bluuebunny/crossref_metadata_2025 huggingface dataset:
Finite analysis of stability between modified articular fusion technique, posterior lumbar interbody fusion and posteriorlateral lumbar fusion
Authors: Han Xiao , Chen Xin , Li Kuan , Li Zheng , Li Shugang
Published: December 2021

Background

It is not clear whether modified facet fusion (MFF) is biomechanically different from traditional fusion techniques such as posterior lateral lumbar fusion (PLF) and posterior lumbar interbody fusion (PLIF).

Methods

In this study, a healthy adult Chinese male volunteer was selected to perform 3D reconstruction of CT image data and simulate the successful fusion of L4–5 MFF, PLF and PLIF, respectively. The motion range of L4–5 segments of the model was simulated under 6 working conditions, including forward flexion, extension, lateral flexion and rotation under normal physiological conditions, and the stability of the three fusion procedures in the pathological segments of the lumbar spine was compared.

Results

There was no difference in range of motion between MFF model and PLF or PLIF model (P < 0.05). Also, the stiffness of the PLFand the MFF model were comparable (P > 0.05), but were smaller than the PLIF model (P < 0.05).

Conclusions

MFF provides reliable stability at the lumbar fixation fusion level and does not differ significantly from PLF and PLIF in terms of range of motion.
Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report
Authors: Siavrienė Evelina , Petraitytė Gunda , Burnytė Birutė , Morkūnienė Aušra , Mikštienė Violeta , Rančelis Tautvydas , Utkus Algirdas , Kučinskas Vaidutis , Preikšaitienė Eglė
Published: December 2021

Background

Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis.

Case presentation

In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)).

Conclusions

Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.
Dental caries and its association with the oral microbiomes and HIV in young children—Nigeria (DOMHaIN): a cohort study
Authors: Coker Modupe O. , Akhigbe Paul , Osagie Esosa , Idemudia Nosakhare L. , Igedegbe Oghenero , Chukwumah Nneka , Adebiyi Ruxton , Mann Allison E. , O’Connell Lauren M. , Obuekwe Ozo , Omoigberale Augustine , Charurat Manhattan E. , Richards Vincent P.
Published: December 2021

Background

This study seeks to understand better the mechanisms underlying the increased risk of caries in HIV-infected school-aged Nigerian children by examining the relationship between the plaque microbiome and perinatal HIV infection and exposure. We also seek to investigate how perinatal HIV infection and exposure impact tooth-specific microbiomes' role on caries disease progression.

Methods

The participants in this study were children aged 4 to 11 years recruited from the University of Benin Teaching Hospital (UBTH), Nigeria, between May to November 2019. Overall, 568 children were enrolled in three groups: 189 HIV-infected (HI), 189 HIV-exposed but uninfected (HEU) and 190 HIV-unexposed and uninfected (HUU) as controls at visit 1 with a 2.99% and 4.9﻿0% attrition rate at visit 2 and visit 3 respectively. Data were obtained with standardized questionnaires. Blood samples were collected for HIV, HBV and HCV screening; CD4, CD8 and full blood count analysis; and plasma samples stored for future investigations; oral samples including saliva, buccal swabs, oropharyngeal swab, tongue swab, dental plaque were collected aseptically from participants at different study visits.

Conclusions

Results from the study will provide critical information on how HIV exposure, infection, and treatment, influence the oral microbiome and caries susceptibility in children. By determining the effect on community taxonomic structure and gene expression of dental microbiomes, we will elucidate mechanisms that potentially create a predisposition for developing dental caries. As future plans, the relationship between respiratory tract infections, immune and inflammatory markers with dental caries in perinatal HIV infection and exposure will be investigated.
Key components and critical factors for developing a telehealth business framework: a qualitative study
Authors: Velayati Farnia , Ayatollahi Haleh , Hemmat Morteza , Dehghan Reza
Published: December 2021

Background

Telehealth technology and related products can help to solve the problems associated with providing health care services and equal distribution of resources. However, in order to run a telehealth business successfully, key components and critical factors need to be taken into account. A telehealth business framework can provide a rich understanding of these components and factors. Therefore, the present study aimed to identify the key components and critical factors for developing a telehealth business framework from the experts’ perspectives.

Methods

The present qualitative study was conducted in 2020. The participants were 22 experts in the fields of medical informatics, health information management, telemedicine, telehealth, health entrepreneurship, health insurance, and digital health start-ups. In depth semi-structured interviews were conducted to collect data, and the data were analyzed using framework analysis.

Results

Four main themes derived from data analysis. The themes included key components for developing a telehealth business framework, success factors, challenges, and barriers of a telehealth business. Overall, the results indicated that the key components in a telehealth business framework included created value, key resources, key activities, key partners, licenses and permissions, product pricing, revenue, marketing, supporting services, and getting feedback from customers. Although receiving support from different individuals and organizations as well as economic benefits of telehealth services may consider as success factors, there are a number of challenges and barriers which should be taken into account. Otherwise, these factors may hinder the success of a telehealth business.

