bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-sectional associations between cardiorespiratory fitness and NMR-derived metabolic biomarkers in children – the PANIC study
Authors: Haapala Eero A. , Leppänen Marja H. , Lehti Maarit , Lintu Niina , Tompuri Tuomo , Viitasalo Anna , Schwab Ursula , Lakka Timo A.
Published: September 2022

Objective

Cardiorespiratory fitness has been inversely associated with cardiovascular risk across the lifespan. Some studies in adults suggest that higher cardiorespiratory fitness is associated with cardioprotective metabolite profile, but the evidence in children is lacking. Therefore, we investigated the cross-sectional association of cardiorespiratory fitness with serum nuclear magnetic resonance derived metabolic biomarkers in children.

Methods

A population sample of 450 children aged 6–8 years was examined. Cardiorespiratory fitness was assessed by a maximal exercise test on a cycle ergometer and quantified as maximal power output normalised for lean body mass assessed by dual-energy X-ray absorbtiometry. Serum metabolites were assessed using a high throughput nuclear magnetic resonance platform. The data were analysed using linear regression analyses adjusted for age and sex and subsequently for body fat percentage (BF%) assessed by DXA.

Results

Cardiorespiratory fitness was directly associated with high density lipoprotein (HDL) cholesterol (β=0.138, 95% CI=0.042 to 0.135, p=0.005), average HDL particle diameter (β=0.102, 95% CI=0.004 to 0.199, p=0.041), and the concentrations of extra-large HDL particles (β=0.103, 95% CI=0.006 to 0.201, p=0.038), large HDL particles (β=0.122, 95% CI=0.025 to 0.220, p=0.014), and medium HDL particles (β=0.143, 95% CI=0.047 to 0.239, p=0.004) after adjustment for age and sex. Higher cardiorespiratory fitness was also associated with higher concentrations of ApoA1 (β=0.145, 95% CI=0.047 to 0.242, p=0.003), glutamine (β=0.161, 95% CI=0.064 to 0.257, p=0.001), and phenylalanine (β=0.187, 95% CI=0.091 to 0.283, p<0.001). However, only the direct associations of cardiorespiratory fitness with the concentrations of HDL cholesterol (β=0.114, 95% CI=0.018 to 0.210, p=0.021), medium HDL particles (β=0.126, 95% CI=0.030 to 0.223, p=0.010), ApoA1 (β=0.126, 95% CI=0.030 to 0.223, p=0.011), glutamine (β=0.147, 95% CI=0.050 to 0.224, p=0.003), and phenylalanine (β=0.217, 95% CI=0.122 to 0.311, p<0.001) remained statistically significant after further adjustment for BF%.

Conclusions

Higher cardiorespiratory fitness was associated with a cardioprotective biomarker profile in children. Most associations were independent of BF% suggesting that the differences in serum metabolites between children are driven by cardiorespiratory fitness and not adiposity.
A functional polymorphism of microRNA-143 is associated with the risk of type 2 diabetes mellitus in the northern Chinese Han population
Authors: Kong Dexian , Duan Ya , Wang Jinli , Liu Yabin
Published: September 2022

Objective

To explore the association between two polymorphisms of microRNA-143 (miR-143) and the risk of type 2 diabetes mellitus (T2DM) in the northern Chinese Han population.

Study Design

This case–control study involved 326 patients with T2DM and 342 healthy controls. Two genetic variants (rs4705342 and rs353292) of miR-143 were genotyped by the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. The levels of miR-143 in the serum from 52 T2DM patients and 55 healthy subjects were investigated by quantitative real-time PCR (qRT–PCR).

Results

The CC genotype frequency of rs4705342 was significantly higher in the T2DM patients than in the healthy controls (P = 0.012). After adjusting for sex, age, and body mass index, the rs4705342 CC genotype was also related to a significantly increased risk of T2DM compared with the TT genotype (adjusted OR: 1.87; 95% CI = 1.09-3.19; P = 0.022). Stratified analyses demonstrated that T2DM patients with the rs4705342 CC genotype had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and glycated haemoglobin (HbA1C) than those carrying the rs4705342 TT genotype. The qRT–PCR results showed that the expression levels of miR-143 were significantly higher in the serum of cases than in the serum of controls (P < 0.001). Furthermore, the levels of miR-143 were significantly higher in the serum of T2DM patients carrying the rs4705342 CC genotype than in those carrying the TC and TT genotypes of rs4705342 (P = 0.005 and 0.003, respectively).

