toxoid injection after a cut wound.
Guide Extension Catheter-Facilitated Reverse Controlled Antegrade and Retrograde Tracking for Retrograde Recanalization of Chronic Total Occlusion
Authors: Mody Rohit , Dash Debabrata , Mody Bhavya , Saholi Aditya
Published: January 2021

Background. In recent years, the retrograde approach has become a common practice in the treatment of chronic total occlusion (CTO) of coronary ostium which is arising abnormally and has an ambiguous proximal cap. In this case report, we report a case of retrograde percutaneous coronary intervention (PCI) done successfully on an abnormally originating artery which was guideliner assisted. Case Presentation. A 65-year-old gentleman with a history of hypertension, diabetes, and PCI presented to us with angina. Physical examination, electrocardiography (ECG), and echocardiography were done. Coronary angiography (CAG) revealed a normal left anterior descending artery (LAD), an anomalous circumflex (CX) artery arising from the right cusp. The abnormal CX had an implanted stent from which the abnormal right coronary artery (RCA) was arising and had a CTO. It also revealed the retrograde filling of distal RCA through grade 2 Werner collateral channels (CCs) from the LAD, a long CTO segment with a distal cap at the bifurcation. PCI of an RCA-CTO was scheduled utilizing a primary retrograde strategy, since antegrade ostium was abnormal in origin, and the patient was previously stented across the origin. The retrograde wire was externalized, and the procedure was completed with 3 overlapping drug-eluting stents (DESs). We used a guideliner which also assisted in the capture of retrograde corsair during the retrograde procedure of CTO [assisted reverse controlled antegrade and retrograde tracking (CART)]. These measures helped us to complete the CTO intervention successfully. Conclusion. The antegrade crossing is the most common approach to CTOs. However, it is sometimes difficult to penetrate the proximal hard ambiguous cap with guidewires, especially in the case of CTOs of anomalous coronary arteries because of a lack of support. Herein, we describe an iteration of reverse CART technique using a guide extensor catheter to facilitate externalizing the retrograde wire from false to true lumen.
Exosome-Derived Noncoding RNAs as a Promising Treatment of Bone Regeneration
Authors: Yin Bei , Ma Qingge , Song Chenghao , Zhao Lingyi , Yu Fanyuan , Wang Chenglin , Shi Yu , Ye Ling
Published: January 2021

The reconstruction of large bone defects remains a crucial challenge in orthopedic surgery. The current treatments including autologous and allogenic bone grafting and bioactive materials have their respective drawbacks. While mesenchymal stem cell (MSC) therapy may address these limitations, growing researches have demonstrated that the effectiveness of MSC therapy depends on paracrine factors, particularly exosomes. This aroused great focus on the exosome-based cell-free therapy in the treatment of bone defects. Exosomes can transfer various cargoes, and noncoding RNAs are the most widely studied cargo through which exosomes exert their ability of osteoinduction. Here, we review the research status of the exosome-derived noncoding RNAs in bone regeneration, the potential application of exosomes, and the existing challenges.
Impulse Propagation in Compositions and Words
Authors: Archibald Margaret , Blecher Aubrey , Brennan Charlotte , Knopfmacher Arnold , Mansour Toufik
Published: January 2021

We consider compositions of

n

represented as bargraphs and subject these to repeated impulses which start from the left at the top level and destroy horizontally connected parts. This is repeated while moving to the right first and then downwards to the next row and the statistic of interest is the number of impulses needed to annihilate the whole composition. We achieve this by conceptualizing a generating function that tracks compositions as well as the number of impulses used. This conceptualization is repeated for words (over a finite alphabet) represented by bargraphs.
Distribution and Numbers of Three Globally Threatened Waterbird Species Wintering in Morocco: The Common Pochard, Marbled Teal, and White-Headed Duck
Authors: Ouassou Asmaâ , Dakki Mohamed , El Agbani Mohammed-Aziz , Qninba Abdeljebbar , El Hamoumi R’himou
Published: January 2021

