bluuebunny/crossref_metadata_2025 huggingface dataset:
The cost of the training and supervision of community health workers to improve exclusive breastfeeding amongst mothers in a cluster randomised controlled trial in South Africa
Authors: George Gavin , Mudzingwa Takunda , Horwood Christiane
Published: February 2020

Background

Interventions targeting community health workers (CHWs) aim to optimise the delivery of health services to underserved rural areas. Whilst interventions are evaluated against their objectives, there remains limited evidence on the economic costs of these interventions, and the practicality and value of scale up. The aim of this paper is to undertake a cost analysis on a CHW training and supervision intervention using exclusive breastfeeding rates amongst mothers as an outcome measure.

Methods

This is a retrospective cost analysis, from an implementer’s perspective, of a cluster randomised controlled trial investigating the effectiveness of a continuous quality improvement (CQI) intervention aimed at CHWs providing care and support to pregnant women and women with babies aged < 1 year in South Africa.

Results

One of the outcomes of the RCT revealed that the prevalence of exclusive breastfeeding (EBF) significantly improved, with the cost per mother EBF in the control and intervention arm calculated at US$760,13 and US$1705,28 respectively. The cost per additional mother practicing EBF was calculated to be US$7647, 88, with the supervision component of the intervention constituting 64% of the trial costs. In addition, women served by the intervention CHWs were more likely to have received a CHW visit and had significantly better knowledge of childcare practices.

Conclusion

Whilst the cost of this intervention is high, adapted interventions could potentially offer an economical alternative for achieving selected maternal and child health (MCH) outcomes. The results of this study should inform future programmes aimed at providing adapted training and supervision to CHWs with the objective of improving community-level health outcomes.
Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model
Authors: Modi Jigar , Menzie-Suderam Janet , Xu Hongyuan , Trujillo Paola , Medley Kristen , Marshall Michael L. , Tao Rui , Prentice Howard , Wu Jang-Yen
Published: February 2020

Background

The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress.

Methods

Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 μg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting.

Results

G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA.

Conclusions

G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.
m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling
Authors: Tang Bo , Yang Yihua , Kang Min , Wang Yunshan , Wang Yan , Bi Yin , He Songqing , Shimamoto Fumio
Published: February 2020

Background

Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation.

Methods

qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models.

Results

Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. DecreasedALKBH5levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway.

Conclusions

Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.
Cost-effectiveness analysis of imaging surveillance in stage II and III extremity soft tissue sarcoma: an Australian perspective
Authors: Bae Susie , Karnon Jonathan , Crane Glenis , Bessen Taryn , Desai Jayesh , Crowe Phillip , Neuhaus Susan
Published: February 2020

Background

Surveillance imaging is used to detect local and/or distant recurrence following primary treatment of localised soft tissue sarcoma (STS), however evidence supporting optimal surveillance modality or frequency is lacking. We used prospectively collected sarcoma data to describe current surveillance imaging practice in patients with AJCC stage II and III extremity STS and evaluate its cost-effectiveness.

Methods

From three selected Australian sarcoma referral centres, we identified patients with stage II and III extremity STS treated between 2009 and 2013. Medical records were reviewed to ascertain surveillance imaging practices, including modality, frequency and patient outcomes. A discrete event simulation model was developed and calibrated using clinical data to estimate health service costs and quality adjusted life years (QALYs) associated with alternative surveillance strategies.

Results

Of 133 patients treated for stage II and III extremity STS, the majority were followed up with CT chest (86%), most commonly at 3-monthly intervals and 62% of patients had the primary site imaged with MRI at 6-monthly. There was limited use of chest-X-ray. A discrete event simulation model demonstrated that CT chest screening was the most cost effective surveillance strategy, gaining additional QALYs at a mean incremental cost of $30,743. MRI alone and PET-CT alone were not cost-effective, whilst a combined strategy of CT + MRI had an incremental cost per QALY gained of $96,556.

Conclusions

Wide variations were observed in surveillance imaging practices in this high-risk STS cohort. Modelling demonstrated the value of CT chest for distant recurrence surveillance over other forms of imaging in terms of cost and QALYs. Further work is required to evaluate cost-effectiveness in a prospective manner.
Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma
Authors: Xu Fengkai , Liu Zhonghe , Liu Ronghua , Lu Chunlai , Wang Lin , Mao Wei , Zhu Qiaoliang , Shou Huankai , Zhang Kunpeng , Li Yin , Chu Yiwei , Gu Jie , Ge Di
Published: February 2020

Background

Esophageal squamous cell cancer (ESCC) is one kind of frequent digestive tumor. The inflammatory environment plays an important role in the tumorigenesis and development of ESCC. Cancer stem cells are a small group of tumor cells with stem cell characteristics, which can potentially hinder the tumor management and treatment.

Methods

ELISA was performed to detect the lipopolysaccharide concentration in cancer tissues. qPCR, Western blot, FACS, Immunohistochemistry, Immunofluorescence and Dot blot were applied to detect target genes expression. CCK-8, Colony-formation, Transwell, Sphere and Xenograft were conducted to investigate the function of cells, influenced by risk factors. The survival curve was drawn with the Kaplan-Meier product limit estimator. Nano-hmC-Seal-seq was utilized to detect the downstream target of TET3. ChIP-qPCR was adopted to demonstrate the transcriptional regulation of stem cell-associated genes by HOXB2.

Results

Lipopolysaccharide concentration was significantly up-regulated in ESCC. High concentration of lipopolysaccharide stimulation induced the stemness of ESCC cells. TET3 expression was elevated with lipopolysaccharide stimulation via p38/ERK-MAPK pathway in ESCC and negatively correlated with patients’ survival. TET3 induced the stemness of ESCC cells. Nano-hmC-Seal-seq showed that TET3 overexpression led to a significant increase in 5hmC levels of HOXB2 gene region, which was thus identified as the downstream target of TET3. The binding of HOXB2 to NANOG and cMYC was verified by ChIP-qPCR.

Conclusions

Lipopolysaccharide served as a tumor promotor in ESCC by inducing cancer cell stemness through the activation of a LPS-TET3-HOXB2 signaling axis, which might provide a novel therapeutic strategy for ESCC.
Targeting the NAD+ salvage pathway suppresses APC mutation-driven colorectal cancer growth and Wnt/β-catenin signaling via increasing Axin level
Authors: Ye Chenyang , Qi Lina , Li Xiaofen , Wang Ji , Yu Jiekai , Zhou Biting , Guo Cheng , Chen Jiani , Zheng Shu
Published: February 2020

Background

The role and mechanism of the nicotinamide adenine dinucleotide (NAD+) salvage pathway in cancer cell proliferation is poorly understood. Nicotinamide phosphoribosyltransferase (NAMPT), which converts nicotinamide into NAD+, is the rate-limiting enzyme in the NAD+ salvage pathway. Here, we assessed the role of NAMPT in the proliferation of colorectal cancer.

Methods

Real-time PCR, immunohistochemistry, western blotting, and analyses of datasets from Oncomine and Gene Expression Omnibus were conducted to assess the expression of NAMPT at the mRNA and protein levels in colorectal cancer. The Kaplan Meier plotter online tool was used to evaluate the prognostic role of NAMPT. Knockdown of NAMPT was performed to assess the role of NAMPT in colorectal cancer cell proliferation and tumorigenesis both in vitro and in vivo. Overexpression of NAMPT was used to evaluate impact of NAMPT on colorectal cancer cell proliferation in vitro. NAD+ quantitation, immunofluorescence, dual luciferase assay and western blot were used to explore the mechanism of colorectal cancer proliferation. Transwell migration and invasion assays were conducted to assess the role of NAMPT in cell migration and invasion abilities of colorectal cancer cells.

Results

Our study indicated that the inhibition of NAMPT decreased proliferation capacity of colorectal cancer cells both in vitro and in vivo. Conversely, overexpression of NAMPT could promote cell proliferation in vitro. NAMPT inhibition induced β-catenin degradation by increasing Axin expression levels; this resulted in the inhibition of Wnt/β-catenin signaling and cell proliferation in colorectal cancer. The addition of nicotinamide mononucleotide, the enzymatic product of NAMPT, effectively reversed β-catenin protein degradation and inhibited growth. Similarly, the knockdown of Axin also decreased the cell death induced by the inhibition of NAMPT. In addition, we showed that colorectal cancer tissues harbored significantly higher levels of NAMPT than the levels harbored by paired normal tissues, especially in colorectal cancer stages I and II. And the overexpression of NAMPT was associated with unfavorable survival results.