Conclusion

The CC genotype of rs4705342 might be a risk factor for developing T2DM by increasing the expression of miRNA-143 in the northern Chinese Han population.
Fluoxetine treatment supports predictive validity of the three hit model of depression in male PACAP heterozygous mice and underpins the impact of early life adversity on therapeutic efficacy
Authors: Gaszner Tamás , Farkas József , Kun Dániel , Ujvári Balázs , Berta Gergely , Csernus Valér , Füredi Nóra , Kovács László Ákos , Hashimoto Hitoshi , Reglődi Dóra , Kormos Viktória , Gaszner Balázs
Published: September 2022

According to the three hit concept of depression, interaction of genetic predisposition altered epigenetic programming and environmental stress factors contribute to the disease. Earlier we demonstrated the construct and face validity of our three hit concept-based mouse model. In the present work, we aimed to examine the predictive validity of our model, the third willnerian criterion. Fluoxetine treatment was applied in chronic variable mild stress (CVMS)-exposed (environmental hit) CD1 mice carrying one mutated allele of pituitary adenylate cyclase-activating polypeptide gene (genetic hit) that were previously exposed to maternal deprivation (epigenetic hit) vs. controls. Fluoxetine reduced the anxiety level in CVMS-exposed mice in marble burying test, and decreased the depression level in tail suspension test if mice were not deprived maternally. History of maternal deprivation caused fundamental functional-morphological changes in response to CVMS and fluoxetine treatment in the corticotropin-releasing hormone-producing cells of the bed nucleus of the stria terminalis and central amygdala, in tyrosine-hydroxylase content of ventral tegmental area, in urocortin 1-expressing cells of the centrally projecting Edinger-Westphal nucleus, and serotonergic cells of the dorsal raphe nucleus. The epigenetic background of alterations was approved by altered acetylation of histone H3. Our findings further support the validity of both the three hit concept and that of our animal model. Reversal of behavioral and functional-morphological anomalies by fluoxetine treatment supports the predictive validity of the model. This study highlights that early life stress does not only interact with the genetic and environmental factors, but has strong influence also on therapeutic efficacy.
Investigating hydrate formation and flow properties in water-oil flow systems in the presence of wax
Authors: Liu Yang , Meng Jiawei , Lv Xiaofang , Ma Qianli , Shi Bohui , Wang Chuanshuo , Huang Huirong , Wu Chengxuan , Zhou Shidong , Song Shangfei
Published: September 2022

The coexistence of wax and hydrates will pose intractable challenges to the safety of offshore oil and gas production and transportation, especially for deep sea or ultra-deep sea reservoirs. Understanding the effect of wax crystals on hydrate formation, flow properties, and plugging risks of flow systems is imperative to the flow assurance industry. Experiments using systems composed of natural gas, water-in-oil emulsion with different wax contents, and AA (anti-agglomerant) were conducted in a high-pressure flow loop. For wax-containing systems, wax precipitates out during the induction period of hydrate formation. The induction time of hydrate formation decreased with the increasing wax content under the experimental conditions in this work. It was also found that the induction time for both wax-free and wax-containing systems increased with the increasing flow rate. The hydrate growth rate and the cumulative gas consumption were significantly reduced due to the existence of wax. Although the hydrate volume fraction of wax-containing systems was much smaller than that of wax-free systems, a stable slurry flow state could not be reached for wax-containing systems, the pressure drop of which gradually increased with the decreasing flow rates. The coexistence of wax and hydrates results in the deterioration of transportability and higher plugging risks. Based on the Darcy–Weisbach hydraulic formula, a dimensionless parameter was defined to characterize the plugging risk of flow systems with the coexistence of wax and hydrates. Additionally, regions with different levels of plugging risks could be evaluated and divided.
Effective Air Purification via Pt-Decorated N3-CNT Adsorbent
Authors: Yang Yinli , Liu Sitong , Guo Kai , Chen Liang , Xu Jing , Liu Wei
Published: September 2022