Morocco plays a key role in the life of many migratory birds and their survival, thanks to the diversity and richness of its ecosystems. The International Waterbird Census (IWC) has been regularly implemented in Morocco since 1983. Thanks to this program, a large database on wintering waterbirds’ populations has been collected. In this article, we summarize the wintering data of three globally threatened waterbirds: Aythya ferina, Marmaronetta angustirostris, and Oxyura leucocephala. The population of Aythya ferina, which is declining, is largely distributed in the country, in over a hundred wetlands, 26 of which verify the national importance criteria. Marmaronetta angustirostris has a stable trend over the years even though its population can know high annual fluctuations; it winters in more or less 50 wetlands, among which 18 host more than 1% of its regional population and 16 verify the criteria for national importance. On the contrary, Oxyura leucocephala, a globally endangered bird only encountered in a dozen wetlands, shows a moderate increase in its numbers; only two wetlands verify the Ramsar criterion 6, while a total of six can be considered of national importance. Furthermore, given the conservation statuses of these waterbirds and according to the Ramsar criterion 2, all their hosting sites are of international importance. The results presented in this paper are a crucial step for the adoption and implementation of adequate conservation measures for the species and their key sites. Nevertheless, comprehensive research and coordinated efforts on the factors (ecological and anthropogenic) influencing the species, at the national and international levels, are required for a better understanding of their populations’ dynamics.
Distinction of High- and Low-Frequency Repetitive Transcranial Magnetic Stimulation on the Functional Reorganization of the Motor Network in Stroke Patients
Authors: Guo Zhiwei , Jin Yu , Bai Xi , Jiang Binghu , He Lin , McClure Morgan A. , Mu Qiwen
Published: January 2021

Objective. To investigate the functional reorganization of the motor network after repetitive transcranial magnetic stimulation (rTMS) in stroke patients with motor dysfunction and the distinction between high-frequency rTMS (HF-rTMS) and low-frequency rTMS (LF-rTMS). Methods. Thirty-three subcortical stroke patients were enrolled and assigned to the HF-rTMS group, LF-rTMS group, and sham group. Each patient of rTMS groups received either 10.0 Hz rTMS over the ipsilesional primary motor cortex (M1) or 1.0 Hz rTMS over the contralesional M1 for 10 consecutive days. A resting-state functional magnetic resonance imaging (fMRI) scan and neurological examinations were performed at baseline and after rTMS. The motor network and functional connectivities intramotor network with the core brain regions including the bilateral M1, premotor area (PMA), and supplementary motor area (SMA) were calculated. Comparisons of functional connectivities and Pearson correlation analysis between functional connectivity changes and behavioral improvement were calculated. Results. Significant motor improvement was found after rTMS in all groups which was larger in two rTMS groups than in the sham group. The functional connectivities of the motor network were significantly increased in bilateral M1, SMA, and contralesional PMA after real rTMS. These changes were only detected in the regions of the ipsilesional hemisphere in the HF-rTMS group and in the regions of the contralesional hemisphere in the LF-rTMS group. Significantly changed functional connectivities of the intramotor network were found between the ipsilesional M1 and SMA and contralesional PMA, between contralesional M1 and contralesional SMA, between contralesional SMA and ipsilesional SMA and contralesional PMA in the HF-rTMS group in which the changed connectivity between ipsilesional M1 and contralesional PMA was obviously correlated with the motor improvement. In addition, the functional connectivity of the intramotor network between ipsilesional M1 and contralesional PMA was significantly higher in the HF-rTMS group than in the LF-rTMS group. Conclusion. Both HF-rTMS and LF-rTMS have a positive effect on motor recovery in patients with subcortical stroke and could promote the reorganization of the motor network. HF-rTMS may contribute more to the functional connectivity reorganization of the ipsilesional motor network and realize greater benefit to the motor recovery.
Fast Clinical, but Long-Term, Biochemical Remission after Waterhouse–Friderichsen Syndrome
Authors: Harsch Igor Alexander
Published: January 2021

