bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative evaluation of network features for the prediction of breast cancer metastasis
Authors: Adnan Nahim , Liu Zhijie , Huang Tim H.M. , Ruan Jianhua
Published: April 2020

Background

Discovering a highly accurate and robust gene signature for the prediction of breast cancer metastasis from gene expression profiling of primary tumors is one of the most challenging tasks to reduce the number of deaths in women. Due to the limited success of gene-based features in achieving satisfactory prediction accuracy, many methodologies have been proposed in recent years to develop network-based features by integrating network information with gene expression. However, evaluation results are inconsistent to confirm the effectiveness of network-based features, because of many confounding factors involved in classification model learning process, such as data normalization, dimension reduction, and feature selection. An unbiased comparative evaluation is essential for uncovering the strength of network-based features.

Methods

In this study, we compared several types of network-based features obtained using different mathematical operators (Mean, Maximum, Minimum, Median, Variance) on geneset (i.e., a gene and its’ neighbors in the network) in protein-protein interaction network and gene co-expression network for their ability in predicting breast cancer metastasis using gene expression data from more than 10 patient cohorts.

Results

While network-based features are usually statistically more significant than gene-based feature, a consistent improvement of prediction performance using network-based features requires a substantial number of patients in the dataset. In contrary to many previous reports, no evidence was found to support the robustness of network-based features and we argue some of the robustness may be due to the inherent bias associated with node degree in the network. In addition, different types of network features seem to cover different pathways and are complementary to each other. Consequently, an ensemble classifier combining different network features was proposed and was found to significantly outperform classifiers based on gene-based feature or any single type of network-based features.

Conclusions

Network-based features and their combination show promise for improving the prediction of breast cancer metastasis but may require a large amount of training data. Robustness claim of network-based features needs to be re-examined with network node degree and other confounding factors in consideration.
A pan-cancer study of class-3 semaphorins as therapeutic targets in cancer
Authors: Zhang Xiaoli , Klamer Brett , Li Jin , Fernandez Soledad , Li Lang
Published: April 2020

Background

Initially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study.

Results

Expression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter- and intra- cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance.

Conclusions

Our systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.
ProGeo-neo: a customized proteogenomic workflow for neoantigen prediction and selection
Authors: Li Yuyu , Wang Guangzhi , Tan Xiaoxiu , Ouyang Jian , Zhang Menghuan , Song Xiaofeng , Liu Qi , Leng Qibin , Chen Lanming , Xie Lu
Published: April 2020

Background

Neoantigens can be differentially recognized by T cell receptor (TCR) as these sequences are derived from mutant proteins and are unique to the tumor. The discovery of neoantigens is the first key step for tumor-specific antigen (TSA) based immunotherapy. Based on high-throughput tumor genomic analysis, each missense mutation can potentially give rise to multiple neopeptides, resulting in a vast total number, but only a small percentage of these peptides may achieve immune-dominant status with a given major histocompatibility complex (MHC) class I allele. Specific identification of immunogenic candidate neoantigens is consequently a major challenge.

Currently almost all neoantigen prediction tools are based on genomics data.

Results

Here we report the construction of proteogenomics prediction of neoantigen (ProGeo-neo) pipeline, which incorporates the following modules: mining tumor specific antigens from next-generation sequencing genomic and mRNA expression data, predicting the binding mutant peptides to class I MHC molecules by latest netMHCpan (v.4.0), verifying MHC-peptides by MaxQuant with mass spectrometry proteomics data searched against customized protein database, and checking potential immunogenicity of T-cell-recognization by additional screening methods. ProGeo-neo pipeline achieves proteogenomics strategy and the neopeptides identified were of much higher quality as compared to those identified using genomic data only.

Conclusions

The pipeline was constructed based on the genomics and proteomics data of Jurkat leukemia cell line but is generally applicable to other solid cancer research. With massively parallel sequencing and proteomics profiling increasing, this proteogenomics workflow should be useful for neoantigen oriented research and immunotherapy.
Somatic synonymous mutations in regulatory elements contribute to the genetic aetiology of melanoma
Authors: Zhang Di , Xia Junfeng
Published: April 2020

Background

Non-synonymous mutations altering tumor suppressor genes and oncogenes are widely studied. However, synonymous mutations, which do not alter the protein sequence, are rarely investigated in melanoma genome studies.

Methods

We explored the role of somatic synonymous mutations in melanoma samples from TCGA (The Cancer Genome Atlas). The pathogenic synonymous mutation and neutral synonymous mutation data were used to assess the significance of pathogenic synonymous mutations in melanoma likely to affect genetic regulatory elements using Fisher’s exact test. Poisson distribution probabilities of each gene were used to mine the genes with multiple potential functional synonymous mutations affecting regulatory elements.