Effectively removal of air pollutants using adsorbents is one of the most important methods to purify the air. In this work, we proposed for the first time that PtN3-CNT is an effective adsorbent for air purification. Its air purification performance was studied by calculating the adsorption behaviors and electronic structures of 12 gas molecules, including the main components of air (N2, O2, H2O, CO2) and the most common air pollutants (NO, NO2, SO3, SO2, CO, O3, NH3, H2S), on the surface of PtN3-CNT using first-principles calculations. The results showed that these gases were adsorbed stably via the coordination between Pt and the coordinated atoms (C, N, O, and S atoms) in the gas molecules, and the adsorption energies vary in the range of −0.81∼−4.28 eV. The obvious chemical interactions between PtN3-CNT and the adsorbed gas molecules are mainly determined by the apparent overlaps between the Pt 5d orbitals and the outmost p orbitals of the coordination atoms. PtN3-CNT has strong adsorption capacity for the toxic gas molecules, while relatively weaker adsorption performance for the main components of the air except oxygen. The recovery time of each adsorbed molecule calculated at different temperatures showed that, CO2, H2O, and N2 can be desorbed gradually at 298∼498 K, while the toxic gases are always adsorbed stably on the surface of PtN3-CNT. Considering the excellent thermal stability of PtN3-CNT at up to 1000 K proved by AIMD, PtN3-CNT is very suitable to act as an adsorbent to remove toxic gases to achieve the purpose of air purification. Our findings in this report would be beneficial for exploiting possible carbon-based air purification adsorbents with excellent adsorbing ability and good recovery performance.
Breaking the reproductive barrier of divergent species to explore the genomic landscape
Authors: Gilles A. , Thevenin Y. , Dione F. , Martin J.-F. , Barascud B. , Chappaz R. , Pech N.
Published: September 2022

Background: Climate change will have significant consequences for species. Species range shifts induce the emergence of new hybrid zones or the spatial displacement of pre-existing ones. These hybrid zones may become more porous as alleles are passed from one species to another. Currently, hybridization between highly divergent species living in sympatry seems extremely limited. Indeed, this phenomenon involves breaking two barriers. The first is the pre-mating barrier, related to the reproductive phenology of the two species. The second is the post-zygotic barrier, related to the genetic divergence between these species. Here, we were interested in identifying new hybridization patterns and potential implications, especially in the context of environmental modifications.

Methods: We sampled Telestes souffia and Parachondrostoma toxostoma wild specimens from different locations across France and genotyped them for SNP markers. We identified discriminant loci using F1-hybrid specimens and parental species and performed principal component analysis and Bayesian model-based clustering to analyze phylogenetic information. Furthermore, we assessed deviation in allele frequency from F1 to F2 and for Hardy–Weinberg equilibrium for F2 and assessed gene function associated with two F2 cohorts.

Results: We demonstrate that by breaking the ecological barrier, massive introgressive hybridization is possible between two endemic lineages of Cyprinidae belonging to two distinct genera. For both cohorts studied (=2 cm and >2 cm), a large majority of loci (>88%) presented no deviation in allele frequency and no departure from the Hardy–Weinberg equilibrium. For individuals beyond the 2 cm stage, two phenomena were observed. The first was an allelic imbalance in favor of P. toxostoma, for some genomic regions, with genes involved in developmental regulatory processes, cytoskeletal organization, and chromosome organization. The second was an excess of heterozygous loci coupled with an equilibrium of allelic frequencies for genes involved in immune response and kidney/liver development. Moreover, the 2 cm-sized specimens with high mortality yielded a particular genomic signature.

Conclusion: Our study displayed important results for understanding the early stages of hybridization between divergent lineages and predicting the emergence of future hybrid zones in the wild. Moreover, this hybridization generates a wide spectrum of hybrids that are a potential source of important evolutionary novelties.
A novel mutation in RS1 and clinical manifestations in a Chinese twin family with congenital retinoschisis
Authors: Wang Xiao-Fang , Chen Fei-Fei , Zhou Xin , Cheng Xin-Xuan , Xie Zheng-Gao
Published: September 2022

Purpose: We aim to analyze the clinical and genetic features in a Chinese family with congenital retinoschisis by whole-exome sequencing and comprehensive clinical examination.

Methods: Six members were recruited from a Chinese family. Three of them were diagnosed as congenital retinoschisis, including two twin siblings. All subjects received a full eye examination. Whole-exome sequencing (WES) and Sanger sequencing were performed on two twin probands and all participants, respectively.