Background. The Waterhouse–Friderichsen Syndrome (WFS) is a course of bacterial meningitis with a lethality rate that is still high today. One hallmark of the clinical course is intravascular coagulopathy. This causes hemorrhagic infarctions in the adrenal glands, rapidly causing a primary adrenal insufficiency. Only few reports highlight the course of the remaining adrenal insufficiency or adrenal restitution in survivors. Case Presentation. After 3 weeks in an intensive care unit, a 45-year-old male survived WFS with necroses on the legs and forefeet and with primary adrenal insufficiency confirmed by the ACTH stimulation test. The substitution therapy with hydrocortisone and fludrocortisone could be gradually discontinued after nine months due to a further positive clinical course. Although the patient reported good mental and physical performance further on, the cortisol response in ACTH testing showed tiny incremental rises of the stimulated serum cortisol, but to reach a formally normal level, it took about five years. Discussion. The report demonstrates a case with a relatively fast clinical remission. A remission of the corticotrophic response occurred in small increments during an observational period of five years. The data suggest that not only a clinical remission is possible but also a complete biochemical remission, although this process may take a much longer timespan.
The Landscape of Interactions between Hypoxia‐Inducible Factors and Reactive Oxygen Species in the Gastrointestinal Tract
Authors: Shao Yirui , Wang Kexing , Xiong Xia , Liu Hongnan , Zhou Jian , Zou Lijun , Qi Ming , Liu Gang , Huang Ruilin , Tan Zhiliang , Yin Yulong
Published: January 2021

The gastrointestinal tract (GT) is the major organ involved in digestion, absorption, and immunity, which is prone to oxidative destruction by high levels of reactive oxygen species (ROS) from luminal oxidants, such as food, drugs, and pathogens. Excessive ROS will lead to oxidative stresses and disrupt essential biomolecules, which also act as cellular signaling molecules in response to growth factors, hormones, and oxygen tension changes. Hypoxia‐inducible factors (HIFs) are critical regulators mediating responses to cellular oxygen tension changes, which are also involved in energy metabolism, immunity, renewal, and microbial homeostasis in the GT. This review discusses interactions between HIF (mainly HIF‐1α) and ROS and relevant diseases in the GT combined with our lab’s work. It might help to develop new therapies for gastrointestinal diseases associated with ROS and HIF‐1α.
Case of Incarcerated Femoral Hernia Treated with Laparoscopic Surgery after Groin Hernia Repair
Authors: Tsuchiya Yuki , Momose Hirotaka , Kure Kazumasa , Ro Hisashi , Takahashi Rina , Okazawa Yu , Kawai Masaya , Takahashi Makoto , Kojima Yutaka , Sakamoto Kazuhiro
Published: January 2021

An 81-year-old man was brought to our hospital due to a suspicion of left incarcerated femoral hernia. He was previously diagnosed with incarcerated left groin hernia and was treated using the mesh plug method 1 month back at another hospital. Abdominal computed tomography scan revealed small bowel obstruction, incarcerated bowel, and compression of the left femoral vein. Thus, the patient was diagnosed with incarcerated femoral hernia. An emergency laparoscopic surgery was then performed, and we found that the small bowel was incarcerated into the let femoral ring and was necrotic. However, there was no recurrence of left inguinal hernia. The small necrotic bowel was resected and the femoral ring was repaired. The patient was discharged 8 days after the surgery, and there was no recurrence of femoral hernia after 1 year.
Novel Endoscopic Therapy for Gastric Varices Using Direct Forward-Viewing Endoscopic Ultrasonography
Authors: Yokoyama Keiji , Miyayama Takashi , Uchida Yotaro , Fukuda Hiromi , Yamauchi Ryo , Tsuchiya Naoaki , Umeda Kaoru , Takata Kazuhide , Tanaka Takashi , Inomata Shinjiro , Morihara Daisuke , Takeyama Yasuaki , Shakado Satoshi , Sakisaka Shotaro , Hirai Fumihito
Published: January 2021

Gastric varices (GV) carry a high risk of massive hemorrhage because of potential rupture. To reduce the risk associated with GV, patients need to undergo hemostatic and preventive treatment. The objective of this retrospective study was to evaluate the usefulness of a new method, direct forward-viewing endoscopic ultrasonography (DFV-EUS) for the treatment of GV. We performed endoscopic injection sclerotherapy with histoacryl (EIS-HA) using DFV-EUS for GV in four patients. The paracentesis success rate was 75% (3/4). DFV-EUS has a significant advantage for the treatment of GV in that it can show physicians endoscopic and ultrasound views in real time during the delivery of the sclerosant into the GV. However, the proper use of the ultrasound view must be elucidated through further research for safer and more effective therapy. In the presence of distance between the mucosal surface and vascular lumen or when the blood flow site requires puncture as an additional treatment, DFV-EUS might be a good candidate for the treatment of GV. Altogether, EIS-HA with DFV-EUS might be a new therapeutic option for patients with GV.
Conjunctival Intraepithelial Neoplasia in a Patient Presenting with Pigmented Conjunctival Lesion
Authors: Chaidaroon Winai , Dejkriengkraikul Chutikarn , Isipradit Sirawit , Lertprasertsuke Nirush
Published: January 2021

