bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of data access and use procedures in clinical data warehouses. A systematic review of literature and publicly available policies
Authors: Pavlenko Elena , Strech Daniel , Langhof Holger
Published: July 2020

Background

The promises of improved health care and health research through data-intensive applications rely on a growing amount of health data. At the core of large-scale data integration efforts, clinical data warehouses (CDW) are also responsible for data governance, managing data access and (re)use. As the complexity of the data flow increases, greater transparency and standardization of criteria and procedures are required in order to maintain objective oversight and control. Therefore, the development of practice oriented and evidence-based policies is crucial. This study assessed the spectrum of data access and use criteria and procedures in clinical data warehouses governance internationally.

Methods

We performed a systematic review of (a) the published scientific literature on CDW and (b) publicly available information on CDW data access, e.g., data access policies. A qualitative thematic analysis was applied to all included literature and policies.

Results

Twenty-three scientific publications and one policy document were included in the final analysis. The qualitative analysis led to a final set of three main thematic categories: (1) requirements, including recipient requirements, reuse requirements, and formal requirements; (2) structures and processes, including review bodies and review values; and (3) access, including access limitations.

Conclusions

The description of data access and use governance in the scientific literature is characterized by a high level of heterogeneity and ambiguity. In practice, this might limit the effective data sharing needed to fulfil the high expectations of data-intensive approaches in medical research and health care. The lack of publicly available information on access policies conflicts with ethical requirements linked to principles of transparency and accountability.

CDW should publicly disclose by whom and under which conditions data can be accessed, and provide designated governance structures and policies to increase transparency on data access. The results of this review may contribute to the development of practice-oriented minimal standards for the governance of data access, which could also result in a stronger harmonization, efficiency, and effectiveness of CDW.
Empirical development of a typology on residential long-term care units in Germany - results of an exploratory multivariate data analysis
Authors: Bergmann Johannes Michael , Ströbel Armin Michael , Holle Bernhard , Palm Rebecca
Published: July 2020

Background

Organizational health care research focuses on describing structures and processes in organizations and investigating their impact on the quality of health care. In the setting of residential long-term care, this effort includes the examination and description of structural differences among the organizations (e.g., nursing homes). The objective of the analysis is to develop an empirical typology of living units in nursing homes that differ in their structural characteristics.

Methods

Data from the DemenzMonitor Study were used. The DemenzMonitor is an observational study carried out in a convenience sample of 103 living units in 51 nursing homes spread over 11 German federal states. Characteristics of living units were measured by 19 variables related to staffing, work organization, building characteristics and meal preparation. Multiple correspondence analysis (MCA) and agglomerative hierarchical cluster analysis (AHC) are suitable to create a typology of living units. Both methods are multivariate and explorative. We present a comparison with a previous typology (created by a nonexplorative and nonmultivariate process) of the living units derived from the same data set.

Results

The MCA revealed differences among the living units, which are defined in particular by the size of the living unit (number of beds), the additional qualifications of the head nurse, the living concept and the presence of additional financing through a separate benefit agreement. We identified three types of living units; these clusters occur significantly with a certain combination of characteristics. In terms of content, the three clusters can be defined as: “house community”, “dementia special care units” and “usual care”.

Conclusion

A typology is useful to gain a deeper understanding of the differences in the care structures of residential long-term care organizations. In addition, the study provides a practical recommendation on how to apply the results, enabling living units to be assigned to a certain type. The typology can be used as a reference for definitions.
Quality analysis of discharge instruction among 602 hospitalized patients in China: a multicenter, cross-sectional study
Authors: Yang Miao-miao , Liang Wei , Zhao Hui Hua , Zhang Ying
Published: July 2020

Background

The aim of this study was to understand the quality of discharge guidance for patients with chronic diseases, to clarify the gap between patient needs and the content of discharge guidance, and to provide a reference for health education and clinical path management of patients with chronic diseases in the future.

Methods

A total of 602 inpatients with stroke, coronary heart disease, cancer, chronic obstructive pulmonary disease and diabetes from the chronic disease-related departments of 7 tertiary general hospitals in China were selected by convenience sampling. Measures included a demographic questionnaire and the Quality of Discharged Teaching Scale(QDTS). Descriptive analysis ANOVA and paired t-test were completed by SPSS 22.0 software.

Results

The overall average score of QDTS in this survey was 155.79 ± 23.29. The total score of QDTS in chronic obstructive pulmonary disease was lower than coronary heart disease (P < 0.001) and cancer (P = 0.02). While coronary heart disease was higher than stroke (P = 0.01) and diabetes (P = 0.01). And the scores of patients on discharge guidance skills and effects were higher than 8.50.