Results

Concentrating on five types of genetic regulatory functions, we found that the mutational patterns of pathogenic synonymous mutations are mostly involved in exonic splicing regulators in near-splicing sites or inside DNase I hypersensitivity sites or non-optimal codon. Moreover, the sites of miRNA binding alteration exhibit a significantly lower rate of evolution than other sites. Finally, 12 genes were hit by recurrent potentially functional synonymous mutations, which showed statistical significance in the pathogenic mutations. Among them, nine genes (DNAH5, ADCY8, GRIN2A, KSR2, TECTA, RIMS2, XKR6, MYH1, SCN10A) have been reported to be mutated in melanoma, and other three genes (SLC9A2, CASR, SLC8A3) have a great potential to impact melanoma.

Conclusion

These findings confirm the functional consequences of somatic synonymous mutations in melanoma, emphasizing the significance of research in future studies.
Deep learning-based cancer survival prognosis from RNA-seq data: approaches and evaluations
Authors: Huang Zhi , Johnson Travis S. , Han Zhi , Helm Bryan , Cao Sha , Zhang Chi , Salama Paul , Rizkalla Maher , Yu Christina Y. , Cheng Jun , Xiang Shunian , Zhan Xiaohui , Zhang Jie , Huang Kun
Published: April 2020

Background

Recent advances in kernel-based Deep Learning models have introduced a new era in medical research. Originally designed for pattern recognition and image processing, Deep Learning models are now applied to survival prognosis of cancer patients. Specifically, Deep Learning versions of the Cox proportional hazards models are trained with transcriptomic data to predict survival outcomes in cancer patients.

Methods

In this study, a broad analysis was performed on TCGA cancers using a variety of Deep Learning-based models, including Cox-nnet, DeepSurv, and a method proposed by our group named AECOX (AutoEncoder with Cox regression network). Concordance index andp-value of the log-rank test are used to evaluate the model performances.

Results

All models show competitive results across 12 cancer types. The last hidden layers of the Deep Learning approaches are lower dimensional representations of the input data that can be used for feature reduction and visualization. Furthermore, the prognosis performances reveal a negative correlation between model accuracy, overall survival time statistics, and tumor mutation burden (TMB), suggesting an association among overall survival time, TMB, and prognosis prediction accuracy.

Conclusions

Deep Learning based algorithms demonstrate superior performances than traditional machine learning based models. The cancer prognosis results measured in concordance index are indistinguishable across models while are highly variable across cancers. These findings shedding some light into the relationships between patient characteristics and survival learnability on a pan-cancer level.
Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model
Authors: Tuttle Richard , Popescu Luca , Hill Scott , Slanczka Amber , Jankowski Jeffrey , Barre Katherine , Krueger Erika , Slade Desmond , Croutch Claire , Robben Matthew , Mesa Zack , Mesa Michael , Dretchen Kenneth L.
Published: April 2020

Background

Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine.

Methods

Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (Cmax), area under plasma concentration-time curve from 1 to 90 min (AUC1–90), and time to reach Cmax (Tmax) were measured. Clinical observations were documented.

Results

In the 12 dogs in this study, nasal congestion occurred at 5–10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in Cmax and AUC1–90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower Tmax versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30–60 min after administration) in the saline group. Clinical observations included salivation and emesis.

Conclusion

IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.
Incarcerated Aboriginal women’s experiences of accessing healthcare and the limitations of the ‘equal treatment’ principle
Authors: Kendall S. , Lighton S. , Sherwood J. , Baldry E. , Sullivan E. A.
Published: April 2020

Background

Colonization continues in Australia, sustained through institutional and systemic racism. Targeted discrimination and intergenerational trauma have undermined the health and wellbeing of Australia’s Aboriginal and Torres Strait Islander population, leading to significantly poorer health status, social impoverishment and inequity resulting in the over-representation of Aboriginal people in Australian prisons. Despite adoption of the ‘equal treatment’ principle, on entering prison in Australia entitlements to the national universal healthcare system are revoked and Aboriginal people lose access to health services modelled on Aboriginal concepts of culturally safe healthcare available in the community. Incarcerated Aboriginal women experience poorer health outcomes than incarcerated non-Indigenous women and Aboriginal men, yet little is known about their experiences of accessing healthcare. We report the findings of the largest qualitative study with incarcerated Aboriginal women in New South Wales (NSW) Australia in over 15 years.

Methods

We employed a decolonizing research methodology, ‘community collaborative participatory action research’, involving consultation with Aboriginal communities prior to the study and establishment of a Project Advisory Group (PAG) of community expert Aboriginal women to guide the project. Forty-three semi-structured interviews were conducted in 2013 with Aboriginal women in urban and regional prisons in NSW. We applied a grounded theory approach for the data analysis with guidance from the PAG.

Results

Whilst Aboriginal women reported positive and negative experiences of prison healthcare, the custodial system created numerous barriers to accessing healthcare. Aboriginal women experienced institutional racism and discrimination in the form of not being listened to, stereotyping, and inequitable healthcare compared with non-Indigenous women in prison and the community.

Conclusions

‘Equal treatment’ is an inappropriate strategy for providing equitable healthcare, which is required because incarcerated Aboriginal women experience significantly poorer health. Taking a decolonizing approach, we unpack and demonstrate the systems level changes needed to make health and justice agencies culturally relevant and safe. This requires further acknowledgment of the oppressive transgenerational effects of ongoing colonial policy, a true embracing of diversity of worldviews, and critically the integration of Aboriginal concepts of health at all organizational levels to uphold Aboriginal women’s rights to culturally safe healthcare in prison and the community.
m6A-dependent glycolysis enhances colorectal cancer progression
Authors: Shen Chaoqin , Xuan Baoqin , Yan Tingting , Ma Yanru , Xu Pingping , Tian Xianglong , Zhang Xinyu , Cao Yingying , Ma Dan , Zhu Xiaoqiang , Zhang Youwei , Fang Jing-Yuan , Chen Haoyan , Hong Jie
Published: April 2020

Background

Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized.

Methods

Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC.

Results

A strong correlation between METTL3 and 18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2, and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively.

Conclusions

METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.
Evidence for measurement bias of the short form health survey based on sex and metropolitan influence zone in a secondary care population
Authors: Ursenbach Jake , O’Connell Megan E. , Kirk Andrew , Morgan Debra
Published: April 2020

Background and objectives

The 12-item Short Form Health Survey (SF-12) is a widely used measure of health related quality of life, but has been criticized for lacking an empirically supported model and producing biased estimates of mental and physical health status for some groups. We explored a model of measurement with the SF-12 and explored evidence for measurement invariance of the SF-12.

Research design and methods

The SF-12 was completed by 429 caregivers who accompanied patients with cognitive concerns to a memory clinic designed to service rural/remote-dwelling individuals. A multi-group confirmatory factor analysis was used to compare the theoretical measurement model to two empirically identified factor models reported previously in general population studies.

Results

A model that allowed mental and physical health to correlate, and some items to cross-load provided the best fit to the data. Using that model, measurement invariance was then assessed across sex and metropolitan influence zone (MIZ; a standardized measure of degree of rurality).

Discussion

Partial scalar invariance was demonstrated in both analyses. Differences by sex in latent item intercepts were found for items assessing feelings of energy and depression. Differences by MIZ in latent item intercepts were found for an item concerning how current health limits activities.

Implications

The fitting model was one where the mental and physical health subscales were correlated, which is not provided in the scoring program offered by the publishers. Participants’ sex and MIZ should be accounted for when comparing their factor scores on the SF-12. Additionally, consideration of geographic residence and associated cultural influences is recommended in future development and use of psychological measures with such populations.
Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells
Authors: Chen Jiao , Yang Jie , Wei Qingyun , Weng Ling , Wu Fei , Shi Yun , Cheng Xiaolan , Cai Xueting , Hu Chunping , Cao Peng
Published: April 2020

Background

IDH2/R140Q mutation is frequently detected in acute myeloid leukemia (AML). It contributes to leukemia via accumulation of oncometabolite D-2-HG. Therefore, mutant IDH2 is a promising target for AML. Discovery of IDH2 mutant inhibitors is in urgent need for AML therapy.

Methods

Structure-based in silico screening and enzymatic assays were used to identify IDH2/R140Q inhibitors. Molecular docking, mutant structure building and molecular dynamics simulations were applied to investigate the inhibitory mechanism and selectivity of CP-17 on IDH2/R140Q. TF-1 cells overexpressed IDH2/R140Q mutant were used to study the effects of CP-17 on cellular proliferation and differentiation, the wild-type TF-1 cells were used as control. The intracellular D-2-HG production was measured by LC-MS. The histone methylation was evaluated with specific antibodies by western blot.