Conclusions

The development of a telehealth business framework might be an important step towards developing a more complete business plan, facilitating the commercialization of telehealth products, and providing a solution for product sustainability in a competitive market. In the current study, the key components and critical factors for developing a telehealth business framework were identified; however, further research is needed to explore how these components and factors can be helpful in developing business plans and running a successful telehealth business.
The economic impact of compassionate use of medicines
Authors: Jommi Claudio , Pantellini Federico , Stagi Lisa , Verykiou Maria , Cavazza Marianna
Published: December 2021

Background

Compassionate use programs (CUP) for medicines respond to the ethical imperative of providing access to medicines before marketing approval to patients not recruited in trials. The economic impact of clinical trials has previously been investigated. No evidence on the net economic benefit of CUP exists. This research aims to address this information gap by estimating the economic consequences of 11 CUP in Italy conducted between March 2015 and December 2020 from the perspective of public health care system in Italy (National Health Service). Eight programs concern cancer treatments, two refer to spinal muscular atrophy, and one is indicated for multiple sclerosis.

Methods

Since CUP medicines are covered by the industry, the net economic benefit includes: (i) avoided costs of the Standard of Care (SoC) the patients would have received had they not joined the CUP, (ii) costs not covered by the pharmaceutical industry sponsor, but instead sustained by payers, such as those associated with adverse events (only severe side effects resulting in hospitalisation and attributable to CUP medicines), and (iii) costs for combination therapies and diagnostic procedures not used with the SoC. The SoC costing relied on publicly available data. Information on adverse events and diagnostic procedures was retrieved from the CUP and monetized using the relevant fee for episode or service. One CUP was excluded since a SoC was not identified.

Results

2,713 patients were treated in the 11 CUP where a SoC was identified. The SoC mean cost per patient ranged from €11,415 to €20,299. The total cost of the SoC ranged between €31.0 and €55.1 million. The mean cost per patient covered by hospitals hosting CUP was equal to €1,646, with a total cost of €4.5 million. The net economic benefit ranged €26.5 million - €50.6 million.

Conclusions

Despite research limitations, this paper illustrates for the first time the net economic impact of CUP from a public payer perspective. It is important to integrate these estimates with the prospective effects of CUP implementation, i.e., the economic value of the comparative benefit profile of medicines used in CUP versus the SoC, including effects from a societal perspective.
Impact of investment case on equitable access to maternal and child health services in Nepal: a quasi-experimental study
Authors: Thapa Janak Kumar , Stöckl Doris , Sangroula Raj Kumar , Thakur Dip Narayan , Mehata Suresh , Pun Asha , Delius Maria
Published: December 2021

Background

Disparities in the use of maternal, neonatal and child health (MNCH) services remain a concern in Low- and Middle-Income countries such as Nepal. Commonly observed disparities exist in education, income, ethnic groups, administrative regions and province-level in Nepal. In order to improve equitable outcomes for MNCH and to scale-up quality services, an Investment Case (IC) approach was lunched in the Asia Pacific region. The study assessed the impact of the IC intervention package in maternal and child health outcomes in Nepal.

Methods

The study used a quasi-experimental design extracting data from the Nepal Demographic Health Surveys – 2011 (pre-assessment) and 2016 (post-assessment) for 16 intervention and 24 control districts. A Difference in Difference (DiD) analysis was conducted to assess the impact of the intervention on maternal and child health outcomes. The linear regression method was used to calculate the DiD, adjusting for potential covariates. The final models were arrived by stepwise backward method including the confounding variables significant at p < 0.05.

Results

The results of the DiD analyses showed at least four antenatal care visits (ANC) decreased in the intervention area (DiD% = − 4.8), while the delivery conducted by skilled birth attendants increased (DiD% = 6.6) compared to control area. However, the adjusted regression coefficient showed that these differences were not significant, indicating a null effect of the intervention. Regarding the child health outcomes, children with underweight (DiD% = 6.3), and wasting (DiD% = 5.4) increased, and stunting (DiD% = − 6.3) decreased in the intervention area compared to control area. The adjusted regression coefficient showed that the difference was significant only for wasting (β = 0.019, p = 0.002), indicating the prevalence of wasting increased in the intervention group compared to the control group.

Conclusion

The IC approach implemented in Nepal did not show improvements in maternal and child health outcomes compared to control districts. The use of the IC approach to improve MCH in Nepal should be discussed and, if further used, the process of implementation should be strictly monitored and evaluated.
Primary care coverage and individual health: evidence from a likelihood model using biomarkers in Brazil
Authors: Postali Fernando Antonio Slaibe , Diaz Maria Dolores Montoya , Ferreira-Batista Natalia Nunes , Teixeira Adriano Dutra , Moreno-Serra Rodrigo
Published: December 2021

Background

Although the use of biomarkers to assess health outcomes has recently gained momentum, literature is still scarce for low- to middle-income countries. This paper explores the relationship between primary care coverage and individual health in Brazil using a dataset of blood-based biomarkers collected by the Brazilian National Health Survey. Both survey data and laboratory results were crossed with coverage data from the Family Health Strategy (ESF) program, the most important primary care program in Brazil; the coverage measures aim to capture both direct (household) and indirect (spill-over) effects.

Methods

The empirical strategy used a probit model to estimate the relationship between ESF program coverage and the likelihood of abnormal biomarker levels while controlling for a rich set of individual and household characteristics based on data from the national survey.

Results

Household ESF coverage was associated with a lower likelihood of abnormal results for biomarkers related to anemia (marginal effect between − 2.16 and − 2.18 percentage points), kidney failure (between − 1.01 and − 1.19 p.p.), and arterial hypertension (between − 1.48 and − 1.64 p.p). The likelihood of abnormal levels of white blood cells and thrombocytes was negatively related to primary care coverage (marginal effect between − 1.8 and − 2 p.p.). The spillover effects were relevant for kidney failure and arterial hypertension, depending on the regional level. Although not sensitive to household coverage, diabetes mellitus was negatively associated with the state supply of primary care, and abnormal cholesterol levels did not present any relationship with ESF program coverage.

Conclusions

The presence of spillover effects of ESF program coverage regarding these conditions reveals that the strengthening of primary care by increasing the household registration and the regional density of ESF teams is an efficient strategy to address important comorbidities.
Proteogenomics analysis of CUG codon translation in the human pathogen Candida albicans
Authors: Mühlhausen Stefanie , Schmitt Hans Dieter , Plessmann Uwe , Mienkus Peter , Sternisek Pia , Perl Thorsten , Weig Michael , Urlaub Henning , Bader Oliver , Kollmar Martin
Published: December 2021

Background

Yeasts of the CTG-clade lineage, which includes the human-infecting Candida albicans, Candida parapsilosis and Candida tropicalis species, are characterized by an altered genetic code. Instead of translating CUG codons as leucine, as happens in most eukaryotes, these yeasts, whose ancestors are thought to have lost the relevant leucine-tRNA gene, translate CUG codons as serine using a serine-tRNA with a mutated anticodon, $$ {\mathrm{tRNA}}_{\mathrm{CAG}}^{\mathrm{Ser}} $$

tRNA
CAG
Ser

. Previously reported experiments have suggested that 3–5% of the CTG-clade CUG codons are mistranslated as leucine due to mischarging of the $$ {\mathrm{tRNA}}_{\mathrm{CAG}}^{\mathrm{Ser}} $$

tRNA
CAG
Ser

. The mistranslation was suggested to result in variable surface proteins explaining fast host adaptation and pathogenicity.

Results

In this study, we reassess this potential mistranslation by high-resolution mass spectrometry-based proteogenomics of multiple CTG-clade yeasts, including various C. albicans strains, isolated from colonized and from infected human body sites, and C. albicans grown in yeast and hyphal forms. Our data do not support a bias towards CUG codon mistranslation as leucine. Instead, our data suggest that (i) CUG codons are mistranslated at a frequency corresponding to the normal extent of ribosomal mistranslation with no preference for specific amino acids, (ii) CUG codons are as unambiguous (or ambiguous) as the related CUU leucine and UCC serine codons, (iii) tRNA anticodon loop variation across the CTG-clade yeasts does not result in any difference of the mistranslation level, and (iv) CUG codon unambiguity is independent of C. albicans’ strain pathogenicity or growth form.

Conclusions

Our findings imply that C. albicans does not decode CUG ambiguously. This suggests that the proposed misleucylation of the $$ {\mathrm{tRNA}}_{\mathrm{CAG}}^{\mathrm{Ser}} $$

tRNA
CAG
Ser

might be as prevalent as every other misacylation or mistranslation event and, if at all, be just one of many reasons causing phenotypic diversity.
Changes in salivary biomarkers of oxidative status in calves at weaning and grouping
Authors: Rubio Camila Peres , Escribano Damián , Mainau Eva , Cerón José Joaquin , Navarro Elena , Manteca Xavier
Published: December 2021

Background

Saliva is being increasingly used as a sample for measuring biomarkers in several species and shows a high potential of use to detect and monitor stress. The weaning and grouping in dairy calves are a particularly stressful time. Therefore, the objectives of this study were to evaluate a panel of antioxidant and oxidant biomarkers in the saliva of calves on the day of weaning (W0), 2 days after weaning or milk withdrawal (W + 2), and 4 days after grouping (G + 4). In addition, to verify if cortisol and oxytocin concentrations are related to the biomarkers measured.

Results

Salivary cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of saliva (FRAS), Trolox equivalent antioxidant capacity (TEAC), advanced oxidation protein products (AOPP), and ferrous oxidation-xylenol orange (FOX) were significantly higher (P < 0.02) 4 days after grouping than the day of weaning and 2 days after. The increases were 50 and 54% for CUPRAC, 93 and 116% for FRAS, 117 and 135% for TEAC, 22 and 49% for AOPP and 10 and 5% for FOX in comparison with weaning and 2 days after, respectively. In addition, oxytocin and cortisol showed significant negative and positive correlations (P < 0.05) respectively with the biomarkers of oxidative status.

Conclusions

Our results showed that calves after grouping show increases in antioxidants and oxidants concentrations, indicating that a balance between these molecules has been tried to maintain during this stressful situation. The dynamic changes of biomarkers of oxidative status should be explored and characterised in other stressful conditions.
Ferulic acid ameliorates lipopolysaccharide-induced tracheal injury via cGMP/PKGII signaling pathway
Authors: Xie Xiaoyong , Yu Tong , Hou Yapeng , Han Aixin , Ding Yan , Nie Hongguang , Cui Yong
Published: December 2021

Background

Tracheal injury is a common clinical condition that still lacks an effective therapy at present. Stimulation of epithelial sodium channel (ENaC) increases Na+ transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects. However, these studies rarely involve the level of ion transport, especially ENaC.

Methods

C57BL/J male mice were treated intraperitoneally with normal saline or FA (100 mg/kg) 12 h before, and 12 h after intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg), respectively. The effects of FA on tracheal injury were not only assessed through HE staining, immunofluorescence assay, and protein/mRNA expressions of ENaC located on tracheas, but also evaluated by the function of ENaC in mouse tracheal epithelial cells (MTECs). Besides, to explore the detailed mechanism about FA involved in LPS-induced tracheal injury, the content of cyclic guanosine monophosphate (cGMP) was measured, and Rp-cGMP (cGMP inhibitor) or cGMP-dependent protein kinase II (PKGII)-siRNA (siPKGII) were applied in primary MTECs, respectively.

Results

Histological examination results demonstrated that tracheal injury was obviously attenuated by pretreatment of FA. Meanwhile, FA could reverse LPS-induced reduction of both protein/mRNA expressions and ENaC activity. ELISA assay verified cGMP content was increased by FA, and administration of Rp-cGMP or transfection of siPKGII could reverse the FA up-regulated ENaC protein expression in MTECs.

Conclusions

Ferulic acid can attenuate LPS-induced tracheal injury through up-regulation of ENaC at least partially via the cGMP/PKGII pathway, which may provide a promising new direction for preventive and therapeutic strategy in tracheal injury.
Extracellular vesicles and pasteurized cells derived from Akkermansia muciniphila protect against high-fat induced obesity in mice
Authors: Ashrafian Fatemeh , Keshavarz Azizi Raftar Shahrbanoo , Lari Arezou , Shahryari Arefeh , Abdollahiyan Sara , Moradi Hamid Reza , Masoumi Morteza , Davari Mehdi , khatami Shohreh , Omrani Mir Davood , Vaziri Farzam , Masotti Andrea , Siadat Seyed Davar
Published: December 2021

Background

Several studies have shown that probiotics have beneficial effects on weight control and metabolic health. In addition to probiotics, recent studies have investigated the effects of paraprobiotics and postbiotics. Therefore, we evaluated the preventive effects of live and pasteurized Akkermansia muciniphila MucT (A. muciniphila) and its extracellular vesicles (EVs) on HFD-induced obesity.

Results

The results showed that body weight, metabolic tissues weight, food consumption, and plasma metabolic parameters were increased in the HFD group, whereas A. muciniphila preventive treatments inhibited these HFD. The effects of pasteurized A. muciniphila and its extracellular vesicles were more noticeable than its active form. The HFD led to an increase in the colonic, adipose tissue, and liver inflammations and increased the expression of genes involved in lipid metabolism and homeostasis. Nevertheless, these effects were inhibited in mice that were administered A. muciniphila and its EVs. The assessment of the gut microbiota revealed significant differences in the microbiota composition after feeding with HFD. However, all treatments restored the alterations in some bacterial genera and closely resemble the control group. Also, the correlation analysis indicated that some gut microbiota might be associated with obesity-related indices.

Conclusions

Pasteurized A. muciniphila and its EVs, as paraprobiotic and postbiotic agents, were found to play a key role in the regulation of metabolic functions to prevent obesity, probably by affecting the gut-adipose-liver axis.

Graphical Abstract
Silencing of the lncRNA H19 enhances sensitivity to X-ray and carbon-ions through the miR-130a-3p /WNK3 signaling axis in NSCLC cells
Authors: Zhao Xueshan , Jin Xiaodong , Zhang Qiuning , Liu Ruifeng , Luo Hongtao , Yang Zhen , Geng Yichao , Feng Shuangwu , Li Chengcheng , Wang Lina , Wang Xiaohu , Li Qiang
Published: December 2021

Background

The lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown.

Methods

The expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells. Flow cytometry and Western blotting were conducted to measure the level of apoptosis. The binding relationship between the lncRNA H19 and miR-130a-3p was determined by a dual-luciferase reporter assay. A binding relationship was also identified between miR-130a-3p and With-No-Lysine Kinase 3 (WNK3).

Results

Expression patterns of lncRNAs revealed that the lncRNA H19 was upregulated in radioresistant NSCLC (A549-R11) cells compared with A549 cells. Knockdown of the lncRNA H19 enhanced the sensitivity of NSCLC cell lines to X-ray and carbon ion irradiation. Mechanistically, the lncRNA H19 serves as a sponge of miR-130a-3p, which downregulates WNK3 expression. The lncRNA H19–miR-130a-3p–WNK3 axis modulates radiosensitivity by regulating apoptosis in NSCLC cell lines.

Conclusion

Knockdown of the lncRNA H19 promotes the sensitivity of NSCLC cells to X-ray and carbon ion irradiation. Hence, the lncRNA H19 might function as a potential therapeutic target that enhances the antitumor effects of radiotherapy in NSCLC.
YTHDC1-mediated VPS25 regulates cell cycle by targeting JAK-STAT signaling in human glioma cells
Authors: Zhu Xiaolong , Yang Hui , Zhang Mengying , Wu Xingwei , Jiang Lan , Liu Xiaocen , Lv Kun
Published: December 2021

Background

Glioma is a common type of malignant brain tumor with a high mortality and relapse rate. The endosomal sorting complex required for transport (ESCRT) has been reported to be involved in tumorigenesis. However, the molecular mechanisms have not been clarified.

Methods

Bioinformatics was used to screen the ESCRT subunits highly expressed in glioma tissues from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The function of the ESCRT subunits in glioma cells was examined in vitro. Transcriptome sequencing analyzed the target genes and signaling pathways affected by the ESCRT subunit. Finally, the relationship between m6A (N6-methyladenosine) modification and high expression of the ESCRT subunit was studied.

Results

VPS25 was upregulated in glioma tissues, which was correlated with poor prognosis in glioma patients. Furthermore, VPS25 knockdown inhibited the proliferation, blocked the cell cycle, and promoted apoptosis in glioma cells. Meanwhile, VPS25 induced a G0/G1 phase arrest of the cell cycle in glioma cells by directly mediating p21, CDK2, and cyclin E expression, and JAK-signal transducer and activator of transcription (STAT) activation. Finally, YTHDC1 inhibited glioma proliferation by reducing the expression of VPS25.

Conclusion

These results suggest that VPS25 is a promising prognostic indicator and a potential therapeutic target for glioma.
Expression profile of RNA binding protein in cervical cancer using bioinformatics approach
Authors: Huang Zhiyuan , Li Fang , Li Qinchuan
Published: December 2021

Background

It has been demonstrated by studies globally that RNA binding proteins (RBPs) took part in the development of cervical cancer (CC). Few studies concentrated on the correlation between RBPs and overall survival of CC patients. We retrieved significant DEGs (differently expressed genes, RNA binding proteins) correlated to the process of cervical cancer development.

Methods

Expressions level of genes in cervical cancer and normal tissue samples were obtained from GTEx and TCGA database. Differently expressed RNA binding proteins (DEGs) were retrieved by Wilcoxon sum-rank test. ClusterProfiler package worked in R software was used to perform GO and KEGG enrichment analyses. Univariate proportional hazard cox regression and multivariate proportional hazard cox regressions were applied to identify DEGs equipped with prognostic value and other clinical independent risk factors. ROC curve was drawn for comparing the survival predict feasibility of risk score with other risk factors in CC patients. Nomogram was drawn to exhibit the prediction model and validated by C-index and calibration curve. Correlations between differentially expressed RNA binding proteins (DEGs) and other clinical features were investigated by t test or Cruskal Wallis analysis. Correlation between Immune and DEGs in cervical cancer was investigated by ssGSEA.

Results

347 differentially expressed RBPs (DEGs) were retrieved from cervical cancer tissue and normal tissue samples. GO enrichment analysis showed that these DEGs involved in RNA splicing, catabolic process and metabolism. Cox regression model showed that there were ten DEGs significantly associated with overall survival of cervical cancer patients. WDR43 (HR = 0.423, P = 0.008), RBM38 (HR = 0.533, P < 0.001), RNASEH2A (HR = 0.474, P = 0.002) and HENMT1 (HR = 0.720, P = 0.071) played protective roles in survival among these ten genes. Stage (Stage IV vs Stage I HR = 3.434, P < 0.001) and risk score (HR = 1.214, P < 0.001) were sorted as independent prognostic risk factors based on multivariate cox regression. ROC curve validated that risk score was preferable to predict survival of CC patients than other risk factors. Additionally, we found some of these ten predictor DEGs were correlated significantly in statistic with tumor grade or stage, clinical T stage, clinical N stage, pathology or risk score (all P < 0.05). Part of immune cells and immune functions showed a lower activity in high risk group than low risk group which is stratified by median risk score.

Conclusion

Our discovery showed that many RNA binding proteins involved in the progress of cervical cancer, which could probably serve as prognostic biomarkers and accelerate the discovery of treatment targets for CC patients.
CCR9 initiates epithelial–mesenchymal transition by activating Wnt/β-catenin pathways to promote osteosarcoma metastasis
Authors: Kong Haoran , Yu Wenhui , Chen Zhuning , Li Haonan , Ye Guiwen , Hong Jiacong , Xie Zhongyu , Chen Keng , Wu Yanfeng , Shen Huiyong
Published: December 2021

Background

Osteosarcoma (OS) patients with lung metastasis have poor prognoses, and effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking. Hence, it is critical to elucidate the underlying mechanisms of OS metastasis and to identify additional new effective treatment strategies for patients.

Methods

Differential expression and functional analyses were performed to identify key genes and relevant signaling pathways associated with OS lung metastasis. The expression of CCR9 in OS cell lines and tissues was measured by RT-qPCR, western blotting and immunohistochemistry. Cell migration and invasion were assessed by wound healing and Transwell Matrigel invasion assays, respectively. The regulatory relationship between CCR9 and the Wnt/β-catenin signaling pathway was further evaluated by rescue experiments.

Results

The expression of CCR9 was elevated in OS cell lines and patients with lung metastasis. CCR9 promoted MG63 and HOS cell migration and invasion by activating the Wnt/β-catenin signaling pathway. Furthermore, knockdown of CCR9 repressed epithelial–mesenchymal transition (EMT) by downregulating mesenchymal markers (N-cadherin and Vimentin) and EMT-associated transcription factors (twist and snail) and upregulating an epithelial marker (E-cadherin).

Conclusions

Our findings suggest that CCR9 promotes EMT by activating Wnt/β-catenin pathways to promote OS metastasis. CCR9 may be a promising therapeutic target to inhibit lung metastasis and serve as a novel prognostic marker for OS.
The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis
Authors: Quintas-Granados Laura Itzel , Cortés Hernán , Carmen Manuel González-Del , Leyva-Gómez Gerardo , Bustamante-Montes Lilia Patricia , Rodríguez-Morales Miguel , Villegas-Vazquez Edgar Yebran , López-Reyes Israel , Alcaraz-Estrada Sofía Lizeth , Sandoval-Basilio Jorge , Soto-Reyes Ernesto , Sharifi-Rad Javad , Figueroa-González Gabriela , Reyes-Hernández Octavio Daniel
Published: December 2021

Background

The ESR1 gene suffers methylation changes in many types of cancers, including breast cancer (BC), the most frequently diagnosed cancer in women that is also present in men. Methylation at promoter A of ESR1 is the worse prognosis in terms of overall survival; thus, the early detection, prognostic, and prediction of therapy involve some methylation biomarkers.

Methods

Therefore, our study aimed to examine the methylation levels at the ESR1 gene in samples from Mexican BC patients and its possible association with menopausal status.

Results

We identified a novel 151-bp CpG island in the promoter A of the ESR1 gene. Interestingly, methylation levels at this CpG island in positive ERα tumors were approximately 50% less than negative ERα or control samples. Furthermore, methylation levels at ESR1 were associated with menopausal status. In postmenopausal patients, the methylation levels were 1.5-fold higher than in premenopausal patients. Finally, according to tumor malignancy, triple-negative cancer subtypes had higher ESR1 methylation levels than luminal/HER2+ or luminal A subtypes.

Conclusions

Our findings suggest that methylation at this novel CpG island might be a promising prognosis marker
Determinants of malaria testing at health facilities: the case of Uganda
Authors: Kigozi Ruth N. , Bwanika JohnBaptist , Goodwin Emily , Thomas Peter , Bukoma Patrick , Nabyonga Persis , Isabirye Fred , Oboth Paul , Kyozira Carol , Niang Mame , Belay Kassahun , Sebikaari Gloria , Tibenderana James K. , Gudoi Sam Siduda
Published: December 2021

Background

The World Health Organization (WHO) recommends prompt malaria diagnosis with either microscopy or malaria rapid diagnostic tests (RDTs) and treatment with an effective anti-malarial, as key interventions to control malaria. However, in sub-Saharan Africa, malaria diagnosis is still often influenced by clinical symptoms, with patients and care providers often interpreting all fevers as malaria. The Ministry of Health in Uganda defines suspected malaria cases as those with a fever. A target of conducting testing for at least 75% of those suspected to have malaria was established by the National Malaria Reduction Strategic Plan 2014–2020.

Methods

This study investigated factors that affect malaria testing at health facilities in Uganda using data collected in March/April 2017 in a cross-sectional survey of health facilities from the 52 districts that are supported by the US President’s Malaria Initiative (PMI). The study assessed health facility capacity to provide quality malaria care and treatment. Data were collected from all 1085 public and private health facilities in the 52 districts. Factors assessed included supportive supervision, availability of malaria management guidelines, laboratory infrastructure, and training health workers in the use of malaria rapid diagnostic test (RDT). Survey data were matched with routinely collected health facility malaria data obtained from the district health information system Version-2 (DHIS2). Associations between testing at least 75% of suspect malaria cases with several factors were examined using multivariate logistic regression.

Results

Key malaria commodities were widely available; 92% and 85% of the health facilities reported availability of RDTs and artemether–lumefantrine, respectively. Overall, 933 (86%) of the facilities tested over 75% of patients suspected to have malaria. Predictors of meeting the testing target were: supervision in the last 6 months (OR: 1.72, 95% CI 1.04–2.85) and a health facility having at least one health worker trained in the use of RDTs (OR: 1.62, 95% CI 1.04–2.55).

Conclusion

The study findings underscore the need for malaria control programmes to provide regular supportive supervision to health facilities and train health workers in the use of RDTs.
Engineered CRISPR-Cas systems for the detection and control of antibiotic-resistant infections
Authors: Wu Yuye , Battalapalli Dheerendranath , Hakeem Mohammed J. , Selamneni Venkatarao , Zhang Pengfei , Draz Mohamed S. , Ruan Zhi
Published: December 2021

Antibiotic resistance is spreading rapidly around the world and seriously impeding efforts to control microbial infections. Although nucleic acid testing is widely deployed for the detection of antibiotic resistant bacteria, the current techniques—mainly based on polymerase chain reaction (PCR)—are time-consuming and laborious. There is an urgent need to develop new strategies to control bacterial infections and the spread of antimicrobial resistance (AMR). The CRISPR-Cas system is an adaptive immune system found in many prokaryotes that presents attractive opportunities to target and edit nucleic acids with high precision and reliability. Engineered CRISPR-Cas systems are reported to effectively kill bacteria or even revert bacterial resistance to antibiotics (resensitizing bacterial cells to antibiotics). Strategies for combating antimicrobial resistance using CRISPR (i.e., Cas9, Cas12, Cas13, and Cas14) can be of great significance in detecting bacteria and their resistance to antibiotics. This review discusses the structures, mechanisms, and detection methods of CRISPR-Cas systems and how these systems can be engineered for the rapid and reliable detection of bacteria using various approaches, with a particular focus on nanoparticles. In addition, we summarize the most recent advances in applying the CRISPR-Cas system for virulence modulation of bacterial infections and combating antimicrobial resistance.

Graphical Abstract
Ultrasound triggered topical delivery of Bmp7 mRNA for white fat browning induction via engineered smart exosomes
Authors: Guo Yitong , Wan Zhuo , Zhao Ping , Wei Mengying , Liu Yunnan , Bu Te , Sun Wenqi , Li Zhelong , Yuan Lijun
Published: December 2021

Background

Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location.

Results

The swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 (Ucp1).

Conclusions

The proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy.

Graphical Abstract
The health impact of smokeless tobacco products: a systematic review
Authors: Hajat C. , Stein E. , Ramstrom L. , Shantikumar S. , Polosa R.
Published: December 2021

Introduction

The objective was to systematically review studies on health outcomes from smokeless tobacco (SLT) products.

Methods

We analysed published literature on the health outcomes from SLT use between 01/01/2015 to 01/02/2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol using PubMed, Embase, Scopus, and Google Scholar.

Results

Of 53 studies included, six were global, 32 from Asia, Middle East and Africa (AMEA), nine from USA and six from Europe. ‘Poor’-rated studies predominated (23;43%), in particular, for global (4;66%) and AMEA (16;50%). Health outcomes differed between SLT-products and regions; those in AMEA were associated with higher mortality (overall, cancer, Coronary heart disease (CHD), respiratory but not cardiovascular disease (CVD)), and morbidity (CVD, oral and head and neck cancers), with odds ratios up to 38.7. European studies showed no excess mortality (overall, CVD, from cancers) or morbidity (ischemic heart disease (IHD), stroke, oral, head and neck, pancreatic or colon cancers) from several meta-analyses; single studies reported elevated risk of rectal cancer and respiratory disorders. Pooled study data showed protection against developing Parkinson’s disease. US studies showed mixed results for mortality (raised overall, CHD, cancer and smoking-related cancer mortality; no excess risk of respiratory or CVD mortality). Morbidity outcomes were also mixed, with some evidence of increased IHD, stroke and cancer risk (oral, head and neck). No studies reported on switching from cigarettes to SLT-products.

Conclusion

Our review demonstrates stark differences between different SLT-products in different regions, ranging from zero harm from European snus to greatly increased health risks in AMEA. The literature on the safety profile for SLT-products for harm reduction is incomplete and potentially misinforming policy and regulation.
Investigating the impact of COVID-19 on performance and image enhancing drug use
Authors: Dunn Matthew , Piatkowski Timothy
Published: December 2021

Background

Emerging research has suggested that the COVID-19 pandemic has had some impact on substance use patterns. The aim of the study was to conduct a rapid survey to assess the impact of COVID-19 on performance and image enhancing drug (PIED) use and training, and any subsequent negative physical or mental health outcomes.

Methods

During 2020, a convenience sample of 60 PIED consumers (mean age = 26.69; 68.3% located outside Australia) completed a quantitative anonymous online survey exploring how the coronavirus pandemic impacted patterns of PIED use and associated exercise habits. The survey was administered via the Qualtrics platform and distributed online through PIED forums as well as through the investigators’ networks. Participants were asked about their PIED use and exercise habits prior to and during restricted movement ‘lockdowns’.

Results

During pre-COVID, the majority of the sample opted to ‘blast-cruise’ (an initial high dose, followed by a lower maintenance dose; 71.7%, n = 43). During lockdown, 45% (n = 27) reported a change in PIED use as a result of the restrictions. In light of health concerns during COVID-19, a majority of men (60%, n = 36) did not take any extra precautions relating to their PIED use. A subgroup of men ceased using PIEDs completely (16.7%, n = 10) with the majority (80%, n = 8) of that subgroup following post-cycle therapy (PCT) of some kind. Only a small proportion of the sample reported negative mental health issues as a result of PCT access issues.

Conclusions

This study contributes to the emerging literature of the impact of the COVID-19 pandemic on substance use, specifically PIED use among men. The results suggest that the pandemic did influence the choice of PIEDs that participants consumed, although there was little disruption to patterns of exercise, an important aspect of PIED use. Of the men who did cease use completely, the majority reported little issue with PCT access; those who reported difficulty accessing PCT compounds indicated experience some mental health concerns related to ceasing their PIED use. Clinicians and those who come into contact with this group should be alert for any negative physical or mental health concerns resulting from disrupted or ceased PIED use.
Optimal authoritative risk assessment score of Cancer-associated venous thromboembolism for hospitalized medical patients with lung Cancer
Authors: Xiong Wei , Zhao Yunfeng , Du He , Wang Yanmin , Xu Mei , Guo Xuejun
Published: December 2021

Background

Cancer-associated venous thromboembolism (VTE) is common in patients with primary lung cancer. It has been understudied which authoritative risk assessment score of cancer-associated VTE is optimal for the assessment of VTE development in hospitalized medical patients with lung cancer.

Methods

Patients with lung cancer who had undergone computed tomography pulmonary angiography (CTPA), compression ultrasonography (CUS) of lower and upper extremities, and/or planar ventilation/perfusion (V/Q) scan to confirm the presence or absence of VTE during a medical hospitalization were retrospectively reviewed. Based on the actual prevalence of VTE among all patients, the possibility of VTE were reassessed with the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score, to compare their assessment accuracy for VTE development.

Results

A total of 1263 patients with lung cancer were incorporated into the final analysis. With respect to assessment efficiency for VTE occurrence, the scores with adjusted agreement from highest to lowest were the ONKOTEV score (78.6%), the PROTECHT score (73.4%), the CONKO score (72.1%), the COMPASS-CAT score (71.7%), the Khorana score (70.9%), and the CATS/MICA score (60.3%). The ONKOTEV score had the highest Youden index which was 0.68, followed by the PROTECHT score (0.58), the COMPASS-CAT score (0.56), the CONKO score (0.55), the Khorana score (0.53), and the CATS/MICA score (0.23).

Conclusions

Among the Khorana score, the PROTECHT score, the CONKO score, the ONKOTEV score, the COMPASS-CAT score, and the CATS/MICA score which are approved by authoritative guidelines, the ONKOTEV score is optimal for the assessment of VTE development in hospitalized medical patients with lung cancer.