Results: A novel splice site mutation RS1.c.53-1G>A was identified in a Chinese congenital retinoschisis family. The mean onset age was 16.7 ± 2.4 years old. The average BCVA in patients was 0.37 ± 0.05. A typical spoke-wheel pattern was observed in all affected eyes. OCT examination results showed fovea schisis and schisis cavities were located in the inner nuclear layer in 100% eyes (6/6). ERG b/a ratio was decreased markedly, but was still more than 1 in the four eyes that were available.

Conclusion: The present study discovered a new pathogenic splice cite variant of RS1 in congenital retinoschisis, which expands the mutational spectrum. In contrast to previous research, the phenotype of patients with the same mutation within one family was highly similar. Early molecular testing is crucial for early diagnosis, clinical management, and genetic counseling of patients with congenital retinoschisis.
An EMT-based risk score thoroughly predicts the clinical prognosis, tumor immune microenvironment and molecular subtypes of bladder cancer
Authors: Xiao Zicheng , Cai Zhiyong , Deng Dingshan , Tong Shiyu , Zu Xiongbing
Published: September 2022

Background

Epithelial mesenchymal transition (EMT) is closely related to the occurrence, development, metastasis and antitumor immunity of tumors. However, comprehensive studies correlating EMT and prognosis, tumor microenvironment (TME) and molecular subtypes of bladder cancer (BLCA) are lacking.

Methods

TCGA-BLCA was chosen as our training cohort, while Xiangya cohort, GSE13507, GSE48075 were selected as our validation cohorts. Prognostic genes were screened out using univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. Then we developed an EMT risk score based on these prognostic genes and systematically correlated the risk score with prognosis, TME and molecular subtypes of BLCA.

Results

Based on EMT related genes, we developed two different EMT patterns, named EMT cluster 1 and cluster 2, and found that cluster 2 showed a worse prognosis and an inflammatory TME phenotype. For personalized prognosis and TME phenotypes predicting, we developed and validated an EMT-based risk score by 7 candidate genes (ANXA10, CNTN1, FAM180A, FN1, IGFL2, KANK4 and TOX3). Patients with high EMT risk scores had lower overall survival (OS) with high predictive accuracy both in the training cohort and validation cohort. In addition, we comprehensively correlated the EMT risk score with TME and molecular subtype, and found that high EMT risk score suggested higher levels of immune cell infiltration and more inclined to present the basal molecular subtype. It was noteworthy that the same results also appeared in the validation of Xiangya cohort.

Conclusions

EMT related genes play an important role in tumor progression and immunity in BLCA. Our EMT risk score could accurately predict prognosis and immunophenotype of a single patient, which could guide more effective precision medical strategies.
Lymphomas in cartilage-hair hypoplasia – A case series of 16 patients reveals advanced stage DLBCL as the most common form
Authors: Kukkola Hanna-Leena , Utriainen Pauliina , Huttunen Pasi , Taskinen Mervi , Mäkitie Outi , Vakkilainen Svetlana
Published: September 2022

Background

Patients with cartilage-hair hypoplasia (CHH) have an increased risk of malignancy, particularly non-Hodgkin lymphoma and basal cell carcinoma. The characteristics, clinical course, response to therapy and outcome of lymphomas in CHH remains unexplored.

Methods

We assessed clinical features of lymphoma cases among Finnish patients with CHH. Data were collected from the Finnish Cancer Registry, hospital records, the National Medical Databases and Cause-of-Death Registry of Statistics Finland.

Results

Among the 160 CHH patients, 16 (6 men, 10 women) were diagnosed with lymphoma during 1953-2016. Lymphoma was diagnosed in young adulthood (median age 26.4 years, range from 6.4 to 69.5 years), mostly in advanced stage. The most common lymphoma type was diffuse large cell B-cell lymphoma (DLBCL) (6/16, 38%). Eight patients received chemotherapy (8/16, 50%), and two of them survived. Standard lymphoma chemotherapy regimens were administered in the majority of cases. Altogether, eleven CHH patients died due to lymphomas (11/16, 69%). In almost all surviving lymphoma patients, the diagnosis was made either during routine follow-up or after evaluation for non-specific mild symptoms. Search for CHH-related clinical predictors demonstrated higher prevalence of recurrent respiratory infections, in particular otitis media, and Hirschsprung disease in patients with lymphoma. However, three patients had no clinical signs of immunodeficiency prior to lymphoma diagnosis.