Conclusions

The level of the patients’ perception of quality of discharge insrtuction is middle to high. Managers should understand the characteristics of various departments, give corresponding guidance and help, and clinical nurses should understand the characteristics of ward patients and pay more attention to individual guidance.
Saccharomyces cerevisiae fermentation products (SCFP) stabilize the ruminal microbiota of lactating dairy cows during periods of a depressed rumen pH
Authors: Tun Hein M. , Li Shucong , Yoon Ilkyu , Meale Sarah J. , Azevedo Paula A. , Khafipour Ehsan , Plaizier Jan C.
Published: July 2020

Background

Effects ofSaccharomyces cerevisiaefermentation products (SCFP) on rumen microbiota were determined in vitro and in vivo under a high and a depressed pH. The in vitro trial determined the effects of Original XPC and NutriTek (Diamond V, Cedar Rapids, IA) at doses of 1.67 and 2.33 g/L, respectively, on the abundances of rumen bacteria under a high pH (> 6.3) and a depressed pH (5.8–6.0) using quantitative PCR (qPCR). In the in vivo trial eight rumen-cannulated lactating dairy cows were used in a cross-over design. Cows were randomly assigned to SCFP treatments (Original XPC, Diamond V, Cedar Rapids, IA) or control (No SCFP) before two 5-week experimental periods. During the second period, SCFP treatments were reversed. Cows on the SCFP treatment were supplemented with 14 g/d of SCFP and 126 g/d of ground corn. Other cows received 140 g/d ground corn. During the first 4 wk. of each period, cows received a basal diet containing 153 g/kg of starch. During week 5 of both periods, the rumen pH was depressed by a SARA challenge. This included replacing 208 g/kg of the basal diet with pellets of ground wheat and barley, resulting in a diet that contained 222 g/kg DM of starch. Microbial communities in rumen liquid digesta were examined by pyrosequencing, qPCR, and shotgun metagenomics.

Results

During the in vitro experiment, XPC and NutriTek increased the relative abundances ofRuminococcus flavefaciens, andFibrobacter succinogenesdetermined at both the high and the depressed pH, with NutriTek having the largest effect. The relative abundances ofPrevotella brevis,R. flavefaciens, ciliate protozoa, andBifidobacteriumspp. were increased by XPC in vivo. Adverse impacts of the in vivo SARA challenge included reductions of the richness and diversity of the rumen microbial community, the abundances of Bacteroidetes and ciliate protozoa in the rumen as determined by pyrosequencing, and the predicted functionality of rumen microbiota as determined by shotgun metagenomics. These reductions were attenuated by XPC supplementation.

Conclusions

The negative effects of grain-based SARA challenges on the composition and predicted functionality of rumen microbiota are attenuated by supplementation with SCFP.
Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens
Authors: Akahane Toshiaki , Kitazono Ikumi , Yanazume Shintaro , Kamio Masaki , Togami Shinichi , Sakamoto Ippei , Nohara Sachio , Yokoyama Seiya , Kobayashi Hiroaki , Hiraki Tsubasa , Suzuki Shinsuke , Ueno Shinichi , Tanimoto Akihide
Published: July 2020

Background

Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses.

Methods

Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues.

Results

A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases.

Conclusion

These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.
The need for fast-track, high-quality and low-cost studies about the role of the BCG vaccine in the fight against COVID-19
Authors: Pereira Marcos , Paixão Enny , Trajman Anete , de Souza Ramon Andrade , da Natividade Marcio Santos , Pescarini Julia M. , Pereira Susan Martins , Barreto Florisneide Rodrigues , Ximenes Ricardo , Dalcomo Margareth , Ichihara Maria Yury , Nunes Ceuci , Barral-Netto Manoel , Barreto Maurício L.
Published: July 2020

Bacillus Calmette-Guérin (BCG) vaccination is routine and near-universal in many low- and middle-income countries (LMIC). It has been suggested that BCG can have a protective effect on COVID-19 morbidity and mortality. This commentary discusses the limitations of the evidence around BCG and COVID-19. We argue that higher-quality evidence is necessary to understand the protective effect of the BCG vaccine from existing, secondary data, while we await results from clinical trials currently conducted in different settings.
Molecular characterization and heterologous expression of two α-glucosidases from Metschnikowia spp, both producers of honey sugars
Authors: Garcia-Gonzalez Martin , Minguet-Lobato Marina , Plou Francisco J. , Fernandez-Lobato Maria
Published: July 2020

Background

α-Glucosidases are widely distributed enzymes with a varied substrate specificity that are traditionally used in biotechnological industries based on oligo- and polysaccharides as starting materials. According to amino acid sequence homology, α-glucosidases are included into two major families, GH13 and GH31. The members of family GH13 contain several α-glucosidases with confirmed hydrolytic activity on sucrose. Previously, a sucrose splitting activity from the nectar colonizing yeast Metschnikowia reukaufii which produced rare sugars with α-(1→1), α-(1→3) and α-(1→6) glycosidic linkages from sucrose was described.

Results

In this study, genes codifying for α-glucosidases from the nectaries yeast M. gruessii and M. reukaufii were characterised and heterologously expressed in Escherichia coli for the first time. Recombinant proteins (Mg-αGlu and Mr-αGlu) were purified and biochemically analysed. Both enzymes mainly displayed hydrolytic activity towards sucrose, maltose and p-nitrophenyl-α-d-glucopyranoside. Structural analysis of these proteins allowed the identification of common features from the α-amylase family, in particular from glycoside hydrolases that belong to family GH13. The three acidic residues comprising the catalytic triad were identified and their relevance for the protein hydrolytic mechanism confirmed by site-directed mutagenesis. Recombinant enzymes produced oligosaccharides naturally present in honey employing sucrose as initial substrate and gave rise to mixtures with the same products profile (isomelezitose, trehalulose, erlose, melezitose, theanderose and esculose) previously obtained with M. reukaufii cell extracts. Furthermore, the same enzymatic activity was detected with its orthologous Mg-αGlu from M. gruessii. Interestingly, the isomelezitose amounts obtained in reactions mediated by the recombinant proteins, ~ 170 g/L, were the highest reported so far.

Conclusions

Mg/Mr-αGlu were heterologously overproduced and their biochemical and structural characteristics analysed. The recombinant α-glucosidases displayed excellent properties in terms of mild reaction conditions, in addition to pH and thermal stability. Besides, the enzymes produced a rare mixture of hetero-gluco-oligosaccharides by transglucosylation, mainly isomelezitose and trehalulose. These compounds are natural constituents of honey which purification from this natural source is quite unviable, what make these enzymes very interesting for the biotechnological industry. Finally, it should be remarked that these sugars have potential applications as food additives due to their suitable sweetness, viscosity and humectant capacity.
Nucleic acids in inclusion bodies obtained from E. coli cells expressing human interferon-gamma
Authors: Krachmarova Elena , Ivanov Ivan , Nacheva Genoveva
Published: July 2020

Background

Inclusion bodies (IBs) are protein aggregates in recombinant bacterial cells containing mainly the target recombinant protein. Although it has been shown that IBs contain functional proteins along with protein aggregates, their direct application as pharmaceuticals is hindered by their heterogeneity and hazardous contaminants with bacterial origin. Therefore, together with the production of soluble species, IBs remain the main source for manufacture of recombinant proteins with medical application. The quality and composition of the IBs affect the refolding yield and further purification of the recombinant protein. The knowledge whether nucleic acids are genuine components or concomitant impurities of the IBs is a prerequisite for the understanding of the IBs formation and for development of optimized protocols for recombinant protein refolding and purification. IBs isolated from Escherichia coli overexpressing human interferon-gamma (hIFNγ), a protein with therapeutic application, were used as a model.

Results

IBs were isolated from E. coli LE392 cells transformed with a hIFNγ expressing plasmid under standard conditions and further purified by centrifugation on a sucrose cushion, followed by several steps of sonication and washings with non-denaturing concentrations of urea. The efficiency of the purification was estimated by SDS-PAGE gel electrophoresis and parallel microbiological testing for the presence of residual intact bacteria. Phenol/chloroform extraction showed that the highly purified IBs contain both DNA and RNA. The latter were studied by UV spectroscopy and agarose gel electrophoresis combined with enzymatic treatment and hybridization. DNA was observed as a diffuse fraction mainly in the range of 250 to 1000 bp. RNA isolated by TRIzol® also demonstrated a substantial molecular heterogeneity. Hybridization with 32P-labelled oligonucleotides showed that the IBs contain rRNA and are enriched of hIFNγ mRNA.

Conclusions

The results presented in this study indicate that the nucleic acids might be intrinsic components rather than co-precipitated impurities in the IBs. We assume that the nucleic acids are active participants in the aggregation of recombinant proteins and formation of the IBs that originate from the transcription and translation machinery of the microbial cell factory. Further studies are needed to ascertain this notion.
Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis
Authors: Xu Ning , Ke Zhi-Bin , Lin Xiao-Dan , Chen Ye-Hui , Wu Yu-Peng , Chen Yu , Dong Ru-Nan , Chen Shao-Hao , Li Xiao-Dong , Wei Yong , Zheng Qing-Shui , Lin Yun-Zhi , Xue Xue-Yi
Published: July 2020

Background

Bladder cancer (BCa) is one of the important tumors that have been proven to be treatable with immunotherapy. This study aims to identify and validate a molecular prognostic index of BCa based on immunogenomic landscape analysis.

Methods

The cancer genome atlas (TCGA) database and immunology database and analysis portal (ImmPort) database were used to identified differentially expressed immune-related genes (IRGs). Prognostic IRGs were screened and protein–protein interaction (PPI) network was constructed. Multivariate Cox analysis was performed to develop a molecular prognostic index of BCa. Internal and external validation were then performed in TCGA cohort and GEO cohort, respectively. Besides, we also explore the relationship between this index and clinical characteristics, immune cell infiltration and tumor microenvironment.

Results

A total of 61 prognostic IRGs were identified and a molecular prognostic index was developed. The top four hub genes included MMP9, IGF1, CXCL12 and PGF. The difference in overall survival between high-risk group and low-risk group was statistically significant. The area under curve of the receiver operating characteristic (ROC) curve was 0.757, suggesting the potential for this index. Besides, Internal validation using TCGA cohort and external validation using GEO cohort indicated that this index was of great performance in predicting outcome. T cells CD8, T cells CD4 memory activated, T cells follicular helper, macrophages M0, macrophages M2 and neutrophils were significantly associated with prognosis of BCa patients. Female, high grade, stage III&IV, N1-3 and T3-4 were associated significantly with higher risk score compared with male, low grade, stage I&II, N0 and T1-2, respectively. High risk score had a positive association with higher stromal score and ESTIMATE score while high risk score had a negative association with tumor purity.

Conclusions

This study identified several prognostic immune-related genes of clinical value. Besides, we developed and validated a molecular index based on immunogenomic landscape analysis, which performed well in predicting prognosis of BCa. Further researches are needed to verify the effectiveness of this index and these vital genes.
Prognostic and clinicopathological significance of SNHG20 in human cancers: a meta-analysis
Authors: Zhu Hanlong , Zhao Si , Jiao Ruonan , Wang Huishan , Tang Ruiyi , Wu Xiaochao , Wang Fei , Ge Xianxiu , Li Quanpeng , Miao Lin
Published: July 2020

Background

It has been widely reported that the expression levels of SNHG20 are elevated in diverse types of cancers, indicating that SNHG20 may participate in cancer initiation and development. Besides, accumulating evidence reveals that SNHG20 overexpression is also connected with poor clinical outcomes among cancer patients. Herein, we carry out a systematic meta-analysis to further determine the prognostic and clinical significance of SNHG20 expression in various human cancers.

Methods

Qualifying publications were selected by searching for keywords in PubMed, Embase, Web of Science and Cochrane Library databases, up to September 1, 2019. Pooled hazard ratio (HR) or odds ratio (OR) with corresponding 95% confidence interval (CI) was computed to estimate the strength of association between SNHG20 and survival of cancer patients or clinicopathology using Stata 14.0 software.

Results

In total, 15 studies encompassing 1187 patients met the inclusion criteria were ultimately enrolled for analysis. According to the meta-analysis, patients with high SNHG20 expression were markedly linked to poorer overall survival (OS) (pooled HR = 2.47, 95% CI 2.05–2.98, P = 0.000) and disease-free survival/recurrence-free survival/progression-free survival (DFS/RFS/PFS) (pooled HR = 2.37, 95% CI 1.60–3.51, P = 0.000). Additionally, regarding clinicopathology of patients, enhanced SNHG20 was correlated with advanced tumour‐node‐metastasis (TNM) stage (OR = 2.80, 95% CI 2.00–3.93, P = 0.000), larger tumor size (OR = 3.08, 95% CI 2.11–4.51, P = 0.000), positive lymph nodes metastasis (OR = 2.99, 95% CI 2.08–4.31, P = 0.000), higher tumor stage (OR = 4.51, 95% CI 2.17–9.37, P = 0.000) and worse histological grade (OR = 1.95, 95% CI 1.44–2.63, P = 0.000), but not with gender, smoking status or distant metastasis.

Conclusions

Up-regulated SNHG20 expression is ubiquitous in different kinds of cancers. Moreover, up-regulated SNHG20 expression is capable of serving as an innovative predictive factor of inferior clinical outcomes in cancer patients. Nevertheless, higher-quality multicenter studies are required to corroborate our results.
Roles for circulating polyunsaturated fatty acids in ischemic stroke and modifiable factors: a Mendelian randomization study
Authors: Yuan Tonghui , Si Shucheng , Li Yunxia , Li Wenchao , Chen Xiaolu , Liu Congcong , Li Jiqing , Wang Bojie , Hou Lei , Liu Yanxun , Xue Fuzhong
Published: July 2020

Background

Available data about the effects of circulating polyunsaturated fatty acids (PUFAs) on ischemic stroke (IS) and its main risk factors remains limited and conflicting. Therefore, we conducted Mendelian randomization (MR) to assess whether genetically predicted PUFA affected IS, lipids and blood pressure (BP).

Methods

Genetic instruments associated with IS were derived from ISGC Consortium (n = 29,633), with lipids were derived from GLGC(n = 188,577), with BP were derived from Neale Lab(n = 337,000). The inverse-variance weighted method was the main analysis to estimate the effect of exposure on outcome. Sensitivity analyses included principal components analysis, MR-Egger, weighted median, and weighted mode.

Results

Per SD increases in serum α-linolenic acid (ALA) were associated with lower IS risk, with odd ratio (OR) of 0.867(0.782,0.961), arachidonic acid (AA) were associated with higher IS risk (OR: 1.053(1.014,1.094)). Likewise, Per SD increases in ALA were associated with the lower-level low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) (β:-0.122(− 0.144, − 0.101), − 0.159(− 0.182, − 0.135), − 0.148(− 0.171, − 0.126), respectively), AA were associated with the higher-level of LDL-C, HDL-C and TC (β:0.045(0.034,0.056), 0.059(0.050,0.067), 0.055(0.046,0.063), respectively). Linoleic acid (LA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) had little or no association with IS, lipids or BP at Bonferroni-corrected significance. Different analytic methods supported these findings. The intercept test of MR-Egger implied no pleiotropy.

Conclusions

High-level plasma ALA was protective for IS but AA was the opposite. LA, EPA, DHA, and DPA had no effects on IS.
The development, validation, and psychometric properties of the Japanese version of the Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) for school-age children
Authors: Minamidate Takao , Haruyama Naoto , Takahashi Ichiro
Published: July 2020

Background

This study was performed to develop and validate a Japanese version of Child Oral Health Impact Profile-Short Form (COHIP-SF) 19 and to assess its psychometric properties in Japanese school-age children.

Methods

The original English COHIP-SF 19 was translated into Japanese (COHIP-SF 19 JP) using a standard forward and backward translation procedure. The psychometric properties of the COHIP-SF 19 JP were assessed in 379 public school students between 7 and 18 years of age in Fukuoka, Japan. Internal consistency (Cronbach’s alpha) and test-retest reliability (intraclass correlation coefficient, ICC) were the metrics used for evaluation of this questionnaire. The discriminant validly was examined using the Wilcoxon rank sum test to identify significant differences in COHIP-SF 19 JP scores according to the results of dental examinations. The convergent validity was examined using the Spearman correlations to determine the relationships between COHIP-SF 19 JP scores and the self-perceived oral health ratings. Confirmatory factor analyses (CFA) were performed to verify the factor structure of the questionnaire.

Results

The COHIP-SF 19 JP revealed good internal consistency (Cronbach’s alpha, 0.77) and test-retest reliability (ICC, 0.81). Discriminant validity indicated that children with dental caries or malocclusion had significantly lower COHIP-SF 19 JP scores (P <  0.05); convergent validity indicated that the self-perceived oral health rating was significantly correlated with the COHIP-SF 19 JP total score and subscores (rs = 0.352–0.567,P <  0.0001), indicating that the questionnaire had a sufficient construct validity. CFA suggested that the modified four-factor model had better model fit indices than the original three-factor model.

Conclusion

The collected data showed that the COHIP-SF 19 JP possesses sufficient psychometric properties for use in Japanese school-age children.
Electronic reporting of patient-reported outcomes in a fragile and comorbid population during cancer therapy – a feasibility study
Authors: Taarnhøj Gry Assam , Lindberg Henriette , Dohn Line Hammer , Omland Lise Høj , Hjøllund Niels Henrik , Johansen Christoffer , Pappot Helle
Published: July 2020

Background

Electronic collection of patient-reported outcomes (ePROs) is becoming widespread in health care, but the implementation into routine cancer care during therapy remains to be seen. Especially, little is known of the use and success of electronic reporting during active cancer treatment in fragile and comorbid patients. The aim of this study was to test the feasibility of ePRO and its incorporation into routine cancer care, measured by physician compliance, for a fragile and comorbid bladder cancer (BC) population receiving chemo- or immunotherapy.

Methods

All BC patients initiating treatment for locally advanced or metastatic bladder cancer at Rigshospitalet or Herlev Hospital, Denmark, were approached during an 8 month period. Exclusion criteria were patients not speaking Danish or not being signed up for electronic communication with health authorities. Enrolled patients were prompted to complete weekly ePROs from home. Patients completed the European Organisation for Research and Treatment of Cancer’s general quality of life questionnaire, QLQ-C30, and the module for muscle-invasive bladder cancer QLQ-BLM30, the Hospital Anxiety and Depression Scale, HADS, and selected items from the Patient Reported-Outcomes version of the Common Terminology Criteria of Adverse Events (PRO-CTCAE), in total 158 questions weekly. If failing to report when prompted, patients were sent two e-mail reminders. Patients were informed that the physician would have an overview of the reported ePROs at their following clinical visits. Physicians were at all clinical visits informed to look at the ePROs in a software solution separate from the medical records. Physicians were logged to check their compliance to the task. No continuous surveillance of ePROs was established.

Results

Of 91 patients screened for enrolment, 19 patients (21%) were not found eligible for standard treatment, eight patients (9%) were not signed up for electronic communication with the health authorities and nine patients (10%) declined participation. Another six patients did not meet other inclusion criteria. In total 49 BC patients were enrolled, 29 initiating chemotherapy and 20 initiating immunotherapy. A total of 466 electronic questionnaires were completed. The overall adherence of the patients to complete ePROs was at an expected level for an elderly cancer population (75%) and remained above 70% until the 6th cycle of treatment. The physician’ compliance was in contrast low (0–52%) throughout the course of treatment.

Conclusions

Electronic reporting of PROs is feasible in a fragile and comorbid population of patients during routine active cancer treatment. Despite clear implementation strategies the physician compliance remained low throughout the study proving the need for further implementation strategies.
Number of embryos transferred and diagnosis of preeclampsia
Authors: Sites Cynthia K. , Wilson Donna , Bernson Dana , Boulet Sheree , Zhang Yujia
Published: July 2020

Background

Multiple births and first pregnancy are associated with higher preeclampsia risk. It is unknown if the transfer of multiple embryos or first embryo transfer with assisted reproductive technology (ART) is also associated with greater preeclampsia risk.

Methods

We performed a retrospective cohort study of IVF clinics and hospitals in Massachusetts. We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data for 21,188 births, considering resident singleton (12,810) and twin (8378) live-births from autologous or donor eggs from 2005 to 2012. We used log binomial and Poisson regression to calculate adjusted relative risks (aRRs) and 95% confidence intervals (CI) for the association between preeclampsia and predictors of preeclampsia. Outcomes were stratified by singleton and twin birth, donor versus autologous cycles, and use of fresh versus cryopreserved embryos.

Results

Considering all singleton births, the transfer of multiple embryos increased the risk of preeclampsia [aRR = 1.10 (95% CI: 1.01–1.19)]. Relative risks were greatest for fresh non-donor cycles [aRR = 1.14 (95% CI: 1.03–1.26)]. Vanishing twin and number of prior ART cycles was not associated with preeclampsia among singleton births [aRR = 1.18 (95% CI: 0.91–1.53)], and aRR = 1.01 (95% CI: 0.96–1.05)], respectively. Considering all twin births, the transfer of > 2 embryos increased the risk of preeclampsia [aRR = 1.09 (95% CI: 1.001–1.19)]. Vanishing triplet and number of prior ART cycles were not associated with preeclampsia among twin births [aRR = 0.93 (95% CI: 0.69–1264), and aRR = 0.98 (CI: 0.95–1.02)], respectively.

Conclusions

Among ART births, the transfer of more than 1 embryo for singleton gestations and more than 2 embryos for twin gestations increased the risk for preeclampsia diagnosis.
The role of Wnt/β-catenin-lin28a/let-7 axis in embryo implantation competency and epithelial-mesenchymal transition (EMT)
Authors: Li Qian , Shi Juanzi , Liu Weimin
Published: July 2020

Background

The pre-implantation embryo in a competent status and post-implantation fully differentiation of the inner cell mass (ICM) and trophectoderm (TE) are prerequisites of successful implantation. Type I embryonic epithelial-mesenchymal transition (EMT) involves in these processes. A high level of the mir-let-7 family was found in the dormant mouse embryo of implantation failure in our previous study. Besides, its natural inhibitor lin28a was found to function in maintained stem cell pluripotency and involved in early embryo nucleolus construction. Until now, few studies got involved in the exact molecular mechanism that affects embryo implantation potential. In this study, the possible function of Wnt/β-catenin-lin28a/let-7 pathway in mouse embryo implantation was studied.

Methods

ICR mouse, Lin28a/Let-7 g transgenic mice (Lin28a-TG/Let-7 g-TG), and implanting dormant mice models were used for the study.

Results

Wnt/β-catenin signaling is essential in embryo implantation, which promotes embryo implantation through directly trigger lin28a expression, thus represses the mir-let-7 family. Lin28a and mir-let-7 both participate in implantation via an inverse function. Lin28a and mir-let-7 participate in embryo implantation through embryonic EMT.

Conclusions

Wnt/β-catenin signaling promotes embryo implantation and accompanying embryonic EMT, which is mediated by directly activate lin28a/let-7 axis.
Prion peptide-mediated calcium level alteration governs neuronal cell damage through AMPK-autophagy flux
Authors: Moon Ji-Hong , Park Sang-Youel
Published: July 2020

Background

The distinctive molecular structure of the prion protein, PrPsc, is established only in mammals with infectious prion diseases. Prion protein characterizes either the transmissible pathogen itself or a primary constituent of the disease. Our report suggested that prion protein-mediated neuronal cell death is triggered by the autophagy flux. However, the alteration of intracellular calcium levels, AMPK activity in prion models has not been described. This study is focused on the effect of the changes in intracellular calcium levels on AMPK/autophagy flux pathway and PrP (106–126)-induced neurotoxicity.

Methods

Western blot and Immunocytochemistry was used to detect AMPK and autophagy-related protein expression. Flow cytometry and a TdT-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay were used to detect the percentage of apoptotic cells. Calcium measurement was employed using fluo-4 by confocal microscope.

Results

We examined the effect of calcium homeostasis alterations induced by human prion peptide on the autophagy flux in neuronal cells. Treatment with human prion peptide increased the intracellular calcium concentration and induced cell death in primary neurons as well as in a neuronal cell line. Using pharmacological inhibitors, we showed that the L-type calcium channel is involved in the cellular entry of calcium ions. Inhibition of calcium uptake prevented autophagic cell death and reduction in AMP-activated protein kinase (AMPK) activity induced by human prion peptide.

Conclusion

Our data demonstrated that prion peptide-mediated calcium inflow plays a pivotal role in prion peptide-induced autophagic cell death, and reduction in AMPK activity in neurons. Altogether, our results suggest that calcium influx might play a critical role in neurodegenerative diseases, including prion diseases.
lncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells
Authors: Topel Hande , Bagirsakci Ezgi , Comez Dehan , Bagci Gulsun , Cakan-Akdogan Gulcin , Atabey Nese
Published: July 2020

Background

Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC.

Methods

Expression of c-Met and lncRNA HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic lncRNA HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits.

Results

In vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC.

Conclusions

Our work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells.
Recent insights on indirect mechanisms in developmental toxicity of nanomaterials
Authors: Dugershaw Battuja Batbajar , Aengenheister Leonie , Hansen Signe Schmidt Kjølner , Hougaard Karin Sørig , Buerki-Thurnherr Tina
Published: July 2020

Background

Epidemiological and animal studies provide compelling indications that environmental and engineered nanomaterials (NMs) pose a risk for pregnancy, fetal development and offspring health later in life. Understanding the origin and mechanisms underlying NM-induced developmental toxicity will be a cornerstone in the protection of sensitive populations and the design of safe and sustainable nanotechnology applications.

Main body

Direct toxicity originating from NMs crossing the placental barrier is frequently assumed to be the key pathway in developmental toxicity. However, placental transfer of particles is often highly limited, and evidence is growing that NMs can also indirectly interfere with fetal development. Here, we outline current knowledge on potential indirect mechanisms in developmental toxicity of NMs.

Short conclusion

Until now, research on developmental toxicity has mainly focused on the biodistribution and placental translocation of NMs to the fetus to delineate underlying processes. Systematic research addressing NM impact on maternal and placental tissues as potential contributors to mechanistic pathways in developmental toxicity is only slowly gathering momentum. So far, maternal and placental oxidative stress and inflammation, activation of placental toll-like receptors (TLRs), impairment of placental growth and secretion of placental hormones, and vascular factors have been suggested to mediate indirect developmental toxicity of NMs. Therefore, NM effects on maternal and placental tissue function ought to be comprehensively evaluated in addition to placental transfer in the design of future studies of developmental toxicity and risk assessment of NM exposure during pregnancy.
Induction of ferroptosis in response to graphene quantum dots through mitochondrial oxidative stress in microglia
Authors: Wu Tianshu , Liang Xue , Liu Xi , Li Yimeng , Wang Yutong , Kong Lu , Tang Meng
Published: July 2020

Background

Graphene quantum dots (GQDs) provide a bright prospect in the biomedical application because they contain low-toxic compounds and promise imaging of deep tissues and tiny vascular structures. However, the biosafety of this novel QDs has not been thoroughly evaluated, especially in the central nervous system (CNS). The microarray analysis provides a hint that nitrogen-doped GQDs (N-GQDs) exposure could cause ferroptosis in microglia, which is a novel form of cell death dependent on iron overload and lipid peroxidation.

Results

The cytosolic iron overload, glutathione (GSH) depletion, excessive reactive oxygen species (ROS) production and lipid peroxidation (LPO) were observed in microglial BV2 cells treated with N-GQDs, which indicated that N-GQDs could damage the iron metabolism and redox balance in microglia. The pre-treatments of a specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) and an iron chelater Deferoxamine mesylate (DFO) not only inhibited cell death, but also alleviated iron overload, LPO and alternations in ferroptosis biomarkers in microglia, which were caused by N-GQDs. When assessing the potential mechanisms of N-GQDs causing ferroptosis in microglia, we found that the iron content, ROS generation and LPO level in mitochondria of BV2 cells all enhanced after N-GQDs exposure. When the antioxidant ability of mitochondria was increased by the pre-treatment of a mitochondria targeted ROS scavenger MitoTEMPO, the ferroptotic biological changes were effectively reversed in BV2 cells treated with N-GQDs, which indicated that the N-GQDs-induced ferroptosis in microglia could be attributed to the mitochondrial oxidative stress. Additionally, amino functionalized GQDs (A-GQDs) elicited milder redox imbalance in mitochondria and resulted in less ferroptotic effects than N-GQDs in microglia, which suggested a slight protection of amino group functionalization in GQDs causing ferroptosis.

Conclusion

N-GQDs exposure caused ferroptosis in microglia via inducing mitochondrial oxidative stress, and the ferroptotic effects induced by A-GQDs were milder than N-GQDs when the exposure method is same. This study will not only provide new insights in the GQDs-induced cell damage performed in multiple types of cell death, but also in the influence of chemical modification on the toxicity of GQDs.
Intraoperative ultrasonography assistance for minimally invasive repair of the acute Achilles tendon rupture
Authors: Yongliang Yang , Honglei Jia , Wupeng Zhang , Shihong Xu , Fu Wang , Bomin Wang , Qinghu Li , Yonghui Wang , Shumei Han
Published: July 2020

Background

Minimally invasive repair is a better option for Achilles tendon rupture with low re-rupture and wound-related complications than conservative treatment or traditional open repair. The major problem is sural nerve injury. The purpose of this study was to evaluate the effect and advantage of the intraoperative ultrasonography assistance for minimally invasive repair of the acute Achilles tendon rupture.

Methods

A retrospective study was performed on 36 cases of acute Achilles tendon rupture treated with minimally invasive repair assisted with intraoperative ultrasonography from January 2015 to December 2017. The relationship of the sural nerve and small saphenous vein was confirmed on the preoperative MRI. The course of the small saphenous vein and the sural nerve was identified and marked by intraoperative ultrasonography. The ruptured Achilles tendon was repaired with minimally invasive Bunnell suture on the medial side of the small saphenous vein (SSV).

Results

All patients were followed up for at least 12 months. No sural nerve injury or other complications was found intraoperatively and postoperatively. All the patients returned to work and light sporting activities at a mean of 12.78 ± 1.40 weeks and 17.28 ± 2.34 weeks, respectively. The Mean American Orthopaedic Foot & Ankle Society (AOFAS) scores improved from 59.17 ± 5.31 preoperatively to 98.92 ± 1.63 at the time of 12 months follow-up. There was a statistically significant difference (P < 0.001). No patient complained of a negative effect on their life.

Conclusions

The minimally invasive repair assisted with intraoperative ultrasonography can yield good clinical outcomes, less surgical time, and less complications, especially sural nerve injury. It is an efficient, reliable, and safe method for acute Achilles tendon (AT) rupture.
Bovine pestivirus is a new alternative virus for multiple myeloma oncolytic virotherapy
Authors: Marchica Valentina , Franceschi Valentina , Vescovini Rosanna , Storti Paola , Vicario Emanuela , Toscani Denise , Zorzoli Alessia , Airoldi Irma , Dalla Palma Benedetta , Campanini Nicoletta , Martella Eugenia , Mancini Cristina , Costa Federica , Donofrio Gaetano , Giuliani Nicola
Published: July 2020

Background

The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients’ antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46.

Methods

We treated several human myeloma cell lines and non-myeloma cell lines with BVDV to evaluate the expression of CD46 and to study the effect on cell viability by flow cytometry. The possible synergistic effect of bortezomib in combination with BVDV was also tested. Moreover, we infected the bone marrow mononuclear cells obtained from myeloma patients and we checked the BVDV effect on different cell populations, defined by CD138, CD14, CD3, CD19, and CD56 expression evaluated by flow cytometry. Finally, the in vivo BVDV effect was tested in NOD-SCID mice injected subcutaneously with myeloma cell lines.

Results

Human myeloma cells were selectively sensitive to BVDV treatment with an increase of cell death and, consequently, of apoptotic markers. Consistently, bone marrow mononuclear cells isolated from myeloma patients treated with BVDV, showed a significant selective decrease of the percentage of viable CD138+ cells. Interestingly, bortezomib pre-treatment significantly increased the cytotoxic effect of BVDV in myeloma cell lines with a synergistic effect. Finally, the in vitro data were confirmed in an in vivo myeloma mouse model showing that BVDV treatment significantly reduced the tumoral burden compared to the vehicle.

Conclusions

Overall, our data indicate, for the first time, a direct oncolytic effect of the BVDV in human myeloma cells suggesting its possible use as novel alternative anti-myeloma virotherapy strategy.
RNA-binding proteins in tumor progression
Authors: Qin Hai , Ni Haiwei , Liu Yichen , Yuan Yaqin , Xi Tao , Li Xiaoman , Zheng Lufeng
Published: July 2020

RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.