Results

CP-17, a heterocyclic urea amide compound, was identified as a potent inhibitor of IDH2/R140Q mutant by in silico screening and enzymatic assay. It exhibits excellent inhibitory activity with IC50 of 40.75 nM against IDH2/R140Q. More importantly, it shows poor activity against the wild-type IDH1/2, resulting in a high selectivity of over 55 folds, a dramatic improvement over previously developed inhibitors such as AGI-6780 and Enasidenib. Molecular simulations suggested that CP-17 binds to IDH2/R140Q at the allosteric site within the dimer interface through extensive polar and hydrophobic interactions, locking the enzyme active sites in open conformations with abolished activity to produce D-2-HG. Cellular assay results demonstrated that CP-17 inhibits intracellular D-2-HG production and suppresses the proliferation of TF-1 erythroleukemia cells carrying IDH2/R140Q mutant. Further, CP-17 also restores the EPO-induced differentiation that is blocked by the mutation and decreases hypermethylation of histone in the TF-1(IDH2/R140Q) cells.

Conclusions

These results indicate that CP-17 can serve as a lead compound for the development of inhibitory drugs against AML with IDH2/R140Q mutant.
Towards individualized cortical thickness assessment for clinical routine
Authors: Tahedl Marlene
Published: April 2020

Background

Cortical thickness measures the width of gray matter of the human cortex. It can be calculated from T1-weighted magnetic resonance images (MRI). In group studies, this measure has been shown to correlate with the diagnosis/prognosis of a number of neurologic and psychiatric conditions, but has not been widely adapted for clinical routine. One of the reasons for this might be that there is no reference system which allows to rate individual cortical thickness data with respect to a control population.

Methods

To address this problem, this study compared different methods to assess statistical significance of cortical thinning, i.e. atrophy. All compared methods were nonparametric and encompassed rating an individual subject’s data set with respect to a control data population. Null distributions were calculated using data from the Human Connectome Project (HCP, n = 1000), and an additional HCP data set (n = 113) was used to calculate sensitivity and specificity to compare the different methods, whereas atrophy was simulated for sensitivity assessment. Validation measures were calculated for the entire cortex (“cumulative”) and distinct brain regions (“regional”) where possible.

Results

The approach yielding the highest combination of specificity and sensitivity implemented generating null distributions for anatomically distinct brain regions, based on the most extreme values observed in the population. With that method, while regional variations were observed, cumulative specificity of 98.9% and cumulative sensitivity at 80% was achieved for simulated atrophy of 23%.

Conclusions

This study shows that validated rating of individual cortical thickness measures is possible, which can help clinicians in their daily routine to discover signs of atrophy before they become visually apparent on an unprocessed MRI. Furthermore, given different pathologies present with distinct atrophy patterns, the regional validation proposed here allows to detect distinct patterns of atrophy, which can further enhance differential diagnosis/prognosis.
Relationship between postoperative lordosis distribution index and adjacent segment disease following L4-S1 posterior lumbar interbody fusion
Authors: Zheng Guoquan , Wang Chunguo , Wang Tianhao , Hu Wenhao , Ji Quanbo , Hu Fanqi , Li Jianrui , Chaudhary Surendra K. , Song Kai , Song Diyu , Zhang Zhifa , Hao Yongyu , Wang Yao , Li Jing , Zheng Qingyuan , Zhang Xuesong , Wang Yan
Published: April 2020

Background

Adjacent segment disease (ASD) is an acknowledged problem of posterior lumbar interbody fusion (PLIF). Many studies have been reported concerning the role of lordosis distribution index (LDI) in spinal biomechanics. However, few reports have been published about the impact of LDI on ASD following L4-S1 PLIF.

Methods

The study enrolled 200 subjects who underwent L4-S1 PLIF for degenerative spine disease from 2009 to 2014. The average follow-up term was 84 months. Several lower lumbar parameters were measured, including lower lumbar lordosis (LLL), lumbar lordosis (LL), pelvic incidence (PI), and LDI on the pre and postoperative radiograph. Perioperative information, comorbidities, and operative data were documented. Kaplan-Meier curves were plotted for the comparisons of ASD-free survival of 3 different types of postoperative LDI subgroups.

Results

The incidence of ASD was found to be 8.5%. LL and LLL increased by 3.96° (38.71° vs 42.67°; P < 0.001) and 3.60° (26.22° vs 28.82°; P < 0.001) after lower lumbar fusion surgery, respectively. Lordosis distribution index (LDI) increased by 0.03 (0.66 vs 0.69, P = 0.004) postoperatively. A significant difference (P = 0.001) was observed when comparing the incidence of ASD among postoperative LDI subgroups. The Kaplan-Meier curves showed a marked difference in ASD-free survival between low and moderate LDI subgroup (log-rank test, P = 0.0012) and high and moderate LDI subgroup (log-rank test, P = 0.0005).

Conclusion

Patients with abnormal postoperative LDI were statistically more likely to develop ASD than those who had normal postoperative LDI. Moreover, patients with low postoperative LDI were at greater risk for developing ASD than those with high postoperative LDI over time.
Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy
Authors: Pan Chongxian , Liu Hongtao , Robins Elizabeth , Song Wenru , Liu Delong , Li Zihai , Zheng Lei
Published: April 2020

Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.
Template for documenting and reporting data in physician-staffed pre-hospital services: a consensus-based update
Authors:   the P-EMS Template Collaborating Group, Tønsager Kristin , Krüger Andreas Jørstad , Ringdal Kjetil Gorseth , Rehn Marius
Published: April 2020

Background

Physician-staffed emergency medical services (p-EMS) are resource demanding, and research is needed to evaluate any potential effects of p-EMS. Templates, designed through expert agreement, are valuable and feasible, but they need to be updated on a regular basis due to developments in available equipment and treatment options. In 2011, a consensus-based template documenting and reporting data in p-EMS was published. We aimed to revise and update the template for documenting and reporting in p-EMS.

Methods

A Delphi method was applied to achieve a consensus from a panel of selected European experts. The experts were blinded to each other until a consensus was reached, and all responses were anonymized. The experts were asked to propose variables within five predefined sections. There was also an optional sixth section for variables that did not fit into the pre-defined sections. Experts were asked to review and rate all variables from 1 (totally disagree) to 5 (totally agree) based on relevance, and consensus was defined as variables rated ≥4 by more than 70% of the experts.

Results

Eleven experts participated. The experts generated 194 unique variables in the first round. After five rounds, a consensus was reached. The updated dataset was an expanded version of the original dataset and the template was expanded from 45 to 73 main variables. The experts approved the final version of the template.

Conclusions

Using a Delphi method, we have updated the template for documenting and reporting in p-EMS. We recommend implementing the dataset for standard reporting in p-EMS.
Robotic radical antegrade modular pancreatosplenectomy (RAMPS) versus standard retrograde pancreatosplenectomy (SRPS): study protocol for a randomized controlled trial
Authors: Zhang Gong , Kang Yuhao , Zhang Haifeng , Wang Fei , Liu Rong
Published: April 2020

Background

Data from meta-analysis suggest that robotic radical antegrade modular pancreatosplenectomy (RAMPS) is a safe and effective procedure for treating adenocarcinoma in the body or tail of the pancreas, and is oncologically superior to standard retrograde pancreatosplenectomy (SRPS). RAMPS is an operation that actively expands the scope of resection, and achieves a higher R0 resection rate and lymph nodes acquisition through expanded resection. However, previous studies on RAMPS were conducted under open and laparoscopic surgery. Robotic surgery, on the other hand, plays a role in ergonomics and offers several advantages, including less fatigue, tremor filtering, 7° of wrist-like motion, motion scaling, and three-dimensional vision. At present, there is still a world-wide lack of clinical studies to observe the safety and clinical efficacy of robotic RAMPS. Hence, prospective randomized controlled trials (RCTs) comparing robotic RAMPS and SRPS are required. We begin an RCT to compare short-term surgical and oncological outcomes of robotic RAMPS and SRPS in patients undergoing distal pancreatectomy.

Methods

This is a randomized, single-center clinical trial. All participants are adult patients with primary pancreatic cancer, who are undergoing RAMPS or SRPS. The primary endpoints are R0 rate (resection margins are classified by a margin to tumor distance ≥ 1 mm). The secondary endpoints are the number of harvested lymph nodes, perioperative complications and perioperative indicators (duration of surgery, blood loss, blood transfusion volume, costs).

Discussion

We are undertaking a prospective RCT to evaluate the surgical and oncological outcomes of robotic RAMPS. This procedure may become a standard approach to robotic pancreatosplenectomy.

Trial registration

Chinese Clinical Trial Registry: ChiCTR1900020833, Registered on 20 January 2019.
The relation between physical joint examination and MRI-depicted inflammation of metatarsophalangeal joints in early arthritis
Authors: Dakkak Yousra J. , Boer Aleid C. , Boeters Debbie M. , Niemantsverdriet Ellis , Reijnierse Monique , van der Helm-van Mil Annette H. M.
Published: April 2020

Background

The relationship between physical joint examination (PE) and MRI-detected inflammation in early inflammatory arthritis has mostly been studied in the hands. Physical examination of MTP joints is considered difficult, and for these joints, this relationship is unknown. Therefore, we studied the concordance of PE with MRI inflammation in MTP joints. Metacarpophalangeal (MCP) joints were included for comparison.

Methods

One thousand seven hundred fifty-nine MTP(2–5) and 1750 MCP(2–5) joints of 441 consecutive patients with early arthritis underwent PE (for joint swelling) and MRI, all evaluated by two assessors. MRI was scored for synovitis, tenosynovitis, and osteitis (summed MRI inflammation). Synovial intermetatarsal bursae may enlarge upon inflammation and become palpable and were therefore also assessed. Analyses (frequencies, GEE) were performed on joint level.

Results

PE and MRI were concordant in 79% of MTP joints. Of 1606 non-swollen MTP joints, 83% showed no MRI inflammation and 17% showed subclinical MRI inflammation. Of 153 swollen MTP joints, 48% had MRI inflammation and 52% (79 MTP joints) did not. Of these 79 swollen MTP joints without MRI inflammation, 31 showed intermetatarsal bursitis and 48 joints had none of these MRI abnormalities (this concerned 31% of swollen MTP joints). MTP swelling was statistically independently associated with tenosynovitis (OR 2.21, 95% CI 1.1–4.3) and intermetatarsal bursitis (OR 2.91, 95% CI 1.8–4.8).

MTP joints showed subclinical inflammation less often than MCP joints (17% vs. 34%,P < 0.001). Swollen MTP joints showed MRI inflammation less often than swollen MCP joints (48% vs. 88%,P < 0.001).

Conclusions

The absence of swelling of MTP joints in early arthritis is mostly accompanied by the absence of MRI-detected inflammation. Swollen MTP joints are, in addition to synovitis, also explained by tenosynovitis and intermetatarsal bursitis and partly unexplained by MRI. Their clinical relevance must be determined in longitudinal studies.
A case of intrathyroid parathyroid tumor that was difficult to diagnose by ultrasonography
Authors: Takemoto Nobuyuki , Koyanagi Ai , Yasuda Masanori , Yamamoto Yuya , Yamamoto Hiroshi
Published: April 2020

Background

With advances in diagnostic imaging such as ultrasonography (US), computed tomography (CT), and 99mTc-MIBI-sestamibi (MIBI) scintigraphy, localized diagnosis of hyperparathyroidism (pHPT) has become possible with considerable accuracy. However, even with the use of these imaging techniques, since intrathyroid parathyroid tumors exist as a mass within the thyroid, it is often difficult to distinguish from thyroid masses. Although there have been various reports on US images of intraparathyroid tumors, we experienced a case with US images that were distinct from previous reports. Herein we present a case of an intrathyroid parathyroid adenoma (IPA) that was difficult to diagnose, with a main focus on US images.

Case presentation

A 53-year-old man with a diagnosis of hyperparathyroidism was referred to our department in December 2018. Ultrasonography revealed a tumor that was located in the inferior pole of the right lobe of the thyroid gland and no parathyroid mass was observed. The tumor had an irregular round shape and showed heterogeneous hyperechogenicity with a defined margin, but within it, there were a few irregular and hypoechogenic area with unclear margins, while the tumor had a mosaic appearance at first glance. Although 99mTc-MIBI scintigraphy showed accumulation at the same location in delayed phase, it was difficult to determine the presence of a parathyroid tumor on the image. The patient underwent an operation on April 2019 and the tumor could not be identified on both naked eye and palpation. We used US intraoperatively to define the location and resected the tumor. A parathyroid adenoma was diagnosed by frozen section and the final diagnosis was an intrathyroid parathyroid adenoma.

Conclusion

We experienced an IPA presenting an US image that was atypical and has previously not been reported. IPA has no established US image to confirm the diagnosis and even with the use of other imaging techniques, a definitive diagnosis often cannot be established. Thus, our recommendation based on the current situation is that operation with intraoperative diagnosis using frozen section should be conducted if hypercalcemia and high I-PTH are observed and when localization sites in MIBI and US coincide.
PI3K/Akt signaling pathway is essential for de novo hair follicle regeneration
Authors: Chen Yu , Fan Zhimeng , Wang Xiaoxiao , Mo Miaohua , Zeng Shu Bin , Xu Ren-He , Wang Xusheng , Wu Yaojiong
Published: April 2020

Background

Cultured epidermal stem cells (Epi-SCs) and skin-derived precursors (SKPs) were capable of reconstituting functional hair follicles after implantation, while the signaling pathways that regulate neogenic hair follicle formation are poorly investigated. In this study, we aimed to understand the interactions between Epi-SCs and SKPs during skin organoid formation and to uncover key signal pathways crucial for de novo hair follicle regeneration.

Methods

To track their fate after transplantation, Epi-SCs derived from neonatal C57BL/6 mice were labeled with tdTomato, and SKPs were isolated from neonatal C57BL/6/GFP mice. A mixture of Epi-SCs-tdTomato and SKPs-EGFP in Matrigel was observed under two-photon microscope in culture and after implantation into excisional wounds in nude mice, to observe dynamic migrations of the cells during hair follicle morphogenesis. Signaling communications between the two cell populations were examined by RNA-Seq analysis. Potential signaling pathways revealed by the analysis were validated by targeting the pathways using specific inhibitors to observe a functional loss in de novo hair follicle formation.

Results

Two-photon microscopy analysis indicated that when Epi-SCs and SKPs were mixed in Matrigel and cultured, they underwent dynamic migrations resulting in the formation of a bilayer skin-like structure (skin organoid), where Epi-SCs positioned themselves in the outer layer; when the mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, a bilayer structure resembling the epidermis and the dermis formed at the 5th day, and de novo hair follicles generated subsequently. RNA-Seq analysis of the two cell types after incubation in mixture revealed dramatic alterations in gene transcriptome, where PI3K-Akt signaling pathway in Epi-SCs was significantly upregulated; meanwhile, elevated expressions of several growth factors and cytokine potentially activating PI3K were found in SKPs, suggesting active reciprocal communications between them. In addition, inhibition of PI3K or Akt by specific inhibitors markedly suppressed the hair follicle regeneration mediated by Epi-SCs and SKPs.

Conclusions

Our data indicate that the PI3K-Akt signaling pathway plays a crucial role in de novo hair follicle regeneration, and the finding may suggest potential therapeutic applications in enhancing hair regeneration.
Ultrasound-targeted microbubble destruction optimized HGF-overexpressing bone marrow stem cells to repair fibrotic liver in rats
Authors: Sun Ting , Li Hualin , Bai Yun , Bai Min , Gao Feng , Yu Jie , Wu Rong , Du Lianfang , Li Fan
Published: April 2020

Background/aims

Bone marrow mesenchymal stem cells (BMSCs) have shown their therapeutic potential in cytotherapy for liver fibrosis. However, the insufficient homing of BMSCs and undefined proliferation of BMSCs represent a significant challenge and largely limit the effective implementation. The aims of the present study were to determine whether stable expression of hepatic growth factor (HGF) in BMSCs coupled with ultrasound-targeted microbubble destruction (UTMD) technique could effectively and definitely alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in rats.

Materials and methods

A rat model of liver fibrosis was acquired by injection of carbon tetrachloride (CCl4). The experimental rats were randomly assigned to the four groups: normal, CCl4, BMSCs-HGF/US, and BMSCs-HGF/UTMD groups. The BMSCs, transfected by recombinant adeno-associated virus vector encoding human genome sequence of HGF (BMSCs-HGF), were transplanted in rat via the tail vein. The homing efficiency of BMSCs was observed by immunofluorescence staining. The liver function and its morphological changes were analyzed by biochemical tests and liver histology. The expression of liver fibrosis markers including α-smooth muscle actin (α-SMA), collagen I, and vimentin were examined by immunohistochemistry and quantitative real-time polymerase chain reaction.

Results

The homing efficiency of BMSCs in the fibrotic liver was significantly greater with the application of UTMD. The biochemical markers of liver function and histopathological results showed significantly better improvement in BMSCs-HGF/UTMD group than the other groups, and the serum levels of biochemical markers returned to normal ranges in 12 weeks in this group. Furthermore, the expression levels of liver fibrosis markers (α-SMA, collagen I, and Vimentin) were all significantly lower in BMSCs-HGF/UTMD group in comparison with other groups.

Conclusions

Our findings have demonstrated that stable expression of HGF in BMSCs and application of the UTMD technique facilitate the homing of BMSCs, and more importantly, which could further improve their alleviation of liver fibrosis. Therefore, these findings have an important clinical implication that AAV-BMSCs-HGF and UTMD hold promise as a novel therapeutic approach for liver fibrosis.
Consumers’ food choices, understanding and perceptions in response to different front-of-pack nutrition labelling systems in Belgium: results from an online experimental study
Authors: Vandevijvere Stefanie , Vermote Marie , Egnell Manon , Galan Pilar , Talati Zenobia , Pettigrew Simone , Hercberg Serge , Julia Chantal
Published: April 2020

Background

Front-of-pack nutrition labels (FoPLs) are increasingly implemented by governments internationally to support consumers to make healthier food choices. Although the Nutri-Score FOPL has officially been implemented in Belgium since April 2019, no study has been conducted before its implementation to compare the effectiveness of different FOPLs.