Conclusion

DLBCL is the most common type of lymphoma in CHH. The outcome is poor probably due to advanced stage of lymphoma at the time of diagnosis. Other CHH-related manifestations poorly predicted lymphoma development, implying that all CHH patients should be regularly screened for malignancy.
Immunogenicity and safety of the booster BNT162b2 vaccine in patients with axial spondyloarthritis treated with biological disease-modifying drugs
Authors: Smetanova Jitka , Milota Tomas , Rataj Michal , Hurnakova Jana , Zelena Hana , Sediva Anna , Horvath Rudolf
Published: September 2022

Background

Vaccination confers relatively short-term protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicating the need for booster doses. Immunocompromised individuals, including those with immune-mediated inflammatory diseases (IMIDs), may have pronounced immune response waning. Vaccine-boosted humoral and T-cell responses minimize poor coronavirus disease 19 (COVID-19) outcome without increasing adverse events (AE). There is limited evidence of third-dose vaccination in axial spondyloarthritis (AxSpA) patients. We investigated immune-response persistence after primary vaccination and immunogenicity and safety after the BNT162b2 booster vaccination.

Methods

This prospective observational study enrolled an AxSpA cohort treated with interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNFα) inhibitors. Serum SARS-CoV-2-specific and virus-neutralizing antibodies for humoral response and flow cytometric detection of intracellular cytokines following SARS-CoV-2-specific peptide-based stimulation for T-cell immune responses were assessed, and safety was evaluated via a clinical questionnaire.

Results

Fifteen male AxSpA patients treated with TNFα (73·3%) or IL-17 (26·7%) inhibitors were enrolled and had humoral response persistence at 6 months: 905·6 ( ± 186·1 SD) and 409·1 ( ± 335·7) U/mL. Specific antibody concentrations further increased after booster vaccination to 989·7 ( ± 12·62) and 1000 U/mL and T-cell responders from 53·3% to 80%, with no differences between AxSpA (including “vaccination only” and “hybrid immunity” subgroups) and healthy control (HC) cohorts. No severe AE occurred; the AE spectrum was comparable to that of the general population.

Conclusion

Immune-response persistence after primary vaccination and immunogenicity after booster vaccination were unaffected by anti-IL17 or anti-TNFα therapy with similar AE as in the general population.
Causes of death and conditional survival estimates of long-term lung cancer survivors
Authors: Zhang Qun , Dai Yuan , Liu Hongda , Sun Wenkui , Huang Yuming , Gong Zheng , Dai Shanlin , Kong Hui , Xie Weiping
Published: September 2022

Introduction

Lung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer.

Methods

We collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients’ survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy era, n=42061).

Results

Of the 612,100 patients, 285,705 were women, the mean (SD) age was 68.3 (11.0) years old. 252,558 patients were characterized as lung adenocarcinoma, 133,302 cases were lung squamous cell carcinoma, and only 78,700 cases were small cell lung carcinomas. TNM stage was I in 140,518 cases, II in 38,225 cases, III in 159,095 cases, and IV in 274,262 patients. 164,394 cases underwent surgical intervention. The 5-y overall survival and cancer-specific survival were 54.2% and 73.8%, respectively. The 5-y conditional survival rate of cancer-specific survival is improved in a time-dependent pattern, while conditional overall survival tends to be steady after 5-y follow-up. Except from age, hazard disparities of other risk factors (such as stage and surgery) diminished over time according to the conditional survival curves. After 8 years since diagnosis, mortality hazard from other causes became higher than that from lung cancer. This critical time point was earlier in elder patients while was postponed in patients with advanced stages. Moreover, both cancer-specific survival and overall survival of metastatic patients in immunotherapy era were significantly better than those in non-immunotherapy era (P<0.001), indicating that immunotherapeutic intervention indeed bring remarkable benefits to advanced lung cancer patients.

Conclusions

Our findings expand on previous studies by demonstrating that non-lung-cancer related death risk becomes more and more predominant over the course of follow-up, and we establish a personalized web-based calculator to determine this critical time point for long-term survivors. We also confirmed the survival benefit of advanced lung cancer patients in immunotherapy era.
Basiliximab for the therapy of acute T cell–mediated rejection in kidney transplant recipient with BK virus infection: A case report
Authors: Chen Tingting , Li Xiaoyu , Wang Jina , Wang Xuanchuan , Zhu Tongyu , Rong Ruiming , Yang Cheng
Published: September 2022

A 66-year-old Chinese man underwent a deceased donor kidney transplantation. Induction-immunosuppressive protocol consisted of basiliximab (BAS) and methyl prednisolone (MP), followed by maintenance immunosuppression with cyclosporin (CsA), mycophenolate mofetil (MMF), and prednisone (PED). The patient’s post-transplantation course was almost uneventful, and the graft was functioning well [serum creatinine (Scr) 2.15 mg/dL]. The MMF and CsA doses were decreased 1-month post-operative as the BK virus activation was serologically positive. His Scr was elevated to 2.45 mg/dL 45 days after the transplant. A graft biopsy showed BKV nephropathy (BKVN) and acute T cell–mediated rejection (TCMR) Banff grade IIA (I2, t2, ptc2, v1, c4d1, g0, and SV40 positive). The conventional anti-rejection therapy could deteriorate his BKVN, therefore, we administered BAS to eliminate activated graft-infiltrating T cells and combined with low-dose steroid. He responded well to the therapy after two doses of BAS were given, and the kidney graft status has been stable (recent Scr 2.1 mg/dL).
Effect of stereotactic radiotherapy on immune microenvironment of lung cancer
Authors: Xiao Yao , Zhuang Hongqing
Published: September 2022

Stereotactic radiotherapy (SRT) is one of the main treatment modalities for lung cancer, and the current SRT approach combined with immunotherapy has initially presented good clinical efficacy in lung cancer. SRT activates the immune system through in situ immunization, releasing antigens into the blood, which promotes the antigen–antibody response and then induces tumor cell apoptosis. Dose fractionation has different effects on the immune microenvironment, and the tumor microenvironment after SRT also changes over time, all of which have an impact on SRT combined immunotherapy. Although much research on the immune microenvironment of SRT has been conducted, many problems still require further exploration.
Neutrophil Extracellular Traps (NETs) Promote Non-Small Cell Lung Cancer Metastasis by Suppressing lncRNA MIR503HG to Activate the NF-κB/NLRP3 Inflammasome Pathway
Authors: Wang Yong , Liu Fen , Chen Lin , Fang Chen , Li Shuangyan , Yuan Shangkun , Qian Xiaoying , Yin Yan , Yu Biao , Fu Biqi , Zhang Xinwei , Li Yong
Published: September 2022

Neutrophil extracellular traps (NETs) that are produced in the tumour microenvironment (TME) have been suggested to play an essential role in the dissemination of metastatic cancer under multiple infectious and inflammatory conditions. However, the functions of NETs in promoting non-small cell lung cancer (NSCLC) metastasis and the underlying mechanisms remain incompletely understood. Here, we found that NETs promoted NSCLC cell invasion and migration by inducing epithelial to mesenchymal transition (EMT). To explore how NETs contribute to NSCLC metastasis, microarrays were performed to identify substantial numbers of long noncoding RNAs (lncRNAs) and mRNAs that were differentially expressed in NSCLC cells after stimulation with NETs. Interestingly, we observed that the expression of lncRNA MIR503HG was downregulated after NETs stimulation, and ectopic MIR503HG expression reversed the metastasis-promoting effect of NETs in vitro and in vivo. Notably, bioinformatics analysis revealed that differentially expressed genes were involved in the NOD-like receptor and NF-κB signalling pathways that are associated with inflammation. NETs facilitated EMT and thereby contributed to NSCLC metastasis by activating the NF-κB/NOD-like receptor protein 3 (NLRP3) signalling pathway. Further studies revealed that MIR503HG inhibited NETs-triggered NSCLC cell metastasis in an NF-κB/NLRP3-dependent manner, as overexpression of NF-κB or NLRP3 impaired the suppressive effect of MIR503HG on NETs-induced cancer cell metastasis. Together, these results show that NETs activate the NF-κB/NLRP3 pathway by downregulating MIR503HG expression to promote EMT and NSCLC metastasis. Targeting the formation of NETs may be a novel therapeutic strategy for treating NSCLC metastasis.
The integration of single-cell sequencing, TCGA, and GEO data analysis revealed that PRRT3-AS1 is a biomarker and therapeutic target of SKCM
Authors: Zhang Wancong , Xie Xuqi , Huang Zijian , Zhong Xiaoping , Liu Yang , Cheong Kit-Leong , Zhou Jianda , Tang Shijie
Published: September 2022