Conclusions

Our findings reveal that NAMPT plays an important role in colorectal cancer proliferation via Wnt/β-catenin pathway, which could have vital implications for the diagnosis, prognosis and treatment of colorectal cancer.
Porcine β-defensin 2 inhibits proliferation of pseudorabies virus in vitro and in transgenic mice
Authors: Huang Jing , Qi Yanhua , Wang Antian , Huang Chao , Liu Xiao , Yang Xi , Li Lu , Zhou Rui
Published: February 2020

Background

Porcine β-defensin 2 (PBD-2), produced by host cells, is an antimicrobial cysteine-rich cationic peptide with multi-functions. Previous studies have demonstrated that PBD-2 can kill various bacteria, regulate host immune responses and promote growth of piglets. However, the antiviral role of PBD-2 is rarely investigated. This study aimed to reveal the antiviral ability of PBD-2 against pseudorabies virus (PRV), the causative pathogen of Aujeszky’s disease, in PK-15 cells and in a PBD-2 expressing transgenic (TG) mouse model.

Methods

In this study, the cytotoxicity of PBD-2 on PK-15 cells was measured by CCK-8 assay. PK-15 cells were incubated with PRV pre-treated with different concentrations of PBD-2 and PRV titers in cell culture supernatants were determined by real-time quantitative PCR (RT-qPCR). TG mice and wild-type (WT) mice were intraperitoneally injected with PRV and the survival rate was recorded for 10 days. Meanwhile, tissue lesions in brain, spleen and liver of infected mice were observed and the viral loads of PRV in brain, liver and lung were analyzed by RT-qPCR.

Results

PBD-2 at a maximum concentration of 80 μg/mL displayed no significant cytotoxicity on PK-15 cells. A threshold concentration of PBD-2 at 40 μg/mL was required to inhibit PRV proliferation in PK-15 cells. The survival rate in PBD-2 TG mice was 50% higher than that of WT mice. In addition, TG mice showed alleviated tissue lesions in brain, spleen and liver compared with their WT littermates after PRV challenge, while viral loads of PRV in brain, liver and lung of TG mice were significantly lower than that of WT mice.

Conclusions

PBD-2 could inhibit PRV proliferation in PK-15 cells and protect mice from PRV infection, which confirmed the antiviral ability of PBD-2 both in vitro and in vivo. The application of PBD-2 in developing anti-viral drugs or disease-resistant animals can be further investigated.
Sequential screening for depression in humanitarian emergencies: a validation study of the Patient Health Questionnaire among Syrian refugees
Authors: Poole Danielle N. , Liao Shirley , Larson Elysia , Hedt-Gauthier Bethany , Raymond Nathaniel A. , Bärnighausen Till , Smith Fawzi Mary C.
Published: February 2020

Background

Despite the need for mental health surveillance in humanitarian emergencies, there is a lack of validated instruments. This study evaluated a sequential screening process for major depressive disorder (MDD) using the two- and eight-item Patient Health Questionnaires (PHQ-2 and PHQ-8, respectively).

Methods

This study analyzed data collected during a cross-sectional survey in a Syrian refugee camp in Greece (n = 135). The response rate for each instrument was assessed, and response burden was calculated as the number of items completed. The sequential screening process was simulated to replicate the MDD classifications captured if the PHQ-2 was used to narrow the population receiving the full PHQ-8 assessment. All respondents were screened using the PHQ-2. Only respondents scoring ≥ 2 are considered at risk for symptoms of MDD and complete the remaining six items. The positive and negative percent agreement of this sequential screening process were evaluated.

Results

The PHQ-2, PHQ-2/8 sequential screening process, and PHQ-8 were completed by 91%, 87%, and 84% of respondents, respectively. The sequential screening process had a positive percent agreement of 89% and a negative percent agreement of 100%, and eliminated the need to complete the full PHQ-8 scale for 34 (25%) respondents.

Conclusions

The benefits of the sequential screening approach for the classification of MDD presented here are twofold: preserving classification accuracy relative to the PHQ-2 alone while reducing the response burden of the PHQ-8. This sequential screening approach is a pragmatic strategy for streamlining MDD surveillance in humanitarian emergencies.
Commercial video games and cognitive functions: video game genres and modulating factors of cognitive enhancement
Authors: Choi Eunhye , Shin Suk-Ho , Ryu Jeh-Kwang , Jung Kyu-In , Kim Shin-Young , Park Min-Hyeon
Published: February 2020

Background

Unlike the emphasis on negative results of video games such as the impulsive engagement in video games, cognitive training studies in individuals with cognitive deficits showed that characteristics of video game elements were helpful to train cognitive functions. Thus, this study aimed to have a more balanced view toward the video game playing by reviewing genres of commercial video games and the association of video games with cognitive functions and modulating factors. Literatures were searched with search terms (e.g. genres of video games, cognitive training) on database and Google scholar.

