bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts
Authors: Fu Yong-Wei , Xu Hong-Zhi
Published: June 2021

Background

Although deubiquitinating enzymes (DUBs) such as CYLD, A20 and OTULIN are expressed in multiple tissues and thought to be linked with inflammatory diseases, their expression in periodontal tissues remains to be determined. This research was designed to assess the expression of CYLD, A20 and OTULIN in human gingiva, and to evaluate the regulation of these DUBs in human gingival fibroblasts (HGFs) upon different stimuli.

Methods

Immunohistochemistry assay was conducted to determine the expression of CYLD, A20 and OTULIN in human gingiva. Immunofluorescence assay was employed to observe the protein expression of CYLD, A20 and OTULIN in HGFs. RT-PCR and western blots were carried out to assess gene and protein expression changes of these DUBs in HGFs upon LPS or TNF-α.

Results

CYLD, A20 and OTULIN were found to be expressed in human gingiva and HGFs. The expression of CYLD, A20 and OTULIN was lower in the inflamed gingival tissue samples compared with the healthy gingival tissue samples. Further, the expression of CYLD, A20 and OTULIN in HGFs exhibited distinct regulation by different stimuli. TNF-α treatment markedly increased NF-κB activation in HGFs

Conclusions

Our findings suggest that CYLD, A20 and OTULIN might play a role in the progression of periodontitis.
Characteristics of hospital differences in missing of clinical laboratory test results in a multi-hospital observational database contributing to MID-NET® in Japan
Authors: Komamine Maki , Fujimura Yoshiaki , Nitta Yasuharu , Omiya Masatomo , Doi Masaaki , Sato Tosiya
Published: June 2021

Background

In Japan, a multiple-hospital observational database system, the Medical Information Database Network (MID-NET®), was launched for post-marketing drug safety assessments. These assessments will be based on datasets with missing laboratory results. The characteristics of missing data considering hospital differences have not been evaluated. We assessed the missing proportion and the association between missingness and a factor through case studies using a database system, a part of MID-NET®.

Methods

Seven scenarios using laboratory results before the prescription of the assessed drug as baseline covariates and data from 10 hospitals of Tokushukai Medical Group were used. The missing proportion and the association between missingness and patient background were investigated per hospital. The associations were assessed using the log of adjusted odds ratio (log-aOR). Additionally, an ad hoc survey was conducted to explore other factors affecting the missingness.

Results

For some laboratory tests, missing proportions varied among hospitals, such as 7.4–44.4% of alkaline phosphatase (ALP) and 8.1–31.2% of triglyceride (TG) among statin users. The association between missingness and affecting factors also differed among hospitals for some factors; example, the log-aOR of hospitalization associated with missingness of TG was − 0.41 (95% CI, − 1.06 to 0.24) in hospital 3 and 1.84 (95% CI, 1.34 to 2.34) in hospital 4. In the ad hoc survey focusing on ALP, hospital-dependent differences in the ordering system settings were observed.

Conclusions

Hospital differences in missing data appeared in some laboratory tests in our multi-hospital observational database, which could be attributed to the affecting factors, including the patient background.
Chronoprevention in hospital falls of older people: protocol for a mixed-method study
Authors: López-Soto Pablo Jesús , López-Carrasco Juan de la Cruz , Fabbian Fabio , Miñarro-Del Moral Rosa María , Segura-Ruiz Rocío , Hidalgo-Lopezosa Pedro , Manfredini Roberto , Rodríguez-Borrego María Aurora
Published: June 2021

Background

Accidental falls in hospitals are serious events concerning the safety of the patients. Recent studies demonstrated that the time of falls is a key factor to be considered in prevention. It has been shown that the time of day, the day of the week and the month of the year impact on the occurrence of falls. The aim of the study is to determine the effect of the application of a programme of preventive measures based on the temporal patterns of the risk factors on the hospital fall occurrence.

Methods

A mixed-method research design. The following three phases will be carried out: 1) Longitudinal prospective study in two parts: (a) audits and seminars of healthcare professionals focused on an effective and efficient hospital falls register. Multi-Component and Single Cosinor analyses will be performed to obtain the temporal patterns of hospital falls and their related variables and (b) implementation of a based-temporal patterns, multidimensional prevention programme. 2) Retrospective study of falls registered in institutional databases. 3) Qualitative study based on focus groups (physicians, nurses and nursing assistants). The study protocol was approved in 2018.

Discussion

With regard to the safety of patients, hospital falls are serious events. Recent studies have demonstrated that the time of falls is a key factor to be considered in prevention. It has been shown that the time of day, the day of the week and the month of the year impact on the occurrence of falls. It is imperative to study temporal patterns of hospital falls to effectively and comprehensively define the aetiology of falls and, therefore, design preventive strategies. A reduction of the number of in-hospital falls and related injuries is expected, as well as an improvement in the quality of life of patients. Considering temporal patterns and levels of mood and sleep of healthcare professionals will achieve an improvement in patient safety.

Trial registration

Retrospectively registered in ClinicalTrials.gov ID: NCT04367298.
Deregulation of lncRNA HIST1H2AG-6 and AIM1-3 in peripheral blood mononuclear cells is associated with newly diagnosed type 2 diabetes
Authors: Jiang Hui , Lou Peian , Chen Xiaoluo , Wu Chenguang , Shao Shihe
Published: June 2021

Background

Type 2 diabetes mellitus (T2DM) is mainly affected by genetic and environmental factors; however, the correlation of long noncoding RNAs (lncRNAs) with T2DM remains largely unknown.

Methods

Microarray analysis was performed to identify the differentially expressed lncRNAs and messenger RNAs (mRNAs) in patients with T2DM and healthy controls, and the expression of two candidate lncRNAs (lnc-HIST1H2AG-6 and lnc-AIM1-3) were further validated using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman’s rank correlation coefficient was used to measure the degree of association between the two candidate lncRNAs and differentially expressed mRNAs. Furthermore, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and GO (Gene Ontology) enrichment analysis were used to reveal the biological functions of the two candidate lncRNAs. Additionally, multivariate logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed.

Results

The microarray analysis revealed that there were 55 lncRNAs and 36 mRNAs differentially expressed in patients with T2DM compared with healthy controls. Notably, lnc-HIST1H2AG-6 was significantly upregulated and lnc-AIM1-3 was significantly downregulated in patients with T2DM, which was validated in a large-scale qRT-PCR examination (90 controls and 100 patients with T2DM). Spearman’s rank correlation coefficient revealed that both lncRNAs were correlated with 36 differentially expressed mRNAs. Furthermore, functional enrichment (KEGG and GO) analysis demonstrated that the two lncRNA-related mRNAs might be involved in multiple biological functions, including cell programmed death, negative regulation of insulin receptor signal, and starch and sucrose metabolism. Multivariate logistic regression analysis revealed that lnc-HIST1H2AG-6 and lnc-AIM1-3 were significantly correlated with T2DM (OR = 5.791 and 0.071, respectively, both P = 0.000). Furthermore, the ROC curve showed that the expression of lnc-HIST1H2AG-6 and lnc-AIM1-3 might be used to differentiate patients with T2DM from healthy controls (area under the ROC curve = 0.664 and 0.769, respectively).

Conclusion

The profiles of lncRNA and mRNA were significantly changed in patients with T2DM. The expression levels of lnc-HIST1H2AG-6 and lnc-AIM1-3 genes were significantly correlated with some features of T2DM, which may be used to distinguish patients with T2DM from healthy controls and may serve as potential novel biomarkers for diagnosis in the future.
Construction of a prognostic model with histone modification-related genes and identification of potential drugs in pancreatic cancer
Authors: Chen Yuan , Xu Ruiyuan , Ruze Rexiati , Yang Jinshou , Wang Huanyu , Song Jianlu , You Lei , Wang Chengcheng , Zhao Yupei
Published: June 2021

Background

Pancreatic cancer (PC) is a highly fatal and aggressive disease with its incidence and mortality quite discouraging. An effective prediction model is urgently needed for the accurate assessment of patients’ prognosis to assist clinical decision-making.

Methods

Gene expression data and clinicopathological data of the samples were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases. Differential expressed genes (DEGs) analysis, univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, random forest screening and multivariate Cox regression analysis were applied to construct the risk signature. The effectiveness and independence of the model were validated by time-dependent receiver operating characteristic (ROC) curve, Kaplan–Meier (KM) survival analysis and survival point graph in training set, test set, TCGA entire set and GSE57495 set. The validity of the core gene was verified by immunohistochemistry and our own independent cohort. Meanwhile, functional enrichment analysis of DEGs between the high and low risk groups revealed the potential biological pathways. Finally, CMap database and drug sensitivity assay were utilized to identify potential small molecular drugs as the risk model-related treatments for PC patients.

Results

Four histone modification-related genes were identified to establish the risk signature, including CBX8, CENPT, DPY30 and PADI1. The predictive performance of risk signature was validated in training set, test set, TCGA entire set and GSE57495 set, with the areas under ROC curve (AUCs) for 3-year survival were 0.773, 0.729, 0.775 and 0.770 respectively. Furthermore, KM survival analysis, univariate and multivariate Cox regression analysis proved it as an independent prognostic factor. Mechanically, functional enrichment analysis showed that the poor prognosis of high-risk population was related to the metabolic disorders caused by inadequate insulin secretion, which was fueled by neuroendocrine aberration. Lastly, a cluster of small molecule drugs were identified with significant potentiality in treating PC patients.

Conclusions

Based on a histone modification-related gene signature, our model can serve as a reliable prognosis assessment tool and help to optimize the treatment for PC patients. Meanwhile, a cluster of small molecule drugs were also identified with significant potentiality in treating PC patients.
A seven-gene prognostic signature predicts overall survival of patients with lung adenocarcinoma (LUAD)
Authors: Al-Dherasi Aisha , Huang Qi-Tian , Liao Yuwei , Al-Mosaib Sultan , Hua Rulin , Wang Yichen , Yu Ying , Zhang Yu , Zhang Xuehong , Huang Chao , Mousa Haithm , Ge Dongcen , Sufiyan Sufiyan , Bai Wanting , Liu Ruimei , Shao Yanyan , Li Yulong , Zhang Jingkai , Shi Leming , Lv Dekang , Li Zhiguang , Liu Quentin
Published: June 2021

Background

Lung adenocarcinoma (LUAD) is one of the most common types in the world with a high mortality rate. Despite advances in treatment strategies, the overall survival (OS) remains short. Our study aims to establish a reliable prognostic signature closely related to the survival of LUAD patients that can better predict prognosis and possibly help with individual monitoring of LUAD patients.

Methods

Raw RNA-sequencing data were obtained from Fudan University and used as a training group. Differentially expressed genes (DEGs) for the training group were screened. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate cox regression analysis were conducted to identify the candidate prognostic genes and construct the risk score model. Kaplan–Meier analysis, time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic power and performance of the signature. Moreover, The Cancer Genome Atlas (TCGA-LUAD) dataset was further used to validate the predictive ability of prognostic signature.

Results

A prognostic signature consisting of seven prognostic-related genes was constructed using the training group. The 7-gene prognostic signature significantly grouped patients in high and low-risk groups in terms of overall survival in the training cohort [hazard ratio, HR = 8.94, 95% confidence interval (95% CI)] [2.041–39.2]; P = 0.0004), and in the validation cohort (HR = 2.41, 95% CI [1.779–3.276]; P < 0.0001). Cox regression analysis (univariate and multivariate) demonstrated that the seven-gene signature is an independent prognostic biomarker for predicting the survival of LUAD patients. ROC curves revealed that the 7-gene prognostic signature achieved a good performance in training and validation groups (AUC = 0.91, AUC = 0.7 respectively) in predicting OS for LUAD patients. Furthermore, the stratified analysis of the signature showed another classification to predict the prognosis.

Conclusion

Our study suggested a new and reliable prognostic signature that has a significant implication in predicting overall survival for LUAD patients and may help with early diagnosis and making effective clinical decisions regarding potential individual treatment.
Activity of Plasmodium vivax promoter elements in Plasmodium knowlesi, and a centromere-containing plasmid that expresses NanoLuc throughout the parasite life cycle
Authors: Moraes Barros Roberto R. , Thawnashom Kittisak , Gibson Tyler J. , Armistead Jennifer S. , Caleon Ramoncito L. , Kaneko Miho , Kite Whitney A. , Mershon J. Patrick , Brockhurst Jacqueline K. , Engels Theresa , Lambert Lynn , Orr-Gonzalez Sachy , Adams John H. , Sá Juliana M. , Kaneko Osamu , Wellems Thomas E.
Published: June 2021

Background

Plasmodium knowlesi is now the major cause of human malaria in Malaysia, complicating malaria control efforts that must attend to the elimination of multiple Plasmodium species. Recent advances in the cultivation of P. knowlesi erythrocytic-stage parasites in vitro, transformation with exogenous DNA, and infection of mosquitoes with gametocytes from culture have opened up studies of this pathogen without the need for resource-intensive and costly non-human primate (NHP) models. For further understanding and development of methods for parasite transformation in malaria research, this study examined the activity of various trans-species transcriptional control sequences and the influence of Plasmodium vivax centromeric (pvcen) repeats in plasmid-transfected P. knowlesi parasites.

Methods

In vitro cultivated P. knowlesi parasites were transfected with plasmid constructs that incorporated Plasmodium vivax or Plasmodium falciparum 5′ UTRs driving the expression of bioluminescence markers (firefly luciferase or Nanoluc). Promoter activities were assessed by bioluminescence, and parasites transformed with human resistant allele dihydrofolate reductase-expressing plasmids were selected using antifolates. The stability of transformants carrying pvcen-stabilized episomes was assessed by bioluminescence over a complete parasite life cycle through a rhesus macaque monkey, mosquitoes, and a second rhesus monkey.

Results

Luciferase expression assessments show that certain P. vivax promoter regions, not functional in the more evolutionarily-distant P. falciparum, can drive transgene expression in P. knowlesi. Further, pvcen repeats may improve the stability of episomal plasmids in P. knowlesi and support detection of NanoLuc-expressing elements over the full parasite life cycle from rhesus macaque monkeys to Anopheles dirus mosquitoes and back again to monkeys. In assays of drug responses to chloroquine, G418 and WR9910, anti-malarial half-inhibitory concentration (IC50) values of blood stages measured by NanoLuc activity proved comparable to IC50 values measured by the standard SYBR Green method.

Conclusion

All three P. vivax promoters tested in this study functioned in P. knowlesi, whereas two of the three were inactive in P. falciparum. NanoLuc-expressing, centromere-stabilized plasmids may support high-throughput screenings of P. knowlesi for new anti-malarial agents, including compounds that can block the development of mosquito- and/or liver-stage parasites.
Getting to zero: micro-foci of malaria in the Solomon Islands requires stratified control
Authors: Russell Tanya L. , Grignard Lynn , Apairamo Alan , Kama Nathan , Bobogare Albino , Drakeley Chris , Burkot Thomas R.
Published: June 2021

Background

The Solomon Islands has made significant progress in the control of malaria through vector control, access and use of improved diagnostics and therapeutic drugs. As transmission is reduced there is a need to understand variations in transmission risk at the provincial and village levels to stratify control methods.

Methods

A cross-sectional survey of malaria in humans was conducted in the Solomon Islands during April 2018. Nineteen villages across 4 provinces were included. The presence of Plasmodium species parasites in blood samples was detected using PCR.

Results

Blood samples were analysed from 1,914 participants. The prevalence of DNA of Plasmodium falciparum was 1.2 % (n = 23) and for Plasmodium vivax was 1.5 % (n = 28). 22 % (n = 5/23) of P. falciparum DNA positive participants were febrile and 17 % of P. vivax DNA positive participants (n = 5/28). The prevalence of both P. falciparum and P. vivax was extremely spatially heterogeneous. For P. falciparum, in particular, only 2 small foci of transmission were identified among 19 villages. Plasmodium falciparum infections were uniformly distributed across age groups. Insecticide-treated bed net use the night prior to the survey was reported by 63 % of participants and significantly differed by province.

Conclusions

Malaria transmission across the Solomon Islands has become increasingly fragmented, affecting fewer villages and provinces. The majority of infections were afebrile suggesting the need for strong active case detection with radical cure with primaquine for P. vivax. Village-level stratification of targeted interventions based on passive and active case detection data could support the progress towards a more cost-effective and successful elimination programme.
Assessment of the accuracy of malaria microscopy in private health facilities in Entebbe Municipality, Uganda: a cross-sectional study
Authors: Mutabazi Tobius , Arinaitwe Emmanuel , Ndyabakira Alex , Sendaula Emmanuel , Kakeeto Alex , Okimat Paul , Orishaba Philip , Katongole Simon Peter , Mpimbaza Arthur , Byakika-Kibwika Pauline , Karamagi Charles , Kalyango Joan Nakayaga , Kamya Moses R. , Dorsey Grant , Nankabirwa Joaniter I.
Published: June 2021

Background

Although microscopy remains the gold standard for malaria diagnosis, little is known about its accuracy in the private health facilities in Uganda. This study evaluated the accuracy of malaria microscopy, and factors associated with inaccurate smear results at private health facilities in Entebbe Municipality, Uganda.

Methods

Between April and May 2018, all patients referred for a malaria smear in 16 private health facilities in Entebbe municipality were screened, and 321 patients were enrolled. A questionnaire was administered to collect demographic and clinical information, facility-based smear results were recorded from the participant’s consultation notes, and a research slide was obtained for expert microscopy during exit interview. A health facility assessment was conducted, and information on experience in performing malaria microscopy was collected from all facility personnel reading smears and the data was linked to the participant’s clinic visit.

Results

The test positivity rate of malaria parasitaemia was 15.0% by expert microscopy. The sensitivity, specificity and negative predictive value of the facility-based microscopy were high (95.8%, 90.1 and 99.2%, respectively). However; the positive predictive value (PPV) was low with 27/73 (63%) patients diagnosed with malaria not having the disease. Majority of the inaccurate results were from 2 of the 23 laboratory personnel reading the smears. The factors associated with inaccurate smear readings included being read by a technician; (1) who had less than 5 years’ experience in reading malaria smears (adjusted Odds Ratio [aOR] = 9.74, 95% confidence interval [CI] (1.06–89.5), p-value = 0.04), and (2) who was examining less than 5 smears a day (aOR = 38.8, 95% CI 9.65–156, p-value < 0.001).

Conclusions

The accuracy of malaria microscopy in this setting was high, although one third of the patients diagnosed with malaria did not have the disease. Majority of the errors in smear readings were made by two laboratory personnel, with the main factor associated with inaccurate smear results being low experience in malaria microscopy. In-service training may be sufficient to eliminate inaccurate smear results in this setting, and these private facilities would be ideal model facilities to improve the quality of malaria microscopy in Uganda especially in the public sector where accuracy is still poor.
The association of carotid artery atherosclerosis with the estimated excretion levels of urinary sodium and potassium and their ratio in Chinese adults
Authors: Peng Shuang , Wang Jiangang , Xiao Yuanming , Yin Lu , Peng Yaguang , Yang Lin , Yang Pingting , Wang Yaqin , Cao Xia , Li Xiaohui , Li Ying
Published: June 2021

Background

Arterial stiffness is an independent cardiovascular risk factor. However, the association between sodium/potassium intake and vascular stiffness was inconsistent. Therefore, a large community-based cross-sectional study was performed to try and achieve more definitive conclusion.

Methods

Urinary sodium, potassium, and creatinine levels were tested in spot urine samples during physical examinations of each recruited participant. The 24-h estimated urinary sodium excretion (eUNaE) and estimated urinary potassium excretion (eUKE) levels were determined using the Kawasaki formula (used as a surrogate for intake). Carotid intima-media thickness (IMT) and plaques were measured using ultrasound.

Results

In 13,523 subjects aged 18–80 years, the relationships between carotid plaques and IMT with eUNaE, eUKE and their ratios were analyzed. Overall, 30.2% of participants were diagnosed with carotid artery plaques. The ratio of estimated sodium vs. potassium excretion (Na/K ratio) of the individuals with carotid artery plaques was significantly higher than that of participants without plaque (2.14 ± 0.73 vs. 2.09 ± 0.61, P < 0.01). After adjusting for age, gender, and other lifestyle covariates, a significant positive relation was found between carotid plaque and Na/K ratios (OR = 1.06, P < 0.05). In participants without plaque, a similar positive association was observed between Na/K ratios and increased bifurcation carotid IMT (β = 0.008, P < 0.01), especially in the females (Pinteraction < 0.01).

Conclusions

In this study, in which sodium intake was estimated on the basis of measured urinary excretion, high estimated excretion levels of urinary sodium and/or low estimated excretion levels of urinary potassium might be associated with an increased presence of carotid atherosclerosis in Chinese individuals.
Parent’s sociodemographic factors, physical activity and active commuting are predictors of independent mobility to school
Authors: Rodríguez-Rodríguez F. , Gálvez-Fernández P. , Huertas-Delgado F. J. , Aranda-Balboa M. J. , Saucedo-Araujo R. G. , Herrador-Colmenero M.
Published: June 2021

Background

Independent mobility (IM) provides young people with many opportunities to increase their autonomy and physical activity (PA). This study aimed to analyse whether the parent’s PA, active commuting to work and sociodemographic factors serve as predictors of IM to school in children and adolescents.

Methods

A total of 684 parents (52.8% mothers) and their offspring (56.4% girls) were included in this study, which was performed in Granada (Spain) and Valparaíso (Chile). The parents self-reported their sociodemographic characteristics, PA and mode of commuting to work. The mode of commuting to and from school and the offspring accompaniment mode were reported. T-test and chi-square test were used to study quantitative and qualitative differences by parental gender, respectively. Binary logistic regression models (odds ratio = OR) and stepwise analysis were performed to study the association between the parents’ sociodemographic variables and IM to school.

Results

Adolescents showed higher IM to school than children (58.9% vs 40.2%; p < 0.001). No car availability and shorter distance to work were positively associated with higher IM to school in children (OR = 2.22 and 2.29, respectively). Mothers' lower salary/month (OR = 2.75), no car availability (OR = 3.17), and mother passive commuting to work (OR = 2.61) were positively associated with higher IM to school in adolescents. The main predictor of IM to school in children and adolescents was no car availability (OR = 6.53).

Conclusion

Parental sociodemographic factors, such as salary, distance to work and car availability, were associated more strongly with IM than parental PA and active commuting to work.
Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade
Authors: Yan Chi , Saleh Nabil , Yang Jinming , Nebhan Caroline A. , Vilgelm Anna E. , Reddy E. Premkumar , Roland Joseph T. , Johnson Douglas B. , Chen Sheau-Chiann , Shattuck-Brandt Rebecca L. , Ayers Gregory D. , Richmond Ann
Published: June 2021

Background

While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.

Methods

Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data.

Results

RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.

Conclusions

Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.

Trial registration

NCT01205815 (Sept 17, 2010).

Graphical abstract
Melatonin alleviates titanium nanoparticles induced osteolysis via activation of butyrate/GPR109A signaling pathway
Authors: Wu Yanglin , He Fan , Zhang Chenhui , Zhang Qin , Su Xinlin , Zhu Xu , Liu Ang , Shi Weidong , Lin Weifeng , Jin Zhongqin , Yang Huilin , Lin Jun
Published: June 2021

Background

Inflammatory osteolysis after total joint replacement (TJR) may cause implant failure, periprosthetic fractures, and be a severe threat to global public health. Our previous studies demonstrated that melatonin had a therapeutic effect on wear-particles induced osteolysis. Gut microbiota is closely related to bone homeostasis, and has been proven to be affected by melatonin. However, whether melatonin could play its anti-osteolysis effects through reprogramming gut microbiota remains elusive.

Results

Here, we demonstrated that melatonin could alleviate Ti-particles induced osteolysis, while this therapeutic effect was blocked by antibiotic cocktail treatment. Interestingly, transplantation of fecal microbiota from mice treated with melatonin reappeared the same beneficial effect. Analysis of the 16S rRNA revealed that melatonin could reverse dysbacteriosis triggered by osteolysis, and elevate the relative abundance of some short chain fatty acid (SCFA) producing bacteria. Moreover, butyrate was enriched by exogenous melatonin administration, while acetate and propionate did not show an evident difference. This was consistent with the results of the metagenomic approach (PICRUSt2) analysis, which revealed a general increase in the synthetic enzymes of butyrate. More importantly, direct supplementation of butyrate could also recapitulate the anti-osteolysis effect of melatonin. Further analysis identified that butyrate alleviated osteolysis via activating its receptor GPR109A, and thus to suppress the activation of NLRP3 inflammasome triggered by Ti-particles.

Conclusions

Taken together, our results suggested that the benefits of melatonin mainly depend on the ability of modulating gut microbiota and regulating butyrate production.

Graphic Abstract
LncRNA TTN-AS1 acts as a tumor promoter in gallbladder carcinoma by regulating miR-107/HMGA1 axis
Authors: Lin Zhaoxia , Li Yaosheng , Shao Rongfeng , Hu Yuqing , Gao Han
Published: June 2021

Background

The incidence of gallbladder carcinoma (GBM) in China has increased in recent years. Here, the functional mechanism of lncRNA TTN-AS1 in GBC was preliminary elucidated.

Methods

The expression levels of lncRNA TTN-AS1, miR-107, and HMGA1 in tissues and cell lines were assessed by RT-qPCR. Cell proliferation was measured by MTT assays. Cell invasion and migration abilities were evaluated by Transwell assays. The relationship between miR-107 and lncRNA TTN-AS1 or HMGA1 was confirmed by luciferase reporter assay.

Results

Upregulation of lncRNA TTN-AS1 and downregulation of miR-107 were detected in GBC. Furthermore, the expressions between TTN-AS1 and miR-107 were mutually inhibited in GBC. Functionally, lncRNA TTN-AS1 promoted cell viability and motility in GBC by sponging miR-107. In addition, miR-107 directly targets HMGA1. And HMGA1 can be positively regulated by lncRNA TTN-AS1 in GBC. Furthermore, HMGA1 promoted GBC progression by interacting with lncRNA TTN-AS1/miR-107 axis.

Conclusion

LncRNA TTN-AS1 acted as a tumor promoter in GBC by sponging miR-107 and upregulating HMGA1.
Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination
Authors: Une Hayato , Yamasaki Ryo , Nagata Satoshi , Yamaguchi Hiroo , Nakamuta Yuko , Indiasari Ulfa Camelia , Cui Yiwen , Shinoda Koji , Masaki Katsuhisa , Götz Magdalena , Kira Jun-ichi
Published: June 2021

Background

Brain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation.

Methods

Because glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35–55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls.

Results

Acute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls.

Conclusions

The ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.
NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1β-mediated neuroinflammation
Authors: Zhang Zi-Teng , Gu Xiao-Lei , Zhao Xin , He Xian , Shi Hao-Wei , Zhang Kun , Zhang Yi-Ming , Su Yi-Nan , Zhu Jiang-Bo , Li Zhi-Wei , Li Guo-Bao
Published: June 2021

Background

Patients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke.

Methods

In this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1β neutralizing antibody was injected to test potential therapeutic effect on heat stroke.

Results

Prior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1β in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1β production with prior infection condition. Furthermore, IL-1β neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke.

Conclusions

Based on the above results, NLRP3/IL-1β induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1β may serve as a biomarker for heat stroke severity and potential therapeutic method.
Sexual and reproductive health of adolescent Syrian refugee girls in Lebanon: a qualitative study of healthcare provider and educator perspectives
Authors: Fahme Sasha Abdallah , Sieverding Maia , Abdulrahim Sawsan
Published: June 2021

Background

Adolescent Syrian refugee girls in Lebanon are thought to experience a disproportionate risk of poor sexual and reproductive health, related in part to conflict and displacement. The purpose of this qualitative study was to explore healthcare provider and educator perceptions of the sexual and reproductive health determinants and care-seeking behaviors of this vulnerable population. The findings of the study will inform a health intervention that aims to reduce early marriage and improve access to sexual and reproductive health information and services.

Methods

In-depth interviews and focus group discussions were conducted with stakeholders who work with adolescent Syrian refugee girls in an under-resourced area of eastern Lebanon bordering Syria. Data analysis followed principles of Clarke and Braun’s thematic analysis.

Results

Study participants perceived adolescent pregnancy, reproductive tract infections, and sexual- and gender-based violence as major population health needs. The study also identified a number of influencing structural and sociocultural determinants of health, including early marriage, adolescent disempowerment, and men’s disengagement from care. A conceptual framework based upon the Gelberg–Andersen Behavioral Model for Vulnerable Populations was developed to relate these determinants and guide pathways for potential interventions.

Conclusions

Adolescent sexual and reproductive health interventions among Syrian refugees in Lebanon should adopt a multi-pronged, community-based approach to address underlying health determinants and engage with men and parents of adolescents. Special attention should be given to provider biases in healthcare settings accessible to adolescents, as these may reflect underlying tensions between host and refugee populations and discourage adolescents from seeking care.
Temporal phylogeny and molecular characterization of echovirus 30 associated with aseptic meningitis outbreaks in China
Authors: Tian Xiaoling , Han Zhenzhi , He Yulong , Sun Qiang , Wang Wenrui , Xu Wenbo , Li Hongying , Zhang Yong
Published: June 2021

Background

An outbreak of aseptic meningitis occurred from June to August 2016, in Inner Mongolia Autonomous Region, China.

Methods

To determine its epidemiological characteristics, etiologic agent, and possible origin, specimens were collected for virus isolation and identification, followed by molecular epidemiological analysis.

Results

A total of 363 patients were clinically diagnosed from June 1st to August 31st 2016, and most cases (63.1%, n = 229) were identified between June 22nd and July 17th, with children aged 6 to 12 years constituting the highest percentage (68.9%, n = 250). All viral isolates from this study belonged to genotype C of echovirus 30 (E30), which dominated transmission in China. To date, two E30 transmission lineages have been identified in China, of which Lineage 2 was predominant. We observed fluctuant progress of E30 genetic diversity, with Lineage 2 contributing to increased genetic diversity after 2002, whereas Lineage 1 was significant for the genetic diversity of E30 before 2002.

Conclusions

We identified the epidemiological and etiological causes of an aseptic meningitis outbreak in Inner Mongolia in 2016, and found that Lineage 2 played an important role in recent outbreaks. Moreover, we found that Gansu province could play an important role in E30 spread and might be a possible origin site. Furthermore, Fujian, Shandong, Taiwan, and Zhejiang provinces also demonstrated significant involvement in E30 evolution and persistence over time in China.
Metabolic and hormonal effects of melatonin and/or magnesium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial
Authors: Alizadeh Mohammad , Karandish Majid , Asghari Jafarabadi Mohammad , Heidari Lida , Nikbakht Roshan , Babaahmadi Rezaei Hossein , Mousavi Reihaneh
Published: June 2021

Background

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. This study was designed to investigate the effects of melatonin and/or magnesium supplementation on metabolic profile and levels of sex hormones in PCOS women.

Methods

In an 8-week randomized double-blind placebo-controlled trial, 84 subjects with PCOS aged 18–40 years were randomly assigned based on the random block procedure to take magnesium, melatonin, magnesium plus melatonin, and placebo. Fasting blood samples were obtained at the beginning and end of the study.

Results

After intervention, the mean Pittsburg Sleep Quality Index score decreased significantly in both co-supplementation and melatonin groups (P < 0.001). Magnesium supplementation in combination with melatonin resulted in a significant greater decrease in testosterone concentrations compared with the placebo (P < 0.05). Co-supplementation of magnesium-melatonin had significantly reduced serum insulin levels (geometric means difference: − 1.11 (mIU/mL) (percent change: − 15.99)), homeostasis model of assessment-insulin resistance (HOMA-IR) (− 0.28 (− 18.66)), serum cholesterol (mean difference: − 16.08 (mg/dl) [95% CI − 24.24, − 7.92]), low-density lipoprotein cholesterol (LDL-C) − 18.96 (mg/dl) [− 28.73, − 9.20]) and testosterone levels (− 0.09 (ng/ml) (− 25.00)), as compared to the baseline values (P < 0.05). An increase in serum high-density lipoprotein cholesterol (HDL-C) levels was also observed following the administration of the melatonin alone (2.76 (mg/dl) [0.57, 4.95]) or in combination with magnesium (2.19 (mg/dl) [0.61, 3.77]) (P < 0.05).

Conclusions

Co-supplementation with magnesium and melatonin had beneficial effects on sleep quality and total testosterone. Additionally, melatonin supplementation alone was found to be associated with a significant reduction in PSQI score. Moreover, combined melatonin and magnesium supplementation was more effective in improving serum levels of cholesterol, LDL-C, HDL-C and insulin, and HOMA-IR.

Trial registration: Iranian Registry of Clinical Trial. http://www.irct.ir: IRCT20191130045556N1, January 2020.
Geometric and dosimetric impact of 3D generative adversarial network-based metal artifact reduction algorithm on VMAT and IMPT for the head and neck region
Authors: Nakamura Mitsuhiro , Nakao Megumi , Imanishi Keiho , Hirashima Hideaki , Tsuruta Yusuke
Published: June 2021

Background

We investigated the geometric and dosimetric impact of three-dimensional (3D) generative adversarial network (GAN)-based metal artifact reduction (MAR) algorithms on volumetric-modulated arc therapy (VMAT) and intensity-modulated proton therapy (IMPT) for the head and neck region, based on artifact-free computed tomography (CT) volumes with dental fillings.

Methods

Thirteen metal-free CT volumes of the head and neck regions were obtained from The Cancer Imaging Archive. To simulate metal artifacts on CT volumes, we defined 3D regions of the teeth for pseudo-dental fillings from the metal-free CT volumes. HU values of 4000 HU were assigned to the selected teeth region of interest. Two different CT volumes, one with four (m4) and the other with eight (m8) pseudo-dental fillings, were generated for each case. These CT volumes were used as the Reference. CT volumes with metal artifacts were then generated from the Reference CT volumes (Artifacts). On the Artifacts CT volumes, metal artifacts were manually corrected for using the water density override method with a value of 1.0 g/cm3 (Water). By contrast, the CT volumes with reduced metal artifacts using 3D GAN model extension of CycleGAN were also generated (GAN-MAR). The structural similarity (SSIM) index within the planning target volume was calculated as quantitative error metric between the Reference CT volumes and the other volumes. After creating VMAT and IMPT plans on the Reference CT volumes, the reference plans were recalculated for the remaining CT volumes.

Results

The time required to generate a single GAN-MAR CT volume was approximately 30 s. The median SSIMs were lower in the m8 group than those in the m4 group, and ANOVA showed a significant difference in the SSIM for the m8 group (p < 0.05). Although the median differences in D98%, D50% and D2% were larger in the m8 group than the m4 group, those from the reference plans were within 3% for VMAT and 1% for IMPT.

Conclusions

The GAN-MAR CT volumes generated in a short time were closer to the Reference CT volumes than the Water and Artifacts CT volumes. The observed dosimetric differences compared to the reference plan were clinically acceptable.
Psychological and social interventions for mental health issues and disorders in Southeast Asia: a systematic review
Authors: Maddock Alan , Blair Carolyn , Ean Nil , Best Paul
Published: June 2021

Background

Mental health issues and disorders are major public health challenges, particularly in low- and middle-income countries in Southeast Asia, where chronic shortages in mental health services and human resources exist. The development of effective and accessible mental health systems in Southeast Asia will require evidence based psychological and social interventions. This systematic review provides a narrative synthesis of the evidence on the effectiveness of such interventions for mental health issues and disorders in Southeast Asia.

Methods

A comprehensive literature search of 7 electronic databases (PsycINFO, Medline (Ovid), Cochrane library, EMBASE, SCOPUS, APA PsycArticles, and Social Care Online) was undertaken.

Results

Thirty two studies employing RCT designs to evaluate the effectiveness of a range of psychological and social mental health interventions on a number of different mental health outcomes were included in this review. The disparate intervention programmes reviewed were categorised as: lay delivered, yoga, aerobic and/or meditation based, cognitive behavioural therapy oriented, eye movement desensitization and reprocessing based (EMDR), health worker delivered, and hybrid programmes. The majority of the studies included in this review were of low to moderate quality due to the variability in the quality of the study design. The highest quality, and most promising evidence came from the evaluations of lay delivered interventions. This evidence demonstrates the feasibility and potential sustainability of implementing such interventions in resource constrained contexts.

Conclusions

The review findings indicate that a disparate array of mental health interventions can be implemented effectively in a range of Southeast Asian mental health and health settings. There is a clear need for significantly more research however, through higher quality and larger scale RCTs before it will be known more definitively, if these interventions are effective, and for whom they are most effective in different Southeast Asian contexts.