Introduction

Skin cutaneous melanoma (SKCM) is the world’s fourth deadliest cancer, and advanced SKCM leads to a poor prognosis. Novel biomarkers for SKCM diagnosis and prognosis are urgently needed. Long non-coding RNAs (lncRNAs) provide various biological functions and have been proved to play a significant role in tumor progression. Single-cell RNA sequencing (scRNA-seq) enables genome analysis at the single-cell level. This study explored prognostic lncRNAs in SKCM based on scRNA-seq and bulk RNA sequencing data.

Materials and methods

The TCGA cohort and melanoma samples in the GEO database (GSE72056, GSE19234, GSE15605, GSE7553, and GSE81383) were included in this study. Marker genes were filtered, and ensemble lncRNAs were annotated. The clinical significance of selected lncRNAs was verified through TCGA and GEO dataset analysis. SiRNA transfection, wound−healing and transwell assays were performed to evaluate the effect of PRRT3-AS1 on cellular function. Immune infiltration of the selected lncRNAs was also exhibited.

Results

A 5-marker-lncRNAs model of significant prognostic value was constructed based on GSE72056 and the TCGA cohort. PRRT3-AS1 combined with DANCR was then found to provide significant prognostic value in SKCM. PRRT3-AS1 was filtered for its higher expression in more advanced melanoma and significant prognosis value. Cellular function experiments in vitro revealed that PRRT3-AS1 may be required for cancer cell migration in SKCM. PRRT3-AS1 was found to be related to epithelial-mesenchymal transition (EMT) signaling pathways. DNA methylation of PRRT3-AS1 was negatively related to PRRT3-AS1 expression and showed significant prognosis value. In addition, PRRT3-AS1 may suppress immune infiltration and be involved in immunotherapy resistance.

Conclusion

PRRT3-AS1 may be a diagnostic and prognostic biomarker of SKCM.
Cytokines and chemokines: The vital role they play in herpes simplex virus mucosal immunology
Authors: Smith Jacinta B. , Herbert Jason J. , Truong Naomi R. , Cunningham Anthony L.
Published: September 2022

Herpes simplex viruses (HSV) types 1 and 2 are ubiquitous infections in humans. They cause orofacial and genital herpes with occasional severe complications. HSV2 also predisposes individuals to infection with HIV. There is currently no vaccine or immunotherapy for these diseases. Understanding the immunopathogenesis of HSV infections is essential to progress towards these goals. Both HSV viruses result in initial infections in two major sites - in the skin or mucosa, either after initial infection or recurrence, and in the dorsal root or trigeminal ganglia where the viruses establish latency. HSV1 can also cause recurrent infection in the eye. At all of these sites immune cells respond to control infection. T cells and resident dendritic cells (DCs) in the skin/mucosa and around reactivating neurones in the ganglia, as well as keratinocytes in the skin and mucosa, are major sources of cytokines and chemokines. Cytokines such as the Type I and II interferons synergise in their local antiviral effects. Chemokines such as CCL2, 3 and 4 are found in lesion vesicle fluid, but their exact role in determining the interactions between epidermal and dermal DCs and with resident memory and infiltrating CD4 and CD8 T cells in the skin/mucosa is unclear. Even less is known about these mechanisms in the ganglia. Here we review the data on known sources and actions of these cytokines and chemokines at cellular and tissue level and indicate their potential for preventative and therapeutic interventions.
COVID-19 in unvaccinated patients with inborn errors of immunity—polish experience
Authors: Kołtan Sylwia , Ziętkiewicz Marcin , Grześk Elżbieta , Becht Rafał , Berdej-Szczot Elżbieta , Cienkusz Magdalena , Ewertowska Marlena , Heropolitańska-Pliszka Edyta , Krysiak Natalia , Lewandowicz-Uszyńska Aleksandra , