bluuebunny/crossref_metadata_2025 huggingface dataset:
PRECYCLE: Multicenter, Randomized Phase IV Intergroup Trial to Evaluate the Impact of E Health-Based Patient Reported Outcome (PRO) Assessment on Quality of Life in Patients with Hormone Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer Treated with Palbociclib and an Aromatase Inhibitor- or Palbociclib and Fulvestrant
Authors: Degenhardt Tom , Fasching Peter A. , Lüftner Diana , Müller Volkmar , Thomssen Christoph , Schem Christian , Witzel Isabell , Decker Thomas , Tesch Hans , Kümmel Sherko , Uleer Christoph , Wuerstlein Rachel , Hoffmann Oliver , Schumacher Johannes , Warm Mathias , Marschner Norbert , Schinköthe Timo , Kates Ronald E. , Otremba Burkhard , Zaiss Matthias , Harbeck Nadia , Schmidt Marcus
Published: June 2021

Background: Efficacy and quality of life (QoL) are key when selecting a therapy for metastatic breast cancer (MBC) patients. In hormone receptor positive (HR+) human epidermal growth factor receptor 2 minus (HER2-) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g. palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. Prerequiste for obtaining such benefit is adherence to therapy over the whole treatment duration. Adherence, maintaining patients’ satisfaction, early detection and management of side effects have thus become important challenges, in particular with these new oral drugs and new ways of continuous support for oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction.Methods: PreCycle is a multicenter, randomized, phase IV trial in HR+ HER2+ MBC. All patients (n=960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g. adherence), genetic background, and drug efficacy, the trial includes both patient reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS).Discussion: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22
Neurological Involvement in Children with Hemolytic Uremic Syndrome
Authors: Costigan Caoimhe Suzanne , Raftery Tara , Carroll Anne G , Wildes Dermot , Reynolds Claire , Cunney Robert , Dolan Niamh , Drew Richard J , Lynch Bryan J , O'Rourke Declan J , Stack Maria , Sweeney Clodagh , Shahwan Amre , Twomey Eilish , Waldron Mary , Riordan Michael , Awan Atif , Gorman Kathleen
Published: June 2021

Our objective was to establish the rate of neurological involvement in STEC-HUS and describe the clinical presentation, management and outcome.

A retrospective chart review of children aged ≤16 years with STEC-HUS in Children’s Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit and/or seizure activity. Data on clinical presentation, management and outcome were collected.

We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (10.9%). The most common presentation was seizures (72.7%). In the neurological group, 19 (86.4%) were treated with plasma exchange and/or Eculizumab. Of the 21 surviving children with neurological involvement, 19 (90.5%) achieved a complete neurological recovery. A higher proportion of children in the neurological group had renal sequelae (26.6% vs. 11.5 %, P=.031). One patient died from multi-organ failure.

Conclusion: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 10.9%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 90.5%) and a low case-fatality rate (4.5%) in our cohort.
Lack of In-Brace X-Rays in Compliant AIS Patients Wearing Full-Time TLSO Braces Associates with Failure
Authors: Alvarez Isabel , Poppino Kiley , Karol Lori , McIntosh Amy L
Published: June 2021

BackgroundIn-brace correction and brace compliance with Thoraco-Lumbo-Sacral Orthotic (TLSO) braces are associated with successful treatment of Adolescent Idiopathic Scoliosis (AIS). This paper compares patients who had consistent radiographic documentation of in-brace correction to those who did not.MethodsAll skeletally immature (Risser 0–2) patients were treated for AIS (25°-45°) with full-time TLSO braces that had compliance temperature monitors. All patients wore their braces at least 12 hours a day. Brace failure was defined as curve progression to a surgical magnitude (≥ 50°). All patients were followed until brace discontinuation.Results90 patients (F:82, M:8) with an average age of 12.1(10.1–15.0) years, Risser grade 0(0–2), BMI percentile 48.5(0.0-98.8), and daily brace wear of 16.5(12.1–21.6) hrs/day were treated for 24.3(8.0-66.6) months. Patients went through 1.7(1–4) braces on average. 42/90(46.7%) patients had some amount of brace time with an unknown in-brace correction, which, on average, was 66.1% of their total treatment course (11.5–100). On univariate analysis, patients that did not have a repeat in-brace x-ray with major brace adjustments or new brace fabrication tended to be more skeletally immature (Risser 0 and tri-radiate open, p = 0.028), wear more braces throughout their treatment (2.0 vs 1.4, p < 0.001), were treated for a longer period of time (27 vs 22 months, p = 0.022), and failed bracing more often (47.6% vs 22.9%, p = 0.014).ConclusionsPatients who did not have new in-brace x-rays with major brace adjustments and/or new brace fabrication were 3.1(95% CI 1.2–7.6) times more likely to fail bracing than patients who were re-checked with new in-brace x-rays.Trial Registration:ClinicalTrials.gov - NCT02412137, Initial Registration Date April 2015
Use of Telepharmacy To Support Patients Using Oral Antineoplastic Agents: A Pilot Study
Authors: Wergles Cristiane Soares Cardozo , Guilarducci Carla Valéria Vieira , Fernandez Cecília de Souza , Calil-Elias Sabrina
Published: June 2021

Purpose This study aims to use teleconsultation to perform pharmaceutical consultations with patients using oral antineoplastic agents, to identify their profile, and carry out activities to support the correct treatment.Methods The telepharmacy flowchart was designed considering the steps of a pharmaceutical consultation. A pilot study was carried out with 66 patients from a military hospital, who had been using oral antineoplastic agents for at least 3 months. Adherence was measured using a self-report semi-structured survey, medication possession ratio (MPR), and the proportion of days covered (PDC). The interventions were carried out through structured phone calls. Results Sixty-seven percent were male, and 33% were aged 65 to 75 years. According to the survey, 16 patients adhered to the oral antineoplastic agent. Based on MPR and PDC, 53 and 52 patients showed good persistence, respectively. When all methods were applied together, 9 patients were adherent. On average, each patient regularly uses 4.73 medicines. Most patients (83 %) reported adverse effects during treatment. Five hundred eighty-one pharmaceutical interventions were carried out, most of them corrective (29%) and related to the correct drug administration technique (29 %).Conclusions The proposed tool helped establish good communication with patients, obtain desired data, and carry out relevant interventions. However, it is necessary to carry out further consultations to verify whether the patients were able to apply the suggested recommendations in practice.
Termite Occurrence And Damage Assessment In Urban Trees From Different Parks Of Lahore, Punjab, Pakistan
Authors: Afzal Muhammad , Rasib Khalid Zamir
Published: June 2021

Termite infestation is one of the fundamental problems associated with the loss of urban trees and ecological services. However, no such study has been performed in Pakistan to investigate the termite occurrence and assess such damages to urban trees caused by termites. For Lahore, research and comparable data on urban tree damages are rare or missing. This study surveyed six different microhabitats, including Bagh-e-Jinnah, Canal vegetation, Model Town Park, Jallo forestry, Race-course Park, and F.C. College vegetation employing three belt transects (100×5 m) method. We geo-referenced termite infested trees to investigate the termite occurrence on living and dead standing trees, termite diversity and assess the tree damage by termites' attack. We recorded four termite species (Odontotermes obesus, Coptotermes heimi, Heterotermes indicola, and Microtermes obesi) representing two families (Rhinotermitidae and Termitidae). However, the diversity indices result revealed that O. obesus (higher termite) and C. heimi (lower termite) were dominant and key species with 46.60 and 36% of occurrence among observed trees, respectively. Kernel density function indicated that the Lahore Canal and Bagh-e-Jinnah plantation shared all four termites' infestation evenly compared to other study sites. We observed the maximum number of damaged trees by termites in canal plantations with the most damaged exotic tree species Populus euramericana along the canal green belt.Additionally, we observed significant (P < 0.05) termite-tree interactions with exotic, living, and dead standing tree species and found termite colony size positively (R = 0.985) correlated with the tree trunk diameter up to breast height DBH. The average population of termites per unit volume of deadwood log was (0.39/cm3) within all plantations-sites. In conclusion, this study provides simple, reckless, and inexpensive knowledge about the assessment of termite damage of trees, which may give a better idea in making decisions on tree selection and management in urban ecosystems.
Nanoindentation Characterization of Single-Crystal Silicon With Oxide Film
Authors: Yin Lianmin , Dai Yifan , Hu Hao
Published: June 2021

In order to obtain ultra-smooth surfaces of single-crystal silicon in ultra-precision machining, an accurate study of the deformation mechanism, mechanical properties, and the effect of oxide film under load is required. The mechanical properties of single-crystal silicon and the phase transition after nanoindentation experiments are investigated by nanoindentation and Raman spectroscopy, respectively. It is found that pop-in events appear in the theoretical elastic domain of single-crystal silicon due to the presence of oxide films, which directly leads the single crystal silicon from the elastic deformation zone into the plastic deformation zone. In addition, the mechanical properties of single-crystal silicon are more accurately measured after it has entered the full plastic deformation.
Total Endoscopic Left Ventricle Lipoma Removal: A Case Report
Authors: Langenaeken Tom , Yilmaz Alaaddin , Basoglu Aydin
Published: June 2021

Background: Left ventricle (LV) lipoma is a very rare, benign cardiac tumor. Due to its rarity, LV lipoma is often misdiagnosed. Aspecific symptoms such as murmurs, arrhythmias, memory loss and palpitation may occur due to the mass effect. Case presentation: We report a case report of a 42 year old woman who was found to have left ventricle mass after check-up for arrhytmia. By a fully endoscopic approach, the mass was successfully resected from the left ventricle without the need for sternotomy. Conclusion: Total endoscopic removal of left ventricle lipoma’s can be done safely and has several advantages to conventional sternotomy. Larger studies are needed to confirm this hypothesis.
Health-Related Quality of Life of Patients With Haemophilia - A Cross-Sectional Survey in the Northeast of China
Authors: Niu Jinyu , Ning Liangwen , Zhang Qiao , Liu Ze , Ma Yi , Xu Xiaoxue , Wu Qunhong , Hao Yanhua , Cui Yu , Liu Chaojie
Published: June 2021