We report a case of conjunctival intraepithelial neoplasia (CIN) in a patient presenting with the pigmented conjunctival lesion.This study involved a 56-year-old woman that presented with right eye irritation for 1 month. She noticed brownish pigmentation arising from her right nasal conjunctiva and growing slowly over time. Biomicroscopic examination showed a gelatinous pigmented conjunctival mass with feeder vessels. Conjunctival impression cytology (CIC) was done and reported as CIN. Treatment was started with 0.02% mitomycin-C eye drops. The conjunctival lesion responded well to medication. This report shows that CIN can manifest as a pigmented tumor, resembling melanoma. CIC plays a role in the diagnosis of this condition. This tumor responded well with 0.02% mitomycin-C eye drops.
Correlation between Computed Tomographic Analysis and Pulmonary Function Measurements in Patients with Relapsing Polychondritis
Authors: Tsuruoka Hajime , Handa Hiroshi , Yamashiro Tsuneo , Nishine Hiroki , Inoue Takeo , Mineshita Masamichi
Published: January 2021

Background: Relapsing polychondritis (RP) is a rare systemic disease of unknown origin, with cartilaginous involvement in multiple organs. Airway involvement is the most important prognostic factor in RP. Objectives: Spirometric measurements and minimum tracheal cross-sectional area (mtCSA) have been reported as useful to assess the degree of airway stenosis. Because the length and severity of tracheal involvement in RP can vary, mtCSA might not provide enough information to assess tracheal abnormalities. We introduced tracheal volume (TrV) as a new method to evaluate correlations between chest computed tomography (CT) measurements and pulmonary function tests, including impulse oscillometry (IOS). Method: We analyzed chest CT images, spirometry, and IOS collected at our institution from April 2004 to March 2019. We calculated correlations between chest CT measurements using software (TrV, TrV/tracheal length [TrV/TL], and mtCSA) and pulmonary function parameters. Results: Twenty-five of 73 clinically diagnosed patients with RP were included. Spirometric findings showed moderate airway obstruction. Peak flow (PEF) was strongly correlated with mtCSA, TrV, and TrV/TL (ρ = 0.74, p < 0.001). FEV1 was significantly correlated with mtCSA (ρ = 0.56, p = 0.004), TrV (ρ = 0.52, p = 0.007), and TrV/TL (ρ = 0.53, p = 0.006). Whereas respiratory resistance at 5 Hz (R5) and 20 Hz (R20) and resonant frequencies (RFs) were significantly correlated with TrV (ρ = −0.46, p = 0.021; ρ = −0.46, p = 0.046; and ρ = −0.42, p = 0.037, respectively), IOS parameters and mtCSA were not. Conclusions: In patients with RP, TrV and mtCSA were strongly correlated with spirometric measurements. Respiratory resistances assessed by IOS correlated only with TrV. This suggests TrV assessment reflects pulmonary function in patients with RP more appropriately than mtCSA.
Computer Vision-Based Assessment of Motor Functioning in Schizophrenia: Use of Smartphones for Remote Measurement of Schizophrenia Symptomatology
Authors: Abbas Anzar , Yadav Vijay , Smith Emma , Ramjas Elizabeth , Rutter Sarah B. , Benavidez Caridad , Koesmahargyo Vidya , Zhang Li , Guan Lei , Rosenfield Paul , Perez-Rodriguez Mercedes , Galatzer-Levy Isaac R.
Published: January 2021