Methods

The aim of this study was to compare food choices, objective understanding and perceptions of Belgian consumers in response to five different FOPLs, currently implemented in different countries internationally, namely the Health Star Ratings (HSR), the Multiple Traffic Lights (MTL), Nutri-Score, Guideline Daily Amounts (GDA), and Warning symbols. During the summer 2019, 1007 Belgian consumers were recruited and randomized to one of the five different FOPLs. Through an online questionnaire they were asked to choose one of three different foods within each of three categories (pizzas, cakes, breakfast cereals), as well as rank those same three foods according to nutritional quality, in the condition without as well as with FOPL. In addition, various questions were asked on their perceptions in relation to the FOPL they were exposed to.

Results

Perceptions of consumers were favorable for all FOPLs with no significant differences between the different FOPLs. There were no significant differences in food choices among the different FOPLs, but Nutri-Score performed best for ranking food products according to nutritional quality.

Conclusions

While there were no significant differences among different FOPLs for food choices and perceptions, the Nutri-Score was the most effective FOPL in informing Belgian consumers of the nutritional quality of food products.
Measuring consumers’ preferences for craft beer attributes through Best-Worst Scaling
Authors: Lerro Marco , Marotta Giuseppe , Nazzaro Concetta
Published: April 2020

The current paper investigates consumers’ consumption behavior and preferences for craft beer. More specifically, it uncovers consumers’ consumption habits and perception about craft beer, as well as their preferences for 13 beer attributes drawn from the literature.

The analysis was carried out in Italy by administering a structured questionnaire to 323 consumers. Best-Worst Scaling was used to detect consumers’ preferences towards the 13 craft beer attributes. The latter were then ranked on the basis of their best-worst scores to identify the level of importance Italian consumers assign to the different attributes.

The study findings reveal that Italian craft beer consumers are young, well-educated, and employed. They drink craft beer more than once per month, mainly in pub and with friends and colleagues. Craft beer is perceived with higher quality and different flavors, while compared with a commercial beer, it results tastier, more genuine, and natural. As for the beer attributes, Italians prefer taste, fermentation process, and color, while store promotion, brand, and price rank as the least important.

The study findings offer several implications for brewers and marketers involved in the beer sector. Based on the preferences detected, breweries should adapt their product offer to meet craft beer consumers’ expectations.
Innovative deep learning artificial intelligence applications for predicting relationships between individual tree height and diameter at breast height
Authors: Ercanlı İlker
Published: April 2020

Background

Deep Learning Algorithms (DLA) have become prominent as an application of Artificial Intelligence (AI) Techniques since 2010. This paper introduces the DLA to predict the relationships between individual tree height (ITH) and the diameter at breast height (DBH).

Methods

A set of 2024 pairs of individual height and diameter at breast height measurements, originating from 150 sample plots located in stands of even aged and pure Anatolian Crimean Pine (Pinus nigra J.F. Arnold ssp. pallasiana (Lamb.) Holmboe) in Konya Forest Enterprise. The present study primarily investigated the capability and usability of DLA models for predicting the relationships between the ITH and the DBH sampled from some stands with different growth structures. The 80 different DLA models, which involve different the alternatives for the numbers of hidden layers and neuron, have been trained and compared to determine optimum and best predictive DLAs network structure.

Results

It was determined that the DLA model with 9 layers and 100 neurons has been the best predictive network model compared as those by other different DLA, Artificial Neural Network, Nonlinear Regression and Nonlinear Mixed Effect models. The alternative of 100 # neurons and 9 # hidden layers in deep learning algorithms resulted in best predictive ITH values with root mean squared error (RMSE, 0.5575), percent of the root mean squared error (RMSE%, 4.9504%), Akaike information criterion (AIC, − 998.9540), Bayesian information criterion (BIC, 884.6591), fit index (FI, 0.9436), average absolute error (AAE, 0.4077), maximum absolute error (max. AE, 2.5106), Bias (0.0057) and percent Bias (Bias%, 0.0502%). In addition, these predictive results with DLAs were further validated by the Equivalence tests that showed the DLA models successfully predicted the tree height in the independent dataset.

Conclusion

This study has emphasized the capability of the DLA models, novel artificial intelligence technique, for predicting the relationships between individual tree height and the diameter at breast height that can be required information for the management of forests.