bluuebunny/crossref_metadata_2025 huggingface dataset:
The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis
Authors: Hennermann Julia , Guffon Nathalie , Cattaneo Federica , Ceravolo Ferdinando , Borgwardt Line , Lund Allan M. , Gil-Campos Mercedes , Tylki-Szymanska Anna , Muschol Nicole M.
Published: July 2020

Background: Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively.Results: The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality of life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion: This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.
Modeling the Cost-effectiveness of Esophageal Cancer Screening in China
Authors: LI Yuanyuan , Du Lingbin , Wang Youqing , Gu Yuxuan , Zhen Xuemei , Hu Xiaoqian , Sun Xueshan , Dong Hengjin
Published: July 2020

Background : This study aimed to examine the cost-effectiveness of standard endoscopic screening with Lugol’s iodine staining for EC (esophageal cancer) screening in China. Methods : A Markov decision analysis model with eleven states was built. Individuals aged 40 to 69 years were classified into six age groups according to five-year intervals. Three different strategies were adopted for each cohort: (1) no screening; (2) endoscopic screening with Lugol’s iodine staining with annual follow-up for low-grade intraepithelial neoplasia; and (3) endoscopic screening with Lugol’s iodine staining without follow-up. Quality-adjusted life-years (QALYs) indicated the effectiveness . The incremental cost-effectiveness ratio (ICER) was used as the evaluating indicator. Sensitivity analysis was performed to assess the robustness of the model. Results : Screening with follow-up was the undominated strategy, which saved USD 10942.57 and USD 6611.73 for individuals aged 40-44 and 45-49 years, respectively, per QALY gained. For those aged 50-69 years, the nonscreening scenarios were undominated. Screening without follow-up were extended dominated strategies. Compared to screening strategies without follow-up, all the follow-up strategies were found to be cost effective, with the ICER increasing from 299.57 USD/QALY for individuals 40-44 years to 1617.72 USD/QALY for individuals 65-69 years. Probabilistic sensitivity analysis supported the results of the base case analysis. Conclusions : EC screening with follow-up targeting individuals aged 40-49 years was the most cost-effective strategy.
Succeeding with prolonged usage of consumer-based activity trackers in clinical studies: A mixed methods approach
Authors: Henriksen André , Sand Anne-Sofie , Deraas Trygve , Grimsgaard Sameline , Hartvigsen Gunnar , Hopstock Laila
Published: July 2020

Background: Lack of physical activity (PA) is a risk factor for death and non-communicable disease. Despite this, more than one fourth of adults worldwide do not follow PA guidelines. As part of a feasibility study to test a complex intervention for increasing PA, we included a consumer-based activity tracker (AT) as a tool to measure PA outcomes and to track heart rate during exercise sessions. The aim of the present study was to identify factors that increase wear time when using a consumer-based AT for monitoring of participants in clinical research. Methods: Sixteen participants aged 55-74 years, with obesity, sedentary lifestyle, and elevated cardiovascular risk were recruited to a 12-month feasibility study. Participants wore a Polar M430 AT to collect continuous PA data during a six-month intervention followed by six months of follow-up. We performed quantitative wear time analysis, tested the validity of the AT, and completed two rounds of qualitative interviews to investigate how individual wear-time was linked to participant responses. Results: From one year of tracking, mean number of valid wear days were 292 (SD=86), i.e. 80%. The Polar M430 provides acceptable measurements for total energy expenditure. Motivations for increased wear time were that participants were asked to wear it and the ability to track PA progress. Perceived usefulness included time keeping, heart rate- and sleep tracking, becoming more conscious about day-to-day activity, and improved understanding of which activity types were more effective for energy expenditure. Sources of AT annoyance were measurement inaccuracies and limited instruction for use. Suggestions for improvement were that the AT was big, unattractive, and complicated to use.Conclusions: Adherence to wearing a consumer-based AT was high. Results indicate that it is feasible to use a consumer-based AT to measure PA over a longer period. Potential success factors for increased wear time includes adequate instruction for AT use, allowing participants to choose different AT designs, and using trackers with accurate measurements. To identify accurate trackers, AT validation studies in the target cohort may be needed. Trial registration: U.S. National Library of Medicine, Clinical Trial registry: NCT03807323; Registered 16 September 2019 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03807323
Social Determinants of Mental Health Care Systems: Intensive Community Based Care in The Veterans Health Administration
Authors: Bhalla Ish P , Stefanovics Elina A , Rosenheck Robert A
Published: July 2020