Introduction: Haemophilia is a hereditary, chronic, and hemorrhagic disorder caused by a deficiency in coagulation factors. Long-term spontaneous bleeding of joints and soft tissues can seriously affect the quality of life of patients. Objectives: The study aimed to assess the health-related quality of life of patients with haemophilia and associated factors. Methods: A snowball sampling strategy was adopted to select study participants. Eligible participants were those who were 18 years or older and had mild, moderate or severe haemophilia. They were asked to self-complete a questionnaire, collecting data regarding their sociodemographic characteristics, target joint status, and health related quality of life measured by the EQ-5D-5L. Results: The respondents reported a mean EQ-5D utility score of 0.51 (SD=0.34). Those with severe haemophilia had a lower utility score than those with mild/moderate haemophilia (0.46±0.37 vs 0.56±0.30, p =0.737). The linear regression analyses showed that older age (>25 years), two or more target joints, not working, low levels of knowledge of the disease, and borrowing money to pay for medical treatments were associated with lower EQ-5D utility scores . Conclusion: Low health related quality of life of haemophilia patients is evident in China. Social support needs to be strengthened to address this issue.
Independent Associations of Thyroid-Related Hormones with Hepatic Steatosis and Insulin Resistance in Euthyroid Overweight/Obese Chinese Adults
Authors: Ma Danyan , Zeng Jinyang , Huang Bingkun , Yan Fangfang , Ye Jiawen , Chen Yun , Zeng Xiying , Zheng Xin , Xiao Fangsen , Lin Mingzhu , Liu Changqin , Li Zhibin
Published: June 2021

Purpose: The aim of the study is to explore the independent association of free triodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) with hepatic steatosis and insulin resistance.Methods: A cross-sectional study of 88 overweight/obese adults who underwent anthropometric measurements (BMI, waist circumference (WC) and waist-to-height ratio (WHtR)), hepatic steatosis assessment (FibroScan) and thyroid-related hormones tests was conducted from 2018 to 2020 in Xiamen, China.Results: Subjects with increasing tertiles of FT3 showed significantly higher levels of controlled attenuation parameter (CAP) ((295.4±44.1, 290.1 ± 68.2 and 331.7 ± 43.6 (dB/m) for tertile 1-3, respectively, p=0.007) and fatty liver index (FLI) score (47.7 (33.9-60.8), 61.5 (45.1-88.9) and 90.5 (84.5-94.8), respectively, p<0.001). FT3 significantly and positively correlated with obesity index (BMI, WC, and WHtR), homeostatic model assessment of insulin resistance (HOMA-IR) and hepatic steatosis (CAP and FLI). Multivariable linear regression analyses with adjustment for potential confounding factors showed FT3 was independently associated with BMI (regression coefficient (β(95%CI): 0.024(0.004-0.043), p=0.020), HOMA-IR (β(95%CI): 0.091(0.007-0.174), p=0.034), CAP (β(95%CI): 25.45(2.59-48.31), p=0.030) and FLI (β(95%CI): 0.121(0.049-0.194), p=0.001). Neither FT4 nor TSH was significantly associated with any indicators of obesity, insulin resistance or hepatic steatosis.Conclusions: Increased FT3, but not FT4 or TSH, was independently associated with higher risks of hepatic steatosis and insulin resistance in euthyroid overweight/obese Chinese adults.Trial registration: Registration is not applicable for our study.
Identification of hidden N4-like viruses and their interactions with hosts in global metagenomes
Authors: Zheng Kaiyang , Liang Yantao , Paez-Espino David , Huang Sijun , Zou Xiao , Gao Chen , Jiang Yong , He Hui , Guo Cui , Shao Hongbing , Wang Hualong , Sung Yeong-Yik , Mok Wen-Jye , Wong Li-Lian , Zhang Yuzhong , Tian Jiwei , Jiao Nianzhi , Suttle Curtis A. , He Jianfeng , McMinn Andrew , Wang Min
Published: June 2021

Background: N4-like viruses, with specific genomic features and propagation signatures, comprise a unique viral clade within the Podoviridae family. N4-like viruses are commonly characterized by the N4-like major capsid protein (MCP) and a giant virion-encapsulated RNA polymerase (N4-like RNAP) with a size of approximately 3,500-aa, which is the largest viral protein so far described. To date, our understanding of N4-like viruses is largely derived from 80 viral isolates that infect bacteria. Thus, it is necessary to expand the diversity of N4-like viruses in culturing-independent methods.Methods: A Hidden-Markov-Module based method was designed based on two characterized N4-specific marker genes, major capsid protein and N4-like virion-encapsulated RNA polymerase. Viral sub-clades were classified based on the monophyly presented in phylogenic tree and the results of pangenome analysis. Further analysis assessed different distribution patterns, genomic properties, hosts’ metabolism reprogramming potentialities, significance of viral tRNA and horizontal gene transfer landscape.Results: We identified 1,000 N4-like virus sequences from genomes and metagenomes representing diverse habitats from around the world. N4-like viruses have been classified into 27 sub-clades and detected in almost all habitats from pole to pole, including some novel habitats, such as oral mucosa and Antarctica. Virulent factors might be crucial for some human-associated N4-like viruses to reprogram the metabolism of host cells and mediate their pathogenic ability through horizontal gene transfer. From the pangenome analysis, the protein diversity was expended over 7-fold and 17 conserved house-keeping genes were identified. Transcriptional compensation of tRNA indicates that producing progeny virion might be the main significance of viral tRNAs. From the horizontal gene transfer network, some N4-like viral sub-clades were observed that potentially infect some important human pathogens, such as Campylobacteria and Veillonella , which have not been considered as potential hosts of N4-like virus or even any virus.Conclusion: This study expands the knowledge of N4-like viruses via global metagenomic datasets, reveals the novel ecological and genomic signatures of these viruses and will provide the backbone for further N4-like virus studies.
Degradation of Polyfurfuryl Alcohol-based Biopolymer by Soil-burial and Photo-degradation Methods
Authors: Singh Priyaragini , Kumar K. Dinesh , Kumar Rakesh
Published: June 2021

Recently, polyfurfuryl alcohol (PFA) based material has been gaining attention. Despite its use as an intermediate in various industries, the degradation process of PFA has rarely been reported. In this study, neat PFA (PF) and polylactic acid (PLA) incorporated PFA (PF-PL) based thermoset biopolymers were prepared by casting method. The degradation of the prepared biopolymer specimens was carried out under environmental conditions via soil-burial test and photo-degradation method for 21-months. The extent of degradation of PF and PF-PL was assessed by evaluating weight loss, structural and morphological change by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM), respectively. Weight loss percentage in case of photo-degraded samples was found to be much higher compared to soil buried specimens. SEM micrographs showed a blistered surface with visible cracks on the surface of soil buried and photo-degraded samples. FTIR spectra of photo-degraded samples showed a new peak at 673 cm-1 indicating the furan ring opening during the degradation process. Significant variation in mechanical properties of PF and PF-PL specimens after soil-burial test also indicated biodegradable nature of the biopolymers. Approximately 45% and 63% of loss in tensile strength was obtained in PF and PF-PL soil buried specimens, respectively. All the obtained data revealed the fragmentation of biopolymers, hence supporting the biodegradable nature of PFA-based biopolymer.
Caregiver Perspective on The Initial Signs and Symptoms of Metachromatic Leukodystrophy
Authors: Eichler Florian , Pang Francis , Howie Kenneth , Walz Markus , Wilds Alexandra , Calcagni Carlo , Chanson Charlotte , Campbell Laura
Published: June 2021

Background
Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes a caregiver perspective of initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis.
Results
Data was collected through a moderator-assisted online 60-minute survey and 30-minute semi-structured follow-up telephone interview with 21 MLD caregivers in the United States (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 13), juvenile (n = 7) or borderline late infantile/juvenile (n = 1) MLD. Caregivers were asked questions related to their child’s initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms, which can be summarized as developmental stagnation, difficulty walking/running, and clonus/tremors, in the absence of notable prior history. Distinctions between late infantile versus juvenile MLD in symptom onset and disease course were also identified.
Conclusions
This study captures the most frequent caregiver-reported physical, behavioral, and cognitive signs of MLD leading up to diagnosis. The understanding of the caregiver experience at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.
Reliability and Validity of The Korean Translation of The Achilles Tendon Total Rupture Score
Authors: Park Young Hwan , Cho Hyun Woo , Choi Jung Woo , Kim Hak Jun
Published: June 2021

Background

The Achilles tendon Total Rupture Score (ATRS) is a widely used patient-reported outcome measure to assess clinical outcomes of Achilles tendon rupture, but it has not been validated in Korean yet. The purpose of this study was to translate the ATRS into Korean and evaluate its reliability and validity in a Korean population.
Methods

The ATRS was translated into Korean according to recommended guidelines for forward-backward translation. Thirty-eight patients who underwent surgical treatment for Achilles tendon rupture from 2017 to 2019 were enrolled. Reliability was evaluated by the intraclass correlation coefficient (ICC), standard error of the measurement (SEM), minimal detectable change (MDC), and Cronbach’s alpha. Construct validity was assessed with Spearman rank correlations with the Foot and Ankle Outcome Score (FAOS) and Numeric Rating Scale (NRS) for pain in daily activity.
Results

The Korean translation of the ATRS had excellent test-retest reliability (ICC = 0.838) and acceptable internal consistency (Cronbach’s alpha = 0.84). The SEM was 6.63, and the MDC was 18.38 at the individual level and 2.98 at the group level. The Korean translation of the ATRS was strongly correlated with the FASO (r = 0.876). Correlation with the NRS in daily activity (r = -0.659) was moderate.
Conclusion

The Korean translation of the ATRS showed sufficient reliability and validity for use in the Korean population.
Surface Modification of Film Chitosan Materials With Aldehydes for Wettability and Biodegradation Control
Authors: Bryuzgina Ekaterina , Yartseva Vitaliya , Bryuzgin Evgeny , Tuzhikov Oleg , Navrotskiy Alexander
Published: June 2021

Chitosan is one of prospective polymer for use in regenerative medicine which has unique properties such as biocompatibility, biodegradability, antimicrobial, anti-inflammatory, and antitumor potency. In this article, we study the peculiarities of the surface modification of chitosan films with carbonyl-containing compounds, which differed both in molecular characteristics and in their hydrophilic and hydrophobic properties. The potential for controlling the biodegradation of the resulting materials has been established, which can be used in the creation of wound dressings. Both the destruction time and lyophilic properties of the surface depend on the length of the modifier's hydrocarbon radical. The contact angle and water absorption of obtained film materials correlate with hydrophobicity, which estimated by the calculated value of the hydrophilic–lipophilic balance (HLB). The cytotoxicity of modified chitosan films was studied, and it was found that they are non-toxic (cytotoxic index of <50%) for human skin cell cultures, which shows their potential for use in the creation of materials for skin protection and external wound healing.
Cav-1 Protein Levels in Serum and Infarcted Brain Correlate with Hemorrhagic Volume in a Mouse Model of Thromboembolic Stroke, Independently of Rt-PA Administration
Authors: Gubern-Mérida Carme , Comajoan Pau , Huguet Gemma , García-Yebenes Isaac , Lizasoain Ignacio , Moro María Angeles , Puig-Parnau Irene , Sánchez Juan Manuel , Serena Joaquin , Kadar Elisabet , Castellanos Mar
Published: June 2021

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is currently the only FDA-approved drug for acute ischemic stroke. However, its administration is still limited due to the associated increased risk of hemorrhagic transformation (HT). rt-PA may exacerbate blood-brain barrier (BBB) injury by several mechanisms that have not been fully elucidated. Caveolin-1 (Cav-1), a major structural protein of caveolae, has been linked to the endothelial barrier function. The effects of rt-PA on Cav-1 expression remains largely unknown. Here, Cav-1 protein expression after ischemic conditions, with or without rt-PA administration, was analyzed in a murine thromboembolic middle cerebral artery occlusion (MCAO) and in brain microvascular endothelial bEnd.3 cells subjected to oxygen/glucose deprivation (OGD). Our results show that Cav-1 is overexpressed in endothelial cells after ischemia in both models. rtPA significantly reduced Cav-1 expression and increases pCav-1/Cav-1 ratio in bEnd.3 cells, but not in the in vivo model. In addition, we first show that increased Cav-1 immunoreactivity in the infarcted area and Cav-1 serum levels are positively correlated at 24 h post-MCAO. Interestingly, Cav-1 expression in infarcted area and baseline serum Cav-1 levels negatively correlate with hemorrhagic volume, supporting a protective role of Cav-1 in cerebral ischemia and pointing to a potential usefulness of baseline serum Cav-1 levels as predictor of hemorrhagic volume, independently of rt-PA administration.
Concomitant Medication Use with Xiyanping Injection and the Risk of Suspected Allergic Reactions: A Nested Case-Control Study Based on China’s National Medical Insurance Database
Authors: Tong Xunliang , Zhu Xiaochen , Wang Chunping , Zhou Yifan , Zhan Siyan , Zhu He , Cheng Yinchu , Han Sheng
Published: June 2021

Introduction Xiyanping injection (XYP), a type of Traditional Chinese Medicine, is often applied in combination with other medications in treating bronchitis, tonsillitis, and bacillary dysentery in China, which is evidently associative with allergic reactions. In recent years, XYP’s adverse drug reactions (ADRs), represented by allergic reactions, have emerged throughout the country.Objective This study aims to investigate the association between the concomitant use of XYP and 25 most frequently co-applied medications with suspected allergic reactions for China’s patients receiving XYP.Methods A nested case-control study was conducted using the sampling data from 2015 China’s Urban Employees Basic Medical Insurance and Urban Residents Basic Medical Insurance database. Four anti-allergic marker drugs were used to evaluate suspected allergic reactions. Univariate analyses and multivariable conditional logistic regression were conducted, and results were reported as odds ratios (ORs) with 95% confidence interval (CI). Sensitivity analyses were performed on the expanded sample by including those prescribed with anti-allergic marker drugs on the same day as XYP and then stopped XYP on the next day.Results Out of 57,612 participants with XYP prescription, we got 949 matched case-control pairs. Multivariable conditional logistic regression revealed that seven concomitant medications including gentamicin (OR = 4.3; 95% CI [2.5, 7.3]), cefoperazone-sulbactam (OR = 4.3; 95% CI [1.4, 13.0]), lidocaine (OR = 2.8; 95% CI [1.8, 4.2]), aminophylline (OR = 1.7; 95% CI [1.1, 2.9]), ribavirin (OR = 1.5; 95% CI [1.1, 2.1)), potassium chloride (OR = 1.4; 95% CI [1.1, 1.9]), and vitamin C (OR = 1.3; 95% CI [1.0, 1.7]) were associated with increased risk, while cefathiamidine (OR = 0.3; 95% CI [0.2, 0.5]) was associated with reduced risk. Sensitivity analysis on 2,438 matched pairs revealed similar findings. Conclusion Increased risks for suspected allergic reactions were found for the concomitant use of XYP with seven medications. Our data suggest that gentamicin, cefoperazone-sulbactam, lidocaine and ribavirin should be applied with precautions for patients receiving XYP, and further studies on drug interactions and allergy mechanisms are warranted.
Genome Instability-related MiRNAs Predict Survival, Immune Landscape, and Immunotherapy Responses In Gastric Cancer
Authors: Liu Yaqiong , Cheng Lin , Huang Wei , Cheng Xin , Peng Weijun
Published: June 2021

Backgroud Increasing evidence suggests that microRNAs (miRNAs) are involved in genome instability (GI) and drive the occurrence of tumors. However, the role of GI-related miRNAs in gastric cancer (GC) remains largely unknown. Herein, we developed a novel GI-related miRNA signature (GIMiSig) and further investigated its role in prognosis, the immune landscape, and immunotherapy responses in GC patients. Methods An analysis of somatic mutation data on 434 gastric cancer cases from The Cancer Genome Atlas (TCGA) database was performed, thereby generating genome stability (GS) and GI groups. By detecting differentially expressed miRNAs between the GS and GI groups that were associated with overall survival, 8 miRNAs were identified and used to construct the GIMiSig. Results The GIMiSig showed high accuracy in detecting GC patients. Using GIMiSig to stratify the patients into high- and low-risk subgroups to predict survival outperformed the use of regular clinical features such as age, gender, or disease stage. Patients with low risk had a more favorable survival time than those with high risk. More importantly, the high-risk patients were associated with decreased UBQLN4 expression, higher accumulation of immune cells, lower Titin (TTN) mutation frequency, worse immunotherapy efficacy, and cancer-associated pathways. Conversely, the low-risk patients were characterized by UBQLN4 overexpression, lower fraction of immune cells, higher TTN mutation frequency, better response to immunotherapy, and GI-related pathways. Conclusion In summary, we constructed a novel GIMiSig that could stratify GC patients into distinct risk groups that have different survival outcomes and immunotherapy efficacy. The results may provide new clues for improving GC outcomes.
Guiding Mesenchymal Stem Cells Differentiation into Chondrocytes using Sulfated Alginate / Cold Atmospheric Plasma Modified Polycaprolactone Nanofibrous Scaffold
Authors: Miri Leila , Irani Shiva , Modaress Mohamad Pezeshki , Daemi Hamed , Atyabi Seyed Mohammad
Published: June 2021

Using tissue engineering approaches is one of interesting strategies to repair cartilage injuries. This study reports the preparation of surface-modified electrospun polycaprolactone nanofibrous scaffolds with highly negatively-charged sulfated alginate as functional support for chondrogenic differentiation of mesenchymal stem cells. In this regard, polycaprolactone (PCL) nanofibers were fabricated by electrospinning, surface-activated by cold atmospheric plasma and further surface-modified with aqueous solutions of sulfated alginate. The scanning electron microscopy (SEM) images showed the nanofibrous structure of electrospun PCL mats. The successful surface modification of PCL nanofibrous scaffolds with sulfated alginate was confirmed by the appearance of fingerprint region of mannuronic acid at 812 cm− 1 in attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) spectra. The cytocompatibility of the nanofibrous scaffolds for mesenchymal stem cells (MSCs) was confirmed using MTT assay. Reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry for type 2 collagen marker were conducted to confirm the chondrogenic differentiation of seeded MSCs on the surface of scaffolds. The expression of type 2 collagen by RT-PCR and immunocytochemistry analyses confirmed the chondrogenic differentiation of MSCs. Our results showed that sulfated alginate surface-modified PCL (SM-PCL) nanofibrous scaffold as an appropriate substrate for cell attachment and growth could promote the MSCs differentiate to chondrocytes.
Mobility of the gradient tracking machine in mating yeast depends on Bud1 inactivation and actin-independent vesicle delivery
Authors: Wang Xin , Stone David
Published: June 2021

The mating of budding yeast depends on chemotropism, a fundamental cellular process. Haploid yeast cells of opposite mating type signal their positions to one another through the secretion of mating pheromones. We have proposed a deterministic gradient sensing model that explains how these cells orient toward their mating partners. Using the cell-cycle determined default polarity site (DS), cells assemble a gradient tracking machine (GTM) composed of signaling, polarity, and trafficking proteins. After assembly, the GTM redistributes up the gradient, aligns with the pheromone source, and triggers polarized growth toward the partner. Because strong positive feedback mechanisms drive polarized growth at the DS, it is unclear how the GTM is released for tracking after its assembly is complete. What prevents the GTM from triggering polarized growth at the DS? Here we describe two mechanisms that enable tracking. First, the Ras GTPase Bud1 must be inactivated to release the GTM. Second, actin-independent – but not actin-dependent – vesicle delivery must be targeted upgradient to effect GTM redistribution.
Identification of Chronic Stress Biomarkers in Dairy Cows
Authors: Grelet Clément , Dries Virginie Vanden , Leblois Julie , Wavreille José , Mirabito Luc , Soyeurt Hélène , Franceschini Sébastien , Gengler Nicolas , Brostaux Yves , consortium HappyMoo , Dehareng Frédéric
Published: June 2021

Stress in dairy herds can occur from multiple sources. When stress becomes chronic because of a long duration and inability of animals to adapt, it is likely to affect the emotional state, health, immunity, fertility and milk production of cows. While assessing chronic stress in herds would be beneficial, no real consensus has emerged from the literature regarding the indicators of interest. The goal of this study was to compare and evaluate potential biomarkers for chronic stress after inducing stress over a 4-week period through severe overstocking, restricted access to feed and punctual unusual events. A total of 30 cows were involved in the experiment and two similar groups were constituted. Over a 4-week period, the 15 cows of the stress group were housed in overstocked conditions, with 4.6 m² per cow, including resting and feeding areas. In this area, only 7 individual places at the feeding area were available for the 15 cows to generate competition for feed access. Once weekly and during 2 hours, an additional stress was induced by moving cows to an unfamiliar barn and diffusion of stressing noises (dog barking). Meanwhile, the 15 cows of the control group stayed in the original barn, with more than 10 m² per cow and more individual places at the feeding area than cow number. On a weekly basis, several variables considered as potential biomarkers for chronic stress were recorded. Collected data were analyzed using single trait linear repeated mixed models. No differences were observed regarding milk yield, bodyweight of cows or body condition score but the milk loss was more pronounced in the stress group. Whereas no differences were observed in terms of activity between the groups, the standard deviation of activity per cow per week was higher and the rumination of cows was lower in the stress group. The heart rate was lower in the stress group and showed more heterogeneity at the end of the stress period. No differences were observed regarding salivary cortisol, blood glucose, β-endorphin, thyroxine and leucocyte profile. A higher level of hair cortisol and blood fructosamine were observed in the stress group at the end of the stress period. Among the variables highlighted, milk losses and fructosamine were not specific biomarkers for stress while heart rate variables were difficult to collect in practice, consequently the hair cortisol content seemed to be the most promising indicator to assess chronic stress at a large scale.
Biomechanical Study on the Treatment of Acromioclavicular Joint Dislocation by Coracoclavicular Ligament Reconstruction With a Novel EndoButton Plate Combined With Suture Anchor
Authors: Song Zhe , Wang Chen , Yang Na , Zhu Yangjun , Zhang Kun , Qiu Yusheng
Published: June 2021

Purpose This study aimed to assess the biomechanical stability of a novel internal fixation system of EndoButton plate combined with suture anchor in treating acromioclavicular joint dislocation in the cadaveric specimens. In addition, it provides a new method for the clinical treatment of acromioclavicular joint dislocation. Methods Twelve complete shoulder joint specimens were randomly divided into groups A, B, C, and D (n = 3). Firstly, a quasi-static non-destructive circulation experiment was carried out of coracoclavicular ligament until its function failed. Four different internal fixation materials were used to reduce and fix the acromioclavicular joint. Group A was treated with 3.5 mm clavicular hook locking compression plates, Group B with 5 mm suture anchor Group C with 10 mm Endo-button plate, and Group D with a novel combination of 5 mm suture anchor and 10 mm Endo-button plate. Fluoroscopy was performed to undertake the X-ray of the restored acromioclavicular joint, to evaluate the internal fixation position and acromioclavicular joint reduction. Finally, the shoulder joint was fixed firmly on an electronic universal testing machine (100KN) with a self-made stationary fixture, to conduct a destructive static tensile mechanical test of each specimen vertically at a 100 mm/min load speed. The stress-deformation curve was recorded using a computer connected with the universal mechanical testing machine, and the failure strength and reasons for internal fixation were also recorded. Results The average load-to-failure of the coracoclavicular ligament in groups A, B, C, and D was 373.4 ±0.57 N, 373.6 ±0.62 N, 374.4 ±0.68 N, and 373.9 ±0.15 N, respectively (P>0.05). After internal fixation failure, Group A showed two specimens with clavicular fracture, and one with acromial fracture, with an average load-to-failure of 409.8 ±2.92 N. Group B and D showed three specimens with prolapse of anchor, with average load-to-failure of 293.5 ±4.10 N and 374.2 ±0.40 N, respectively. Group C showed three specimens with basilar coracoid fracture, with average load-to-failure of 373.2 ±2.35 N. Statistical differences existed in the biomechanical load of internal fixation failure among the four groups. Group D was statistically different from Group A and Group B, but not Group C. Conclusion The newly designed EndoButton plate combined with suture anchor for coracoclavicular ligament reconstruction was found to boast simple operation and has high feasibility. Thus it was found effective in the reduction of acromioclavicular joint and treatment of acromioclavicular joint dislocation and fitted the biomechanical characteristics of the acromioclavicular joint.
The miR-423-5p/MMP-2 Axis Regulates Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis
Authors: Tzeng Huey-En , Lin Syuan-Ling , Thadevoos Louis Anoop , Ko Chih-Yuan , Liu Ju-Fang , Lin Chih-Yang , Fong Yi-Chin , Tang Chih-Hsin
Published: June 2021

Background: The effects of Nerve growth factor (NGF) in chondrosarcoma are not confirmed, although NGF is capable of promoting the progression and metastasis of several different types of tumors. Here we aim to explore the role of NGF in chondrosarcoma and elucidate how NGF acts.Methods: Immunohistochemistry (IHC)-stained tissue samples from chondrosarcoma patients were stained with NGF and MMP-2 antibodies. Cell migration was examined by Transwell and wound healing assays. The expression levels of MMP-2, microRNA-423-5p (miR-423-5p) were measured by quantitative real-time polymerase chain reaction. MMP-2, FAK, and c-Src protein expression were examined by Western blot assays. The interaction between MMP-2 3’-UTRs and miR-423-5p binding site was explored by luciferase assay. We established the orthotopic in vivo model of chondrosarcoma lung metastasis to further investigate the promoting effects of NGF in metastatic chondrosarcoma.Results: Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with tumor stage in patients with chondrosarcoma. NGF facilitated MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells, while overexpression of NGF enhanced lung metastasis in a mouse model of chondrosarcoma. NGF promoted MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of metastatic chondrosarcoma.Conclusions: Our study has identified that NGF promotes MMP-2-dependent cell migration in human chondrosarcoma tissue by inhibiting miR-423-5p synthesis via the FAK and c-Src signaling cascades
Trifluoro-Icaritin Ameliorates Complete Freund’s Adjuvant-Induced Inflammatory Pain by α7nAChR-Mediated Inhibition of HMGB1/NF-κB Signaling in the Spinal Cord of Rats
Authors: Sun Yalan , Jia Dandan , Xue Meng , Liu Guangsen , Huang Zhihua , Huang Cheng
Published: June 2021

Objectives: To explore whether Trifluoro-icaritin (ICTF) has anti-nociceptive effect on CFA-induced inflammatory pain and its potential mechanisms. Methods: Intraperitoneal injection (0.3, 1.0, and 3.0 mg/kg, i.p.) of ICTF to complete Freund’s adjuvant (CFA)-induced inflammatory pain rats once daily for 21 consecutive days. Pain-related behaviors were evaluated with paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis. Hematoxylin eosin (HE) staining was applied to determine the morphological alterations in inflamed paw. Molecular docking was conducted to assess the possible targets for ICTF. Expression of pain-related signaling molecules in the spinal cord were detected using qRT-PCR, western blot assay, and immunoﬂuorescence staining. Results:This results showed that ICTF(3.0 mg/kg) effectively alleviated mechanical allodynia and thermal hyperalgesiabut not 0.3 and 1.0 mg/kg in CFA rats. Both paw edema volume and paw tissue inflammatory response were obviously reduced by ICTF. Subsequently, we further observed that ICTF dramatically decreased the mRNA and protein levels of HMGB1, NF-κB p65, and IL-1β but markedly enhanced α7nAChR and IL-10 expression in the spinal cord of CFA rats, and inhibitedthe co-expression of spinal α7nAChR with IBA-1 in double immunofluorescence staining,along with suppressing the alterations of gait parameters induced by CFA. Moreover, Intrathecal injection (i.t.) of α7nAChR antagonist alpha-bungarotoxin (α-Bgtx, 1.0 μg/kg) not only reversed the anti-nociceptive effect of ICTF on pain hypersensitivity, but also inhibited the down-regulation of HMGB1, NF-κB p65, and IL-1β as well as the up-regulation of α7nAChR and IL-10 protein expression induced by ICTF treatment.Conclusion: Our results illustrate that ICTF enables to alleviate CFA-induced inflammatory pain through α7nAChR-mediated inhibition of HMGB1/NF-κB signaling pathway in the spinal cord of rats, suggesting that ICTF may be exploited as a potential painkiller against chronic inflammatory pain.
The Novel LSD1 Inhibitor ZY0511 Suppresses Diffuse Large B Cell Lymphoma Proliferation by Inducing Apoptosis and Autophagy
Authors: Liu Huan , Wei Jing , Sang Na , Zhong Xi , Zhou Xia , Yang Xinyu , Zhang Jing , Zuo Zeping , Zhou Yang , Yang Shengyong , Du Junrong , Zhao Yinglan
Published: June 2021

Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is an attractive agent for treatment of cancer. Nevertheless, the anti-tumor effect of LSD1 inhibitors against diffuse large B-cell lymphoma (DLBCL) and the underlying mechanism are still unclear. Here, we report that KDM1A is overexpressed in human DLBCL tissues, and negatively related to overall survival rate in DLBCL patients. ZY0511, a novel and potent LSD1 inhibitor, developed by our group inhibited the proliferation of human DLBCL cells and blocked cell cycle at G0/G1 phase. Cellular thermal shift assay (CETSA) showed that ZY0511 interacted with LSD1 in DLBCL cells. Furthermore, intraperitoneal administration of ZY0511 significantly suppressed SU-DHL-6 xenograft tumor growth in vivo. Mechanistically, transcriptome sequencing results indicated that ZY0511 induced the genes enrichment significantly related to cell cycle, autophagy and apoptosis signaling pathways. Further study confirmed that ZY0511 decreased mitochondrial membrane potential and induced apoptosis, which can be reverted by a pan-caspase inhibitor, Z-VAD-FMK. Moreover, ZY0511 treatment significantly increased autophagy-associated marker proteins and autophagosomes formation in DLBCL cells. In conclusion, our finding identifies that ZY0511 inhibits DLBCL growth both in vitro and in vivo via the induction of apoptosis and autophagy, and LSD1 inhibitor might be a promising strategy for treating DLBCL.