Introduction: Motor abnormalities have been shown to be a distinct component of schizophrenia symptomatology. However, objective and scalable methods for assessment of motor functioning in schizophrenia are lacking. Advancements in machine learning-based digital tools have allowed for automated and remote “digital phenotyping” of disease symptomatology. Here, we assess the performance of a computer vision-based assessment of motor functioning as a characteristic of schizophrenia using video data collected remotely through smartphones. Methods: Eighteen patients with schizophrenia and 9 healthy controls were asked to remotely participate in smartphone-based assessments daily for 14 days. Video recorded from the smartphone front-facing camera during these assessments was used to quantify the Euclidean distance of head movement between frames through a pretrained computer vision model. The ability of head movement measurements to distinguish between patients and healthy controls as well as their relationship to schizophrenia symptom severity as measured through traditional clinical scores was assessed. Results: The rate of head movement in participants with schizophrenia (1.48 mm/frame) and those without differed significantly (2.50 mm/frame; p = 0.01), and a logistic regression demonstrated that head movement was a significant predictor of schizophrenia diagnosis (p = 0.02). Linear regression between head movement and clinical scores of schizophrenia showed that head movement has a negative relationship with schizophrenia symptom severity (p = 0.04), primarily with negative symptoms of schizophrenia. Conclusions: Remote, smartphone-based assessments were able to capture meaningful visual behavior for computer vision-based objective measurement of head movement. The measurements of head movement acquired were able to accurately classify schizophrenia diagnosis and quantify symptom severity in patients with schizophrenia.
Efficacy and Safety of Lipegfilgrastim in Lung Cancer Patients Receiving Myelosuppressive Chemotherapy in a Real-World Setting: Results of an Analysis of Pooled Data from Two Non-Interventional European Studies
Authors: Gessner Christian , Potthoff Karin , Frost Nikolaj
Published: January 2021

Background/Aim: Chemotherapy-induced neutropenia is a common and serious complication in cancer patients receiving myelosuppressive chemotherapy. This analysis was undertaken to evaluate the effectiveness and safety of prophylaxis with lipegfilgrastim, a glycoPEGylated granulocyte colony-stimulating factor, in lung cancer patients undergoing chemotherapy in real-world clinical practice. Methods: Data from two European non-interventional studies (NIS NADIR and NIS LEOS) investigating lipegfilgrastim for primary and secondary prophylaxis were pooled. Outcomes included the incidence of chemotherapy-induced neutropenia and febrile neutropenia (FN), use of anti-infectives and antimycotics, and adverse events and their relationship to lipegfilgrastim. Results: The safety population included 361 patients with lung cancer (median age, 66 years [range, 36–88]), of whom 322 had received 2 or more consecutive cycles of lipegfilgrastim (efficacy population [primary prophylaxis, 75.5%; secondary prophylaxis, 16.5%]). Almost 40% of the patients were considered to have a high risk (>20%) of FN, and around 60% had an intermediate risk (10–20%). For all cycles, FN was reported in 3 patients (0.9%), neutropenia in 14 (4.3%), and grade 4 neutropenia in 9 (2.8%). Anti-infectives were used in 27 patients (8.4%) and antimycotics in 6 (1.9%). The incidence rates were lower for the patients’ first cycle (FN, 0.4%; neutropenia, 0.8%; grade 4 neutropenia, 0.8%; anti-infectives, 0.6%; antimycotics, 0.6%). Adverse drug reactions considered lipegfilgrastim related were reported in 35 patients (9.7%), and serious adverse drug reactions in 10 (2.8%). None of the fatal events reported in 28 patients (7.8%) were lipegfilgrastim related. Conclusion: Lipegfilgrastim administered to patients with lung cancer undergoing chemotherapy in real-world clinical practice showed similar effectiveness and safety to that reported in published pivotal trials.
Duchenne and Becker Muscular Dystrophies’ Prevalence in MD STARnet Surveillance Sites: An Examination of Racial and Ethnic Differences
Authors: Zhang Yanan , Mann Joshua R. , James Katherine A. , McDermott Suzanne , Conway Kristin M. , Paramsothy Pangaja , Smith Tiffany , Cai Bo ,   the MD STARnet
Published: January 2021

Introduction: Previous studies indicated variability in the prevalence of Duchenne and Becker muscular dystrophies (DBMD) by racial/ethnic groups. The Centers for Disease Control and Prevention’s (CDC) Muscular Dystrophy Surveillance, Tracking, and Research network (MD STARnet) conducts muscular dystrophy surveillance in multiple geographic areas of the USA and continues to enroll new cases. This provides an opportunity to continue investigating differences in DBMD prevalence by race and ethnicity and to compare the impact of using varying approaches for estimating prevalence. Objective: To estimate overall and race/ethnicity-specific prevalence of DBMD among males aged 5–9 years and compare the performance of three prevalence estimation methods. Methods: The overall and race/ethnicity-specific 5-year period prevalence rates were estimated with MD STARnet data using three methods. Method 1 used the median of 5-year prevalence, and methods 2 and 3 calculated prevalence directly with different birth cohorts. To compare prevalence between racial/ethnic groups, Poisson modeling was used to estimate prevalence ratios (PRs) with non-Hispanic (NH) whites as the referent group. Comparison between methods was also conducted. Results: In the final population-based sample of 1,164 DBMD males, the overall 5-year prevalence for DBMD among 5–9 years of age ranged from 1.92 to 2.48 per 10,000 males, 0.74–1.26 for NH blacks, 1.78–2.26 for NH whites, 2.24–4.02 for Hispanics, and 0.61–1.83 for NH American Indian or Alaska Native and Asian or Native Hawaiian or Pacific Islander (AIAN/API). The PRs for NH blacks/NH whites, Hispanics/NH whites, and NH AIAN/API/NH whites were 0.46 (95% CI: 0.36–0.59), 1.37 (1.17–1.61), and 0.61 (0.40–0.93), respectively. Conclusions: In males aged 5–9 years, compared to the prevalence of DBMD in NH whites, prevalence in NH blacks and NH AIAN/API was lower and higher in Hispanics. All methods produced similar prevalence estimates; however, method 1 produced narrower confidence intervals and method 2 produced fewer zero prevalence estimates than the other two methods.
Effectiveness of Biological Agents in the Treatment of Pediatric Patients with Crohn’s Disease and Anal Fistulae
Authors: Arai Nobuyasu , Kudo Takahiro , Tokita Kazuhide , Kyodo Reiko , Sato Masamichi , Miyata Eri , Hosoi Kenji , Ikuse Tamaki , Jimbo Keisuke , Ohtsuka Yoshikazu , Shimizu Toshiaki
Published: January 2021

Introduction: Anal fistulae have a significant impact on the quality of life of patients with Crohn’s disease (CD). In this cross-sectional study, we aimed to determine whether biological agents were effective in treating anal fistulae in patients with CD. Methods: Fifty-three patients diagnosed with CD were retrospectively enrolled. Their data regarding symptoms, treatments, and disease progression from January 2007 to December 2016 were reviewed from the medical records. Fifteen (28%) patients with CD were complicated by anal fistulae. Results: The male-to-female ratio was 13:2, and the mean age at onset was 11 years and 6 months. Among the 15 patients, 14 (93%) had anal fistulae as an initial symptom. Almost all patients were treated by providing elemental diet, 5-aminosalicylic acid, and steroids as induction therapy. Biological agents were used in 8 patients (53.3%), and fistula closure was confirmed in all of them. Among the 7 patients not treated with biological agents, 1 (14.3%) had a recurrent anal fistula, while another had incomplete fistula closure. Regarding surgical management, 2 patients were treated using the seton method, and no patients required a colostomy. Conclusion: Treatment with biological agents is highly effective concerning the closure of anal fistulae in patients with CD, and reducing pain may improve their quality of life.
Complete Genomes of the Anaerobic Degradation Specialists Aromatoleum petrolei ToN1T and Aromatoleum bremense PbN1T
Authors: Weiten Arne , Kalvelage Kristin , Becker Patrick , Reinhardt Richard , Hurek Thomas , Reinhold-Hurek Barbara , Rabus Ralf
Published: January 2021

The betaproteobacterial genus Aromatoleum comprises facultative denitrifiers specialized in the anaerobic degradation of recalcitrant organic compounds (aromatic and terpenoid). This study reports on the complete and manually annotated genomes of Ar. petrolei ToN1T (5.41 Mbp) and Ar. bremense PbN1T (4.38 Mbp), which cover the phylogenetic breadth of the genus Aromatoleum together with previously genome sequenced Ar. aromaticum EbN1T [Rabus et al., Arch Microbiol. 2005 Jan;183(1):27–36]. The gene clusters for the anaerobic degradation of aromatic and terpenoid (strain ToN1T only) compounds are scattered across the genomes of strains ToN1T and PbN1T. The richness in mobile genetic elements is shared with other Aromatoleum spp., substantiating that horizontal gene transfer should have been a major driver in shaping the genomes of this genus. The composite catabolic network of strains ToN1T and PbN1T comprises 88 proteins, the coding genes of which occupy 86.1 and 76.4 kbp (1.59 and 1.75%) of the respective genome. The strain-specific gene clusters for anaerobic degradation of ethyl-/propylbenzene (strain PbN1T) and toluene/monoterpenes (strain ToN1T) share high similarity with their counterparts in Ar. aromaticum strains EbN1T and pCyN1, respectively. Glucose is degraded via the ED-pathway in strain ToN1T, while gluconeogenesis proceeds via the reverse EMP-pathway in strains ToN1T, PbN1T, and EbN1T. The diazotrophic, endophytic lifestyle of closest related genus Azoarcus is known to be associated with nitrogenase and type-6 secretion system (T6SS). By contrast, strains ToN1T, PbN1T, and EbN1T lack nif genes for nitrogenase (including cofactor synthesis and enzyme maturation). Moreover, strains PbN1T and EbN1T do not possess tss genes for T6SS, while strain ToN1T does and facultative endophytic “Aromatoleum” sp. CIB is known to even have both. These findings underpin the functional heterogeneity among Aromatoleum members, correlating with the high plasticity of their genomes.
GPVI (Glycoprotein VI) Interaction With Fibrinogen Is Mediated by Avidity and the Fibrinogen αC-Region
Authors: Xu Rui-Gang , Gauer Julia S. , Baker Stephen R. , Slater Alexandre , Martin Eleyna M. , McPherson Helen R. , Duval Cédric , Manfield Iain W. , Bonna Arkadiusz M. , Watson Steve P. , Ariëns Robert A.S.
Published: January 2021

Objective:

GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role in platelet aggregation and thrombus growth through interaction with fibrin(ogen). However, there are discrepancies in the literature regarding whether the monomeric or dimeric form of GPVI binds to fibrinogen at high affinity. The mechanisms of interaction are also not clear, including which region of fibrinogen is responsible for GPVI binding. We aimed to gain further understanding of the mechanisms of interaction at molecular level and to identify the regions on fibrinogen important for GPVI binding.

Approach and Results:

Using multiple surface- and solution-based protein-protein interaction methods, we observe that dimeric GPVI binds to fibrinogen with much higher affinity and has a slower dissociation rate constant than the monomer due to avidity effects. Moreover, our data show that the highest affinity interaction of GPVI is with the αC-region of fibrinogen. We further show that GPVI interacts with immobilized fibrinogen and fibrin variants at a similar level, including a nonpolymerizing fibrin variant, suggesting that GPVI binding is independent of fibrin polymerization.

Conclusions:

Based on the above findings, we conclude that the higher affinity of dimeric GPVI over the monomer for fibrinogen interaction is achieved by avidity. The αC-region of fibrinogen appears essential for GPVI binding. We propose that fibrin polymerization into fibers during coagulation will cluster GPVI through its αC-region, leading to downstream signaling, further activation of platelets, and potentially stimulating clot growth.

Graphic Abstract:

A graphic abstract is available for this article.
Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A)
Authors: Kurosawa Ryo , Satoh Kimio , Nakata Takashi , Shindo Tomohiko , Kikuchi Nobuhiro , Satoh Taijyu , Siddique Mohammad A.H. , Omura Junichi , Sunamura Shinichiro , Nogi Masamichi , Takeuchi Yutaro , Miyata Satoshi , Shimokawa Hiroaki
Published: January 2021

Objective:

Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated.

Approach and Results:

First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs.

Conclusions:

These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA.

Graphic Abstract:

A graphic abstract is available for this article.
Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation
Authors: Hosseini Zeinab , Marinello Michael , Decker Christa , Sansbury Brian E. , Sadhu Sudeshna , Gerlach Brennan D. , Bossardi Ramos Ramon , Adam Alejandro P. , Spite Matthew , Fredman Gabrielle
Published: January 2021

Objective:

Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis; therefore, we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques.

Approach and Results:

To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of
Mlkl
, an effector of necroptosis.
Mlkl
−/−
mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic
Mlkl
−/−
mice had a significant increase in proresolving mediators including resolvin D1 (RvD1) and a decrease in prostanoids including thromboxane in plaques and in vitro. We found that exuberant thromboxane released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK (AMP-activated protein kinase), increased fatty acid oxidation, and enhanced oxidative phosphorylation in macrophages.

Conclusions:

These results suggest that NCs derange resolution by limiting key SPMs and impairing the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing proresolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues.

Graphic Abstract:

A graphic abstract is available for this article.
Targeting 5-HT
2B
Receptor Signaling Prevents Border Zone Expansion and Improves Microstructural Remodeling After Myocardial Infarction
Authors: Snider J. Caleb , Riley Lance A. , Mallory Noah T. , Bersi Matthew R. , Umbarkar Prachi , Gautam Rekha , Zhang Qinkun , Mahadevan-Jansen Anita , Hatzopoulos Antonis K. , Maroteaux Luc , Lal Hind , Merryman W. David
Published: January 2021

Background:

Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT
2B
) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI.

Methods:

We used 2 pharmacological antagonists to explore the effect of 5-HT
2B
inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT
2B
ablation driven by
Tcf21

MCM

and
Postn

MCM

was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT
2B
, respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype.

Results:

5-HT
2B
antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT
2B
antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT
2B
from
Tcf21
-lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT
2B
after onset of injury in
Postn
-lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in
Dnajb4
expression and Src phosphorylation.

Conclusions:

Together, our findings illustrate that 5-HT
2B
expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI.
The dominance of big teams in China’s scientific
output
Authors: Liu Linlin , Yu Jianfei , Huang Junming , Xia Feng , Jia Tao
Published: January 2021

Modern science is dominated by scientific productions from teams. A recent finding shows that teams of both large and small sizes are essential in research, prompting us to analyze the extent to which a country’s scientific work is carried out by big or small teams. Here, using over 26 million publications from Web of Science, we find that China’s research output is more dominated by big teams than the rest of the world, which is particularly the case in fields of natural science. Despite the global trend that more papers are written by big teams, China’s drop in small team output is much steeper. As teams in China shift from small to large size, the team diversity that is essential for innovative work does not increase as much as that in other countries. Using the national average as the baseline, we find that the National Natural Science Foundation of China (NSFC) supports fewer small teams than the National Science Foundation (NSF) of the United States does, implying that big teams are preferred by grant agencies in China. Our finding provides new insights into the concern of originality and innovation in China, which indicates a need to balance small and big teams.
Profiling and predicting the problem-solving patterns in
China’s research systems: A methodology of intelligent bibliometrics and
empirical insights
Authors: Zhang Yi , Wu Mengjia , Hu Zhengyin , Ward Robert , Zhang Xue , Porter Alan
Published: January 2021

Uncovering the driving forces, strategic landscapes, and evolutionary mechanisms of China’s research systems is attracting rising interest around the globe. One topic of interest is to understand the problem-solving patterns in China’s research systems now and in the future. Targeting a set of high-quality research articles published by Chinese researchers between 2009 and 2018, and indexed in the Essential Science Indicators database, we developed an intelligent bibliometrics-based methodology for identifying the problem-solving patterns from scientific documents. Specifically, science overlay maps incorporating link prediction were used to profile China’s disciplinary interactions and predict potential cross-disciplinary innovation at a macro level. We proposed a function incorporating word embedding techniques to represent subjects, actions, and objects (SAO) retrieved from combined titles and abstracts into vectors and constructed a tri-layer SAO network to visualize SAOs and their semantic relationships. Then, at a micro level, we developed network analytics for identifying problems and solutions from the SAO network, and recommending potential solutions for existing problems. Empirical insights derived from this study provide clues to understand China’s research strengths and the science policies underlying them, along with the key research problems and solutions that Chinese researchers are focusing on now and might pursue in the future.