Results

video games, of which purpose is players’ entertainment, were found to be positively associated with cognitive functions (e.g. attention, problem solving skills) despite some discrepancy between studies. However, the enhancement of cognitive functions through video gaming was limited to the task or performance requiring the same cognitive functions. Moreover, as several factors (e.g. age, gender) were identified to modulate cognitive enhancement, the individual difference in the association between video game playing and cognitive function was found.

Conclusion

Commercial video games are suggested to have the potential for cognitive function enhancement. As understanding the association between video gaming and cognitive function in a more balanced view is essential to evaluate the potential outcomes of commercial video games that more people reported to engage, this review contributes to provide more objective evidence for commercial video gaming.
A cucumber green mottle mosaic virus vector for virus-induced gene silencing in cucurbit plants
Authors: Liu Mei , Liang Zhiling , Aranda Miguel A. , Hong Ni , Liu Liming , Kang Baoshan , Gu Qinsheng
Published: February 2020

Background

Cucurbits produce fruits or vegetables that have great dietary importance and economic significance worldwide. The published genomes of at least 11 cucurbit species are boosting gene mining and novel breeding strategies, however genetic transformation in cucurbits is impractical as a tool for gene function validation due to low transformation efficiency. Virus-induced gene silencing (VIGS) is a potential alternative tool. So far, very few ideal VIGS vectors are available for cucurbits.

Results

Here, we describe a new VIGS vector derived from cucumber green mottle mosaic virus (CGMMV), a monopartite virus that infects cucurbits naturally. We show that the CGMMV vector is competent to induce efficient silencing of the phytoene desaturase (PDS) gene in the model plant Nicotiana benthamiana and in cucurbits, including watermelon, melon, cucumber and bottle gourd. Infection with the CGMMV vector harboring PDS sequences of 69–300 bp in length in the form of sense-oriented or hairpin cDNAs resulted in photobleaching phenotypes in N. benthamiana and cucurbits by PDS silencing. Additional results reflect that silencing of the PDS gene could persist for over two months and the silencing effect of CGMMV-based vectors could be passaged.

Conclusions

These results demonstrate that CGMMV vector could serve as a powerful and easy-to-use tool for characterizing gene function, controlling viral pathogens or even performing resistance breeding in cucurbits. Moreover, this study will possess considerable important reference value for developing different viral vectors.
Correction to: Effects of the Bragg peak degradation due to lung tissue in proton therapy of lung cancer patients
Authors: Baumann Kilian-Simon , Flatten Veronika , Weber Uli , Lautenschläger Stefan , Eberle Fabian , Zink Klemens , Engenhart-Cabillic Rita
Published: February 2020

Following publication of the original article [1], we have been notified that the below text parts of the Discussion chapter should be changed.
Kaposiform hemangioendothelioma: current knowledge and future perspectives
Authors: Ji Yi , Chen Siyuan , Yang Kaiying , Xia Chunchao , Li Li
Published: February 2020

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm with high morbidity and mortality. The initiating mechanism during the pathogenesis of KHE has yet to be discovered. The main pathological features of KHE are abnormal angiogenesis and lymphangiogenesis. KHEs are clinically heterogeneous and may develop into a life-threatening thrombocytopenia and consumptive coagulopathy, known as the Kasabach-Merritt phenomenon (KMP). The heterogeneity and the highly frequent occurrence of disease-related comorbidities make the management of KHE challenging. Currently, there are no medications approved by the FDA for the treatment of KHE. Multiple treatment regimens have been used with varying success, and new clinical trials are in progress. In severe patients, multiple agents with variable adjuvant therapies are given in sequence or in combination. Recent studies have demonstrated a satisfactory efficacy of sirolimus, an inhibitor of mammalian target of rapamycin, in the treatment of KHE. Novel targeted treatments based on a better understanding of the pathogenesis of KHE are needed to maximize patient outcomes and quality of life. This review summarizes the epidemiology, etiology, pathophysiology, clinical features, diagnosis and treatments of KHE. Recent new concepts and future perspectives for KHE will also be discussed.
Correction to: Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease
Authors: Huebecker Mylene , Moloney Elizabeth B. , van der Spoel Aarnoud C. , Priestman David A. , Isacson Ole , Hallett Penelope J. , Platt Frances M.
Published: February 2020

The original article [1] contains an error in the y-axes of Fig. 8’s sub-figures whereby ‘CSF’ is mistakenly mentioned instead of ‘serum’.
Genome-wide MNase hypersensitivity assay unveils distinct classes of open chromatin associated with H3K27me3 and DNA methylation in Arabidopsis thaliana
Authors: Zhao Hainan , Zhang Wenli , Zhang Tao , Lin Yuan , Hu Yaodong , Fang Chao , Jiang Jiming
Published: February 2020

Background

Regulation of transcription depends on interactions betweencis-regulatory elements (CREs) and regulatory proteins. Active CREs are imbedded in open chromatin that are accessible to nucleases. Several techniques, including DNase-seq, which is based on nuclease DNase I, and ATAC-seq, which is based on transposase Tn5, have been widely used to identify genomic regions associated with open chromatin. These techniques have played a key role in dissecting the regulatory networks in gene expression in both animal and plant species.

Results

We develop a technique, named MNase hypersensitivity sequencing (MH-seq), to identify genomic regions associated with open chromatin inArabidopsis thaliana. Genomic regions enriched with MH-seq reads are referred as MNase hypersensitive sites (MHSs). MHSs overlap with the majority (~ 90%) of the open chromatin identified previously by DNase-seq and ATAC-seq. Surprisingly, 22% MHSs are not covered by DNase-seq or ATAC-seq reads, which are referred to “specific MHSs” (sMHSs). sMHSs tend to be located away from promoters, and a substantial portion of sMHSs are derived from transposable elements. Most interestingly, genomic regions containing sMHSs are enriched with epigenetic marks, including H3K27me3 and DNA methylation. In addition, sMHSs show a number of distinct characteristics including association with transcriptional repressors. Thus, sMHSs span distinct classes of open chromatin that may not be accessible to DNase I or Tn5. We hypothesize that the small size of the MNase enzyme relative to DNase I or Tn5 allows its access to relatively more condensed chromatin domains.

Conclusion

MNase can be used to identify open chromatin regions that are not accessible to DNase I or Tn5. Thus, MH-seq provides an important tool to identify and catalog all classes of open chromatin in plants.
Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study
Authors: Chabriat Hugues , Bassetti Claudio L. , Marx Ute , Picarel-Blanchot Françoise , Sors Aurore , Gruget Celine , Saba Barbara , Wattez Marine , Audoli Marie-Laure , Hermann Dirk M.
Published: February 2020

Background

The GABAA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019.

Methods/design

The study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included.

The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed.

Discussion

The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS.

Trial registration

Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016–001005-16. Registered 24 August 2016
Integrated systems analysis of salivary gland transcriptomics reveals key molecular networks in Sjögren’s syndrome
Authors: Min Hong Ki , Moon Su-Jin , Park Kyung-Su , Kim Ki-Jo
Published: February 2020

Background

Treatment of patients with Sjögren’s syndrome (SjS) is a clinical challenge with high unmet needs. Gene expression profiling and integrative network-based approaches to complex disease can offer an insight on molecular characteristics in the context of clinical setting.

Methods

An integrated dataset was created from salivary gland samples of 30 SjS patients. Pathway-driven enrichment profiles made by gene set enrichment analysis were categorized using hierarchical clustering. Differentially expressed genes (DEGs) were subjected to functional network analysis, where the elements of the core subnetwork were used for key driver analysis.

Results

We identified 310 upregulated DEGs, including nine known genetic risk factors and two potential biomarkers. The core subnetwork was enriched with the processes associated with B cell hyperactivity. Pathway-based subgrouping revealed two clusters with distinct molecular signatures for the relevant pathways and cell subsets. Cluster 2, with low-grade inflammation, showed a better response to rituximab therapy than cluster 1, with high-grade inflammation. Fourteen key driver genes appeared to be essential signaling mediators downstream of the B cell receptor (BCR) signaling pathway and to have a positive relationship with histopathology scores.

Conclusion

Integrative network-based approaches provide deep insights into the modules and pathways causally related to SjS and allow identification of key targets for disease. Intervention adjusted to the molecular traits of the disease would allow the achievement of better outcomes, and the BCR signaling pathway and its leading players are promising therapeutic targets.
Serial magnetic resonance imaging and ultrasound examinations demonstrate differential inflammatory lesion patterns in soft tissue and bone upon patient-reported flares in rheumatoid arthritis
Authors: Kuettel Dorota , Glinatsi Daniel , Østergaard Mikkel , Terslev Lene , Primdahl Jette , Möller Sören , Pedersen Andreas , Petersen Randi , Weber Ulrich , Hørslev-Petersen Kim
Published: February 2020

Background

Magnetic resonance imaging (MRI) and ultrasonography (US) are more sensitive than clinical evaluation in assessing inflammation in rheumatoid arthritis (RA). Data is scarce regarding potential link between patient-reported flares and inflammation on imaging. The aim of the study was to explore the pattern and longitudinal associations of inflammatory lesions detected by serial MRI and US in relation to patient-reported flares in patients with RA.

Methods

Eighty RA patients with baseline DAS28CRP < 3.2 and no swollen joints were examined at baseline and followed for 1 year. Patients were requested to contact the hospital in case of patient-reported hand flare accompanied by ≥ 1 tender and swollen joint. The 29 patients who reported hand flare had four extra visits within 4 months from flare onset comprising clinical examination, patient-reported outcomes, MRI, and US of wrists and hands. MRI synovitis/tenosynovitis/bone marrow edema (BME) and US synovitis/tenosynovitis were scored. MRI and US scores at and after the flare were compared to baseline before the flare, and associations were explored by linear mixed models for repeated measurements.

Results

Synovitis and tenosynovitis by MRI/US increased significantly at flare onset. Synovitis waned quickly, as did US tenosynovitis. BME showed delayed increase yet persisted, once the patient-reported flare had resolved, as did MRI tenosynovitis. In univariate models, patient-reported flares were associated with all MRI and US inflammatory markers, except for BME, which was only associated with SJC28 and long-lasting flares > 14 days. Independent associations were observed between patient-reported flares and tenosynovitis by MRI and US (p < 0.05).

Conclusions

Patient-reported flares were linked to inflammation detected by serial MRI and US. Differential patterns of inflammatory lesion evolution were observed by serial imaging with early synovial and tenosynovial inflammation, followed by delayed-onset BME.
High-throughput sequencing of virus-infected Cucurbita pepo samples revealed the presence of Zucchini shoestring virus in Zimbabwe
Authors: Karavina Charles , Ibaba Jacques Davy , Gubba Augustine
Published: February 2020

Objectives

Plant-infecting viruses remain a serious challenge towards achieving food security worldwide. Cucurbit virus surveys were conducted in Zimbabwe during the 2014 and 2015 growing seasons. Leaf samples displaying virus-like symptoms were collected and stored until analysis. Three baby marrow samples were subjected to next-generation sequencing and the data generated were analysed using genomics technologies. Zucchini shoestring virus (ZSSV), a cucurbit-infecting potyvirus previously described in South Africa was one of the viruses identified. The genomes of the three ZSSV isolates are described analysed in this note.

Results

The three ZSSV isolates had the same genome size of 10,297 bp excluding the polyA tail with a 43% GC content. The large open reading frame was found at positions 69 to 10,106 on the genome and encodes a 3345 amino acids long polyprotein which had the same cleavage site sequences as those described on the South African isolate except for the P1-pro site. Genome sequence comparisons of all the ZSSV isolates showed that the isolates F7-Art and S6-Prime had identical sequence across the entire genome while sharing 99.06% and 99.34% polyprotein nucleotide and amino acid sequence identities, respectively with the isolate S7-Prime.
Effector function of anti-pyroglutamate-3 Aβ antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer’s-like mice
Authors: Crehan Helen , Liu Bin , Kleinschmidt Martin , Rahfeld Jens-Ulrich , Le Kevin X. , Caldarone Barbara J. , Frost Jeffrey L. , Hettmann Thore , Hutter-Paier Birgit , O’Nuallain Brian , Park Mi-Ae , DiCarli Marcelo F. , Lues Inge , Schilling Stephan , Lemere Cynthia A.
Published: February 2020

Background

Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer’s disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology.

Methods

We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APPSWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aβ in an ex vivo phagocytosis assay and following treatment in APPSLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific 18F-GE180 tracer following a single bolus antibody injection in young and old Tg mice.

Results

We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APPSWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aβ. Treatment of APPSLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal 18F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice.

Conclusion

Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.
Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial
Authors: Gu Jiaowei , Huang Li , Zhang Che , Wang Yong , Zhang Ruibo , Tu Ziliang , Wang Hengdong , Zhou Xihui , Xiao Zhousheng , Liu Zegan , Hu Xiang , Ke Zunchen , Wang Dabin , Liu Li
Published: February 2020

Background

Cerebral palsy (CP) is a syndrome of childhood movement and posture disorders. Clinical evidence is still limited and sometimes inconclusive about the benefits of human umbilical cord mesenchymal stem cells (hUC-MSCs) for CP. We conducted a randomized trial to evaluate the safety and efficacy of hUC-MSC transplantation concomitant with rehabilitation in patients with CP.

Methods

Eligible patients were allocated into the hUC-MSC group and control group. In addition to rehabilitation, the patients in the hUC-MSC group received four transfusions of hUC-MSCs intravenously, while the control group received a placebo. Adverse events (AEs) were collected for safety evaluation in the 12-month follow-up phase. Primary endpoints were assessed as activities of daily living (ADL), comprehensive function assessment (CFA), and gross motor function measure (GMFM) scales. In addition, cerebral metabolic activity was detected by18F-FDG-PET/CT to explore the possible mechanism of the therapeutic effects. Primary endpoint data were analyzed by ANOVA using SPSS version 20.0.

Results

Forty patients were enrolled, and 1 patient withdrew informed consent. Therefore, 39 patients received treatments and completed the scheduled assessments. No significant difference was shown between the 2 groups in AE incidence. Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation.

Conclusions

Our clinical data showed that hUC-MSC transplantation was safe and effective at improving the gross motor and comprehensive function of children with CP when combined with rehabilitation. Recovery of cerebral metabolic activity might play an essential role in the improvements in brain function in patients with CP. The therapeutic window, transfusion route, and dosage in our study were considerable for reference in clinical application.

Trial registration

Chictr.org.cn,ChiCTR1800016554. Registered 08 June 2018—retrospectively registered. The public title was “Randomized trial of umbilical cord-derived mesenchymal stem cells for cerebral palsy.”
In vivo monitoring of dynamic interaction between neutrophil and human umbilical cord blood-derived mesenchymal stem cell in mouse liver during sepsis
Authors: Ahn Sung Yong , Maeng Yong-Sun , Kim Yu Rim , Choe Young Ho , Hwang Han Sung , Hyun Young-Min
Published: February 2020

Background

Sepsis is a global inflammatory disease that causes death. It has been reported that mesenchymal stem cell (MSC) treatment can attenuate inflammatory and septic symptoms. In this study, we investigated how interactions between neutrophils and human umbilical cord blood (hUCB)-MSCs in the liver of septic mice are involved in mitigating sepsis that is mediated by MSCs. Accordingly, we aimed to determine whether hUCB-MSC application could be an appropriate treatment for sepsis.

Methods

To induce septic condition, lipopolysaccharide (LPS) was intraperitoneally (i.p.) injected into mice 24 h after the intravenous (i.v.) injection of saline or hUCB-MSCs. To determine the effect of hUCB-MSCs on the immune response during sepsis, histologic analysis, immunoassays, and two-photon intravital imaging were performed 6 h post-LPS injection. For the survival study, mice were monitored for 6 days after LPS injection.

Results

The injection (i.v.) of hUCB-MSCs alleviated the severity of LPS-induced sepsis by increasing IL-10 levels (p < 0.001) and decreasing mortality (p < 0.05) in septic mice. In addition, this significantly reduced the recruitment of neutrophils (p < 0.001) to the liver. In hUCB-MSC-treated condition, we also observed several distinct patterns of dynamic interactions between neutrophils and hUCB-MSCs in the inflamed mouse liver, as well as vigorous interactions between hepatic stellate cells (HSCs or ito cells) and hUCB-MSCs. Interestingly, hUCB-MSCs that originated from humans were not recognized as foreign in the mouse body and consequently did not cause graft rejection.

Conclusions

These distinct interaction patterns between innate immune cells and hUCB-MSCs demonstrated that hUCB-MSCs have beneficial effects against LPS-induced sepsis through associations with neutrophils. In addition, the immunomodulatory properties of hUCB-MSCs might enable immune evasion in the host. Taken together, our results suggest the prospects of hUCB-MSCs as a therapeutic tool to inhibit inflammation and alleviate pathological immune responses such as sepsis.
Receptor autoimmunity: diagnostic and therapeutic implications
Authors: Tozzoli Renato
Published: February 2020

Receptor autoimmunity is one of the ways in which autoimmune diseases appear in humans. Graves’ disease, myasthenia gravis, idiopathic membranous nephropathy, and autoimmune acute encephalitis are the major autoimmune diseases belonging to this particular group. Receptor autoimmune disease are dependent on the presence of autoantibodies directed against cell-surface antigens, namely TSH receptor in thyrocytes, acetylcholine receptor in neuromuscular junction, phospholipase 2 receptor in podocytes, and NMDA receptor in cortical neurons. In this article we outline the distinctive features of receptor autoimmunity and the specific relationship between the autoimmunology laboratory and the presence/concentration of autoantibodies. Some immunological features distinguish receptor autoimmunity. Anti-receptor autoantibody pathologies are considered T cell-dependent, B-cell-mediated autoimmune disorders: the knowledge about the presence of circulating and/or localized autoantibodies to target organs and identification of autoantigens involved in the autoimmune reaction is of paramount importance. Due to the close correlation between the concentration of anti-receptor autoantibodies, the autoimmune target of some cell-surface receptors and the intensity of symptoms, the measurement of these immunoglobulins has become central to diagnose autoimmune diseases in all affected patients, not just in clinically dubious cases. The measurement of autoantibodies is also relevant for differential diagnosis of autoimmune and non-autoimmune forms with similar symptoms. From the methodological point of view, quantitative immunoassay methods of measurement should be preferred over semi-quantitative ones, for the capacity of the first class of methods to define precisely the reference ranges and decision levels overcoming the measurement uncertainty of semi-quantitative methods.
Prone positioning monitored by electrical impedance tomography in patients with severe acute respiratory distress syndrome on veno-venous ECMO
Authors: Franchineau Guillaume , Bréchot Nicolas , Hekimian Guillaume , Lebreton Guillaume , Bourcier Simon , Demondion Pierre , Le Guennec Loïc , Nieszkowska Ania , Luyt Charles-Edouard , Combes Alain , Schmidt Matthieu
Published: February 2020

Background

Prone positioning (PP) during veno-venous ECMO is feasible, but its physiological effects have never been thoroughly evaluated. Our objectives were to describe, through electrical impedance tomography (EIT), the impact of PP on global and regional ventilation, and optimal PEEP level.

Methods

A monocentric study conducted on ECMO-supported severe ARDS patients, ventilated in pressure-controlled mode, with 14-cmH2O driving pressure and EIT-based “optimal PEEP”. Before, during and after a 16-h PP session, EIT-based distribution and variation of tidal impedance, VTdorsal/VTglobal ratio, end-expiratory lung impedance (EELI) and static compliance were collected. Subgroup analyses were performed in patients who increased their static compliance by ≥ 3 mL/cmH2O after 16 h of PP.

Results

For all patients (n = 21), tidal volume and EELI were redistributed from ventral to dorsal regions during PP. EIT-based optimal PEEP was significantly lower in PP than in supine position. Median (IQR) optimal PEEP decreased from 14 (12–16) to 10 (8–14) cmH2O. Thirteen (62%) patients increased their static compliance by ≥ 3 mL/cmH2O after PP on ECMO. This subgroup had higher body mass index, more frequent viral pneumonia, shorter ECMO duration, and lower baseline VTdorsal/VTglobal ratio than patients with compliance ≤ 3 mL/cmH2O (P < 0.01).

Conclusion

Although baseline tidal volume distribution on EIT may predict static compliance improvement after PP on ECMO, our results support physiological benefits of PP in all ECMO patients, by modifying lung mechanics and potentially reducing VILI. Further studies, including a randomized–controlled trial, are now warranted to confirm potential PP benefits during ECMO.
Numerical analysis for time-fractional Schrödinger equation on two space dimensions
Authors: Zhang Jun , Wang JinRong , Zhou Yong
Published: February 2020

In this paper, we study the numerical methods for solving the time-fractional Schrödinger equation (TFSE) with Caputo or Riemann–Liouville fractional derivative. The numerical schemes are implemented by using the L1 scheme in time direction and Fourier–Galerkin/Legendre-Galerkin spectral methods in spatial variable. We prove that the two schemes are unconditionally stable and numerical solutions converge with the order $\mathcal{O}( \Delta t^{2-\alpha }+N^{-s}+ N^{-m})$O(Δt2−α+N−s+N−m), where α is the order of the fractional derivative, Δt, N are the step of time and polynomial degree, respectively, m, s are the regularity of u and V. Several numerical results are performed to confirm the theoretical analysis.