Background: Since deinstitutionalization in the 1950s-1970s, public mental health care has changed its focus from asylums to general hospitals, outpatient clinics and specialized community-based programs addressing both clinical and social determinants of mental health. Analysis of the place of community-based programs within a comprehensive health system such as the Veterans Health Administration (VHA) may illuminate the role of social forces in shaping contemporary public mental health systems. Methods: National VHA administrative data were used to compare veterans who exclusively received outpatient clinic care to those receiving four types of specialized community-based services, addressing: 1) functional disabilities from severe mental illness (SMI), 2) justice system involvement, 3) homelessness, and 4) vocational rehabilitation. Bivariate comparisons and multinomial logistic regression analyses compared groups on demographics, diagnoses, service use, and psychiatric prescription fills. Results: An hierarchical classification of 1,386,487 Veterans who received specialty mental health services from VHA in Fiscal Year 2012, showed 1,134,977 (81.8%) were seen exclusively in outpatient clinics; 27,931 (2.0 %) received intensive SMI-related services; 42,985 (3.1%) criminal justice services; 160,273 (11.6%) specialized homelessness services; and 20,921 (1.5%) vocational services. Compared to those seen only in clinics, veterans in the four community treatment groups were more likely to be black, diagnosed with HIV and hepatitis, had more numerous substance use diagnoses and made far more extensive use of mental health outpatient and inpatient care. Conclusions: Almost one-fifth of VHA mental health patients receive community-based services prominantly addressing major social determinants of health and multimorbid substance use disorders.
Comparison of the clinical effect between the lower sternal incision and the left parasternal fourth intercostal incision in the transthoracic closure of ventricular septal defect
Authors: Ma Jun , Shangguan Wenlin , Chen Liang-wan , Liao Dong-Shan
Published: July 2020

Background: To analyze the clinical effect of two different ways of minimally invasive transthoracic closure in children with ventricular septal defect (VSD) Methods: From January 2015 to July 2019, 294 children with VSD were enrolled in the Fujian Medical University Union Hospital, who underwent VSD closure through the left sternal fourth intercostal incision (group A: n = 95) and the lower sternal incision (group B: n = 129) Results: The operation time, bleeding volume, postoperative mechanical ventilation time, postoperative ICU monitoring time, postoperative hospitalization time and complication rate in group A were significantly lower than those in group B (P < 0.05). There was no significant difference between the two groups in the operation success rate, mechanical ventilation time and total hospitalization cost (P > 0.05). Conclusion : The transthoracic closure of ventricular septal defect through the left sternal fourth intercostal incision is feasible, safe, cosmetic, and worth popularizing.
A Systematic Review of Green-Light Laser Vaporization for Superficial Bladder Cancer
Authors: Xu Zhi , Gan Guifen , Chen Guojun , Wu Guanlin
Published: July 2020

Background: The related research of green-light laser vaporization in the treatment of non-muscle invasive bladder cancer (NMIBC) is limited. This study focused on analyzing the effectiveness and safety of it from the perspective of an extensive literature review. Methods: A comprehensive search of CNKI, WanFang, VIP, PubMed, Embase, and CENTRAL databases for photoselective vaporization of bladder tumor and transurethral resection of bladder tumor treatment of non-muscle invasive bladder cancer (NMIBC). The search included studies from January 1996 to December 2019. Two reviewers independently screened literature, extracted data, assessed the risk of bias of included studies. RevMan 5.3 software was used for Meta-analysis. Results: A total of 18 RCTs involving 1648 patients met the predefined criteria. Meta-analysis data demonstrated that the PVBT group exhibited a significant advantage over the TURBT group in intraoperative obturator nerve reflex and bladder perforation and postoperative 1-year recurrence. The PVBT procedure has advantages over TURBT in the amount of surgical bleeding and the length of hospital stay, bladder irrigation time, and catheter indwelling time. There was no difference between the two types of surgery in the incidence of postoperative urethral stricture and the length of surgery. Conclusion: Our systematic review and meta-analysis suggests that PVBT is better than TURBT as an alternative treatment for patients with NMIBC in safe aspect. However, whether it is equally effective in terms of oncological control remains to be elucidated, and additional high quality RCTs are needed to confirm our findings.
Risk Factors Related to Acute Respiratory Distress Syndrome and Death in Patients with COVID-19: A Retrospective Cohort Study in Wuhan, China
Authors: Wang Jing , Wang Lu , Jin Meng , Lu Zequn , Xiao Jun , Li Yao , Yao Zhi , Dong Tianyi , Wang Yanan , Niu Siyuan , Li Qinglin , Liu Cai , Qi Jirong , Tian Jianbo , Wang Zhihua
Published: July 2020

Background: The COVID-19 pandemic has been considered as the great threat to global public health. We aimed to clarify the risk factors associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death and construct a risk prediction model.Methods: In this single-centered, retrospective, and observational study, 796 COVID-19 patients developed ARDS and 735 COVID-19 patients without ARDS were matched by propensity score at an approximate ratio of 1:1 based on age, sex and comorbidities. Demographic data, symptoms, radiological findings, laboratory examinations, and clinical outcomes were compared between with or without ARDS. Univariable and multivariable logistic regression models were applied to explore the risk factors for development of ARDS and progression from ARDS to death and establish a comprehensive risk model. Results: Higher SOFA, qSOFA, APACHE II and SIRS scores, elevated inflammatory cytokines, dysregulated multi-organ damage biomarkers, decreased immune cell subsets were associated with higher proportion of death (34.17% vs 1.22%; P<0.001) and increased risk odds of death (OR=57.216, 95%CI=28.373-115.378; P<0.001) in COVID-19 patients with ARDS. In addition to previous reported risk factors related to ARDS development and death, such as neutrophils, IL-6, D-Dimer, leukocytes and platelet, we identified elevated TNF-α (OR=1.146, 95%CI=1.100-1.194; P<0.001), CK-MB (OR=1.350, 95%CI=1.180-1.545; P<0.001), declined ALB (OR=0.834, 95%CI=0.799-0.872; P<0.001), CD8+ T cells (OR=0.983, 95%CI=0.976-0.990; P<0.001) and CD3-CD19+ B cells (OR=0.992, 95%CI=0.988-0.997; P=0.003) as novel risk factors. Most importantly, the predictive accuracy of the combined model integrating four score systems and these risk factors demonstrated highest among all models for the development of ARDS (AUC= 0.904) and the progression from ARDS to death (AUC= 0.959).Conclusion: COVID-19 patients with ARDS were more likely to develop into death. The potential risk factors and the comprehensive prediction model could be helpful to identify patients developed ARDS with poor prognosis at an early stage, which might help physicians to formulate a timely therapeutic strategy.
Current Curative Expenditure of Respiratory Diseases and Its Influencing Factors，A Research Based on“System of Health Account 2011”
Authors: Li Ling , Zhan Huan , Wang Xin , Zhou Liangrong
Published: July 2020

Background: Respiratory disease is now the leading cause of morbidity and mortality worldwide. They simultaneously impact public health at the population level and also cause great financial distress for families . Understanding the distribution of diseases and the Current Curative Expenditure (CCE) can provide a basis for policy decisions and interventions. This study analyzed the status of respiratory diseases spending using data from “System of Health Accounts 2011” (SHA 2011) to provide health policy advice to Hunan Province, China, and insights for other more developed areas in China. Methods: Data were collected by multi-stage stratified random sampling approach and the medical expenses of patients with respiratory diseases were calculated based on the SHA 2011, including the dimensions of institutional resource flow and service function. Regression analyses were conducted to identify influencing factors of hospitalization expenses. All analyses were conducted using software SPSS 25.0. Results: The CCE for Respiratory diseases in 2017 was 215.42 billion Chinese yuan (CNY), accounting for 15.94% of total expenditure on health in Hunan Province, China. Children aged 0-4 and elderly aged 60-69 spent the most on the treatment for such diseases. Length of stay, age, and institution level were the three most important factors affecting hospitalization expenses. Conclusions: The CCE of respiratory diseases is extremely high, with problems related to treatment efficiency and equity. It is essential to expand health insurance coverage, establish hierarchical medical system, and reduce curative expenditure.
Patient and Service-Level Factors Affecting Length of Inpatient Stay in an Acute Mental Health Service: A Retrospective Case Cohort Study
Authors: Crossley Neil Edward , Sweeney Brian
Published: July 2020

Background:Despite the focus on community-based care, demand for inpatient psychiatric care still remains high. Trusts strive for safe, efficient patient throughput with reduced length of stay.Previous studies have attempted to analyse factors influencing length of stay in mental health units, focussing mostly on patient factors. These models fail to sufficiently explain the variation in duration of inpatient stay. We assess how the type of service delivered by a trust, in addition to patient factors, influences length of stay.Methods:We conducted a retrospective case cohort study in a large inner-city NHS mental health trust for all admissions in a one month period. Data was gathered from electronic notes of 105 patients and analysed using IBM SPSS version 26. Descriptive univariate and bivariate analyses were conducted on the data, with multiple regression analysis conducted on statistically significant data. Results:Short-stay assessment ward admission significantly reduced length of stay. Patients under outpatients or under care co-ordination, admitted through Mental Health Act assessment and formally detained all had longer length of stay. Out of area admissions, locum Consultant care, changing Responsible Clinician and ward transfers all led to longer length of stay. Factors indicating more severe illness such as increased observation level and polypharmacy, as well as diagnoses of psychosis or bipolar disorder were associated with longer duration of stay. Discharges requiring referral to accommodation or rehabilitation led to longer stays. The most significant factors that influenced length of stay were higher observation levels, diagnosis of psychotic illness or bipolar, and discharge to rehabilitation placement.The final model, taking into account all these factors, was able to account for 59.6% of the variability in length of stay.Conclusions:The study backs up existing literature which shows patient-factors have an influence on length of stay. The study also demonstrates that service-level factors have an impact on the duration of stay. This data may be used to inform further studies which may aid provision of inpatient and community services in the future.
Impact of the COVID-19 pandemic on attitudes towards the lifting of confinement through the Algerians people
Authors: Madani Azzeddine , Boutebal Saad Eddine
Published: July 2020

The aim of this study was to investigate the impact of the COVID-19 pandemic on the attitudes towards the lifting of confinement. Methods: The data were collected using a questionnaire applied to 344 people in different regions of Algeria from April 21, 2020, for two weeks afterward, in order to determine the attitudes of the Algerian people towards the post-coronavirus COVID -19 phase. Results: The results of this study indicate that 94.2% of respondents insist on lifting the confinement to apply gradually and partially. Accordingly, there is a significant impact of gender and age on social attitudes towards the post-coronavirus phase. Similarly, the results highlighted the existence of a positive level of attitude towards the post-coronavirus phase COVID-19 in the need to digitize education, digitize social transactions, and develop sustainable transport and the public health sector. Results: People living in confinement indicate that it is necessary to prepare for the post-coronavirus period, in particular through the vital sectors linked to daily life.
Serum Asprosin Level in Different Subtypes of Polycystic Ovary Syndrome: A Cross-sectional Study
Authors: jiang yonghui , liu yue , yu zhiheng , yang ping , xie lei , shang xuejun , zhao shigang
Published: July 2020

Objective
Polycystic ovary syndrome (PCOS) can be divided into different subtypes, including insulin resistance (IR) and hyperandrogenism (HA). Asprosin is a novel hormone associated with IR; however, the role of asprosin in women with PCOS has not been investigated. Thus, the aim of this study was to investigate the relationship between serum asprosin levels and PCOS subtypes.
Methods
Ninety-three women with PCOS and 77 healthy women as controls were selected for this study. Clinical and laboratory data were compared between the PCOS group and the control group. The PCOS group was further divided into subgroups: 1) women with or without HA (PCOS HA and PCOS NHA, respectively); 2) women with or without IR (PCOS IR and PCOS NIR, respectively). Serum asprosin was measured by ELISA.
Results
Serum asprosin levels showed no significant difference between the PCOS and control groups. However, it was significantly lower in the PCOS HA and IR groups compared to the respective PCOS NHA and NIR groups (P < .05). In the PCOS group, serum asprosin was negatively correlated with body mass index, luteinizing hormone, testosterone, basal antral follicles, fasting insulin, Homeostatic Model Assessment of Insulin Resistance, and triglycerides. After adjusting for BMI, the correlations were not significant and asprosin was only positively correlated with prolactin (r = 0.426, P < .001).
Conclusions
Our study shows that women with PCOS HA or IR exhibit significantly lower serum asprosin levels compared to controls, and the lower asprosin level directly correlated with PRL level.
Diagnostic precision and identification of rare diseases is dependent on distance of residence relative to tertiary medical facilities
Authors: Walter Anna-Lena , Baty Florent , Rassouli Frank , Bilz Stefan , Brutsche Martin Hugo
Published: July 2020

Background Diagnostic precision and the identification of rare diseases (RDs) is a daily challenge, which needs specialized expertise. We hypothesized, that there is a correlation between the distance of residence to the next tertiary medical facility with specialized care and the diagnostic precision, especially for rare diseases.Results We found a negative association between diagnostic diversity and travel time to the next tertiary hospital when including all cases throughout the overall International Classification of Diseases version 10 (ICD-10) diagnosis codes. This was paralleled with a negative association of standardized incidence rates in all groups of rare diseases except for rare teratologic and rare allergic diseases. The effect started at travel times of > 21 minutes.Conclusion Our findings indicate towards a higher risk of being mis-, under- or late diagnosed especially in rare diseases when living more distant to a tertiary medical facility. Greater distance to the next tertiary medical facility basically increases the chance for hospitalization in a non-comprehensive regional hospital with less diagnostic capacity, and, thus, impacts on adapted health care access. Therefore, solutions for overcoming the distance to specialized care as an indicator of health care access are a major goal in the future.
Cooperative Coverage Based Lifetime Prolongation for Microgrid Monitoring WSN in Smart Grid
Authors: Shao Sujie , Wu Lei , Zhang Qinghang , Zhang Neng , Wang Kaixuan
Published: July 2020

To take full advantage of the flexibility of access and disconnection from smart grid, organizing distributed renewable energy resources in form of microgrid becomes one solution of energy replenishment in smart grid. A large amount of accurate and comprehensive information data are needed to be monitored by a variety of different types of sensors to guarantee the effective operation of this kind of microgrid. Energy consumption of microgrid monitoring WSN consequently becomes an issue. This paper presents a novel lifetime prolongation algorithm based on cooperative coverage of different types of sensors. Firstly, according to the requirements of monitoring business, the construction of cooperative coverage sets and connected monitoring WSN are discussed. Secondly, energy consumption is analyzed based on cooperative coverage. Finally, the cooperative coverage based lifetime prolongation algorithm (CC-LP) is proposed. Both the energy consumption balancing inside the cooperative coverage set and the switching scheduling between cooperative coverage sets are discussed. Then we draw into an improved ant colony optimization algorithm to calculate the switching scheduling. Simulation results show that this novel algorithm can effectively prolong the lifetime of monitoring WSN, especially in the monitoring area with a large deployed density of different types of sensors.
MAIP: A Prediction Platform for Predicting Blood-Stage Malaria Inhibitors
Authors: Bosc Nicolas , Felix Eloy , Arcila Ricardo , Mendez David , Saunders Martin , Green Darren , Ochoada Jason , Shelat Anang , Martin Eric , Iyer Preeti , Engkvist Ola , Verras Andreas , Duffy James , Burrows Jeremy , Gardner Mark , Leach Andrew
Published: July 2020

Malaria is a disease affecting hundreds of millions of people across the world, mainly in developing countries and especially in Sub-Saharan Africa. It is the cause of hundreds of thousands of deaths each year and there is an ever-present need to identify and develop effective new therapies to tackle the disease and overcome increasing drug resistance. Here, we extend a previous study in which a number of partners collaborated to develop a consensus in silico model that can be used to identify novel molecules that may have antimalarial properties. The performance of machine learning methods generally improves with the number of data points available for training. One practical challenge in building large training sets is that the data is often proprietary and cannot be straightforwardly integrated. Here, this was addressed by sharing QSAR models, each built on a private data set. We describe the development of an open-source software platform for creating such models, a comprehensive evaluation of methods to create a single consensus model and a web platform called MAIP available at https://www.ebi.ac.uk/chembl/maip/. MAIP is freely available for the wider community to make large-scale predictions of potential malaria inhibiting compounds. This project also highlights some of the practical challenges in reproducing published computational methods and the opportunities that open source software can offer to the community.
Anterior dural ectasia associated with cauda equine syndrome in ankylosing spondylitis: a case report
Authors: Liu Shaoqiang , Chen Wei , Liang Guiqing
Published: July 2020

Background: Cauda equina syndrome (CES) is a rare neurologic complication in patients with long-standing ankylosing spondylitis (AS). MRI characteristically shows an enlarged caudal thecal sac, bone erosion and dural ectasia. Dural ectasia is more likely to occur in the posterior elements rather than the vertebral bodies. Methods: We report an uncommon case of CES in AS with formation of anterior dural ectasia. The origin of this rare pathology is analysed and relevant literatures are reviewed. Results: The patient had a 50-year history of AS and presented with weakness of his left leg but without bladder or rectal dysfunction. Radiographs of the full spine showed the classic features of AS with fusion of all spinal ligaments and bilateral sacroiliac joints. CT scanning demonstrated erosion-like lesions with marginal sclerosis in the posterior aspect of the T12 and L1 vertebral bodies. Lumbar MRI revealed anterior dural ectasia into the vertebral body, and ventral herniation of the spinal cord and adhesion to the dural sac. Conclusions: The clinical manifestations of anterior dural ectasia in AS with CES include lower limb numbness and weakness, bladder and rectal dysfunction, impotence, etc. MRI characteristically shows an enlarged caudal thecal sac, bone erosion and anterior dural ectasia at the junction of thoracolumbar and upper lumbar.
Suppression of Autophagy Sensitizes Osteosarcoma to mTOR Inhibition
Authors: Zeng Ke , Jin Lei , Yang Xiao , Yang Zhengjie , Zhu Guoxin
Published: July 2020

Aim

Osteosarcoma is some major health problem. We intended to investigate the role of Rapamycin and autophagy inhibition in the treatment of osteosarcoma.
Method

We conducted a series of in vitro studies using two osteosarcoma cell lines. Using genetic and pharmaceutical interventions we studied whether combined autophagy inhibition could sensitize osteosarcoma sales to a Rapamycin treatment. Proliferation, innovation, migration, and colony formation assays were performed.
Results

Osteosarcoma cells had low basal autophagy levels. Inhibition of mTOR only demonstrated moderate effects but induced increased autophagy levels, indicating possible resistance mechanism. Inhibition of both autophagy and mTOR axis synergistically inhibited proliferation, migration, invasion, and colony formation of osteosarcoma cells. The combination therapy induced apoptosis, which could be restored in part by NEC1.
Conclusion

Increased autophagy level was responsible for compromised effect of mTOR inhibition in osteosarcoma. Combination therapy using rapamycin and chloroquine held promise to the development of novel mortality.
Reproductive fluids, used for the in vitro production of pig embryos, result in healthy offspring and avoid aberrant placental expression of PEG3 and LUM.
Authors: Paris-Oller Evelynne , Navarro-Serna Sergio , Soriano-Úbeda Cristina , Lopes Jordana Sena , Matas Carmen , Ruiz Salvador , Latorre Rafael , López-Albors Octavio , Romar Raquel , Cánovas Sebastián , Coy Pilar
Published: July 2020

Background: In vitro embryo production (IVP) and embryo transfer (ET) are two very common assisted reproductive technologies (ART) in human and cattle. However, in pig, the combination of either procedures, or even their use separately, is still considered suboptimal due to the low efficiency of IVP plus the difficulty of performing ET in the long and contorted uterus of the sow. In addition, the potential impact of these two ART on the health of the offspring is unknown. We investigated here if the use of an improved IVP system, with natural reproductive fluids (RF) as supplements to the culture media, combined with a minimal invasive surgery to perform ET, affects the output of the own IVP system as well as the reproductive performance of the mother and placental molecular traits.Results: The blastocyst rates obtained by both in vitro systems, conventional (C-IVP) and improved (RF-IVP), were similar. Pregnancy and farrowing rates were also similar. However, when compared to in vivo control (artificial insemination, AI), litter sizes of both IVP groups were lower, while placental efficiency was higher in AI than in RF-IVP. Gene expression studies revealed aberrant expression levels for PEG3 and LUM in placental tissue for C-IVP group when compared to AI, but not for RF-IVP group. Conclusions: The use of reproductive fluids as additives for the culture media in pig IVP does not improve reproductive performance of recipient mothers but can mitigate the impact of artificial procedures in the offspring.
PAZ Domain is Critical for PIWIL1 Function During Spermatogenesis in Chicken
Authors: Guo Qixin , Xu Lu , Yuan Xiaoya , Jiang Yong , Bai Hao , Chang Guobin
Published: July 2020

Background: Piwi-like protein 1 (PIWIL1) plays a crucial role in stem cell proliferation, embryogenesis, growth, and development. The aim of this study was to reveal the function of PIWIL1 and its PAZ (Piwi/Argonaute/Zwille) domain in chicken embryogenesis. Results: PIWI1 expression was analyzed in different stages of spermatogenesis by RT-PCR and the PAZ domain was mutated based on its 3D structure model using the CRISPR/Cas9 technology. The results indicated that PIWIL1 mRNA was specifically expressed in spermatogonium cells undergoing meiosis. After targeting the PAZ domain (300–370 amino acid residues), we obtained two mutant DF-1 cell clones with 23-bp and 8-bp deletions. Injection of the pCMV-Cas9-puro-sgRNA-2 construct into 2.5-day embryos resulted in generation of 19 different PAZ mutants (13 males and 6 females), which had delayed hatching, reduced quality of semen, and decreased expression of PIWIL1 and SOX2 at embryonic days 5 and 18. However, we could not obtain PAZ double knockout (KO) chickens by crossing of the F0 generation, suggesting that PAZ double KO may halt embryonic development. Conclusions: Our results indicate that PIWIL1 plays an important role in meiosis and that PAZ mutations can lead to decreased sperm quality, whereas its double KO may arrest embryogenesis in chicken.
Mid-term Outcome Of Surgical Treatment In Pediatric Patients With Ebstein's Anomaly: A Single-center Cohort Study.
Authors: Li Jia-chen , Jiang Xian-chao , Zhang Si-meng , Liu Jin-yang , Zhang Ya-juan , Yan Jun , Li Shou-jun , Wang Qiang
Published: July 2020

Background: Ebstein’s anomaly is a malformation of the tricuspid valve and myopathy of the right ventricle. Surgery is now the main treatment for the defect. To summarize our surgical results and experience based on patients with Ebstein’s anomaly who were under 7 years of age and treated with different surgical treatments.Materials and Methods: From January 2010 to December 2019, 80 patients under 7 years old who were diagnosed of Ebstein’s anomaly and underwent different surgical treatments were consecutively enrolled and followed up in detail. Results: The median age of the 80 patients at the time of surgery was 3.63 years. Sixty-four (80.00%) patients underwent biventricular repair while 13 (16.25%) underwent 1.5-ventricle repair. With the median follow-up 27.50 months, the long-term survival of the total cohort, 1.5-ventricular repair and biventricular repair was 82.35%, 91.67% and 100%, respectively. The long-term freedom from reoperation rate was 97.50%, 92.31% and 98.44%, respectively. Mild, moderate and severe TR before surgery occurred in 6 (7.50%), 18 (22.50%) and 56 (70.00%), respectively. The early outcomes of 78 patients were 65 (83.33%), 11 (14.11%) and 2 (2.56%); the mid-term outcomes of 72 patients were 49 (68.06%), 19 (26.38%) and 4 (5.56%). Both early and long-term valve regurgitation were significantly decreased (p< 0.001) compared with preoperative condition. No more severe regurgitation occurred (p=0.404), though some early mild regurgitation became acceptable moderate regurgitation during long-term follow-up (p=0.036). Compared with Carpentier procedure, cone procedure had better long-term effect, while the effect of whole-valve technique needed more operation and long-term follow-up.Conclusion: The reoperation rate and mid-term mortality of surgical treatment for Ebstein’s anomaly were both low, tricuspid regurgitation was significantly improved during mid-term follow up. Cone procedure had the best mid-term effect among anatomic repair.
Intensity-modulated radiation therapy versus three-dimensional conformal radiotherapy in head and neck squamous cell carcinoma: long-term and mature outcomes of a prospective randomized trial
Authors: Gupta Tejpal , Sinha Shwetabh , Laskar Sarbani Ghosh , Budrukkar Ashwini , Mummudi Naveen , Swain Monali , Phurailatpam Reena , Prabhash Kumar , Agarwal Jai Prakash
Published: July 2020

Background: To compare long-term disease-related outcomes and late radiation morbidity between intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in head and neck squamous cell carcinoma (HNSCC) in the setting of a prospective randomized controlled trial.Methods: Previously untreated patients with early to moderately advanced non-metastatic squamous carcinoma of the oropharynx, larynx, or hypopharynx (T1-T3, N0-N2b, M0) were randomly assigned to either IMRT or 3D-CRT after written informed consent. Patients were treated with 6MV photons to a total dose of 70Gy/35 fractions over 7 weeks (3D-CRT) or 66Gy/30 fractions over 6 weeks (IMRT). A sample size of 60 patients was estimated to demonstrate 35% absolute difference in the incidence of ≥grade 2 acute xerostomia between the two arms. All time-to-event outcomes were calculated from date of randomization till the defined event using the product-limit method of Kaplan-Meier. Results: At a median follow-up of 140 months for surviving patients, 10-year Kaplan-Meier estimates of loco-regional failure free-survival (LRFFS); final loco-regional control (LRC) including surgical salvage; and overall survival (OS) with 95% confidence interval (95%CI) were 72% (95%CI: 59.4-84.6%); 79.7% (95%CI: 68.7-90.7%); and 50.3% (95%CI: 37.1-63.5%) respectively. There were no significant differences in 10-year disease-related outcomes between 3D-CRT and IMRT for LRRFS [75.7% (95%CI: 58.1-93.3%) vs 68.7% (95%CI: 51.1-86.3%), p=0.56]; final LRC [83% (95%CI: 67.2-98.8%) vs 76.9% (95%CI: 61.5-92.3%), p=0.50]; or OS [44.9% (95%CI: 25.7-64.1%) vs 55.0% (95%CI: 37-73%), p=0.49]. Significantly lesser proportion of patients in the IMRT arm experienced ≥grade 2 late xerostomia and subcutaneous fibrosis at all time-points. However, at longer follow-up, lesser number of patients remained evaluable for late radiation toxicity reducing statistical power and precision. Conclusions: IMRT provides a clinically meaningful and sustained reduction in the incidence of moderate to severe xerostomia and subcutaneous fibrosis compared to 3D-CRT without compromising disease-related outcomes in long-term survivors of non-nasopharyngeal HNSCC. Trial registration: Registered at the Clinical Trials Registry of India (CTRI/2008/091/000045) (Retrospectively registered)
Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex
Authors: Franco-Pérez Javier , Montes Sergio , Sanchez-Hernández Josué , Ballesteros-Zebadúa Paola
Published: July 2020

Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are both highly connected to the hypothalamus and its regulatory processes. Methods: Male Wistar rats were exposed to whole-brain irradiation with 11 Gy (BED= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, glutamine, in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the relative expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05). Results: Whole-brain irradiation with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus, one month after exposure. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significantly increased levels of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusions: Our findings confirm that whole-brain irradiation can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex both indicate a modified neurochemical balance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.
TRIM8 Inhibits Breast Cancer Proliferation by Regulating Estrogen Signaling
Authors: Tian Zelin , Tang Jianing , Liao Xing , Yang Qian , Wu Yumin , Wu Gaosong
Published: July 2020

Background: Breast cancer (BC) ranks first in female malignancies wordwide, 70% of which are estrogen receptor alpha (ERα) positive. Endocrine treatment, such as tamoxifen, is primary adjuvant therapy for patients with ER-positive BC, while some of them can develop acquired resistance during long-time treatment. Thus, further research on estrogen signaling is of significance to improve the prognosis of BC patients. Methods: In this study, we report that the E3 ubiquitin ligase TRIM8 acts as a novel regulator of ERα signaling. TRIM8 and ERα target genes expression levels were measured by RT-PCR, while protein expression levels were measured by western blot. CCK8 assay, clone formation, and EDU assay were used to measure cells proliferation. Wound healing assay was used to measure cells migration. Protein stability assay and protein ubiquitination analysis were used to detect ERα protein degradation. Co-immunoprecipitation assay was used to detect the interaction domain between TRIM8 and ERα. Results: TRIM8 is downregulated in BC and is associated with poor prognosis. The protein level of TRIM8 is negatively correlated with ERα. RNA-seq result revealed that estrogen signaling maybe a potential target of TRIM8. Knockdown of TRIM8 can significantly enhance BC cell proliferation and migration in vitro and in vivo. And this effect can be reversed by ERα depletion. Further mechanistic studies have shown that TRIM8 interacts with AF1 domain of ERα via its RING domain in the cytoplasm, and affects poly-ubiquitination of ERα protein. Conclusion: Our study reveals an interesting post-translational mechanism between ERα and TRIM8 in ER-positive BC, TRIM8 may be a potential therapeutic target for BC treatment.
The DDX39B/FUT3/TGFβR-I Axis Promotes Tumor Metastasis and EMT in Colorectal Cancer
Authors: He Chengcheng , Li Aimin , Lai Qiuhua , Ding Jian , Yan Qun , Liu Side , Li Qingyuan
Published: July 2020

Background: DDX39B is a member of the DEAD box (DDX) RNA helicase family required for nearly all cellular RNA metabolism processes. The exact role and potential molecular mechanism of DDX39B in the progression of human colorectal cancer (CRC) remain to be investigated. Methods: Western blotting and quantitative real-time PCR (qRT-PCR) were conducted to detect the expression of DDX39B in CRC tissues and cell lines. Transwell and wound healing assays were conducted to assess the migration and invasion ability of CRC cells with DDX39B overexpressed or silencing. Orthotopic transplantation model of nude mice was performed to validate CRC metastasis in vivo. RNA sequencing (RNA-seq) and RNA binding protein immunoprecipitation (RIP) assay verified the direct regulation of DDX39B on the splicing and nuclear export of FUT3 mRNA, cytoplasmic and nuclear RNA isolation confirmed the nuclear export effect of DDX39B on FUT3. qRT-PCR was conducted to quantify FUT3 splicing variants. Lectin blotting was conducted to evaluate the fucosylation level of TGFβR-I.Results: In the present study, we demonstrate that DDX39B expression was higher in CRC tissues than in adjacent normal tissues. Gain- and loss- of- function assays revealed that DDX39B facilitated the metastasis of CRC in vivo and in vitro. Mechanistically, RNA-seq and RIP showed that DDX39B upregulated FUT3 expression by binding the first exon of FUT3 mRNA, which promote the mRNA splicing and export of FUT3. RNA-seq results and qRT-PCR showed that overexpression of DDX39B may favor the longer FUT3 mRNA products that contain the complete and longer exon 2, suggesting an alternative splicing of FUT3. Upregulation of FUT3 accelerated the fucosylation of TGFβR-I, thus activating the TGFβ/SMAD signaling pathway, eventually driving the epithelial-mesenchymal transition (EMT) program and contributing to CRC progression. Conclusions: Our finding demonstrated for the first time that the DDX39B/FUT3/TGFβR-I axis promotes the progression of CRC. These findings not only provide new insight into the role of DDX39B in mRNA splicing and export and tumorigenesis, but also shed light on the effect of aberrant fucosylation on CRC progression.
Loss of Exosomal miR-146a-5p from Cancer-Associated Fibroblasts After Androgen Deprivation Therapy Contributes to Prostate Cancer Metastasis
Authors: Zhang Yu , Zhao Jing , Ding Mao , Su Yiming , Cui Di , Jiang Chenyi , Zhao Sheng , Jia Gaozhen , Wang Xiaohai , Ruan Yuan , Jing Yifeng , Xia Shujie , Han Bangmin
Published: July 2020

Background: Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAF-derived exosomes involving in metastasis of PCa after ADT. Methods: PCa cells were co-cultured with exosomes derived from 10 nM dihydrotestosterone (DHT)-treated (simulating the high androgen level of prostate cancer microenvironment） or ethanol (ETOH) -treated (simulating the castration level of prostate cancer microenvironment after ADT) CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot.Results: Compared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increase migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway. Conclusions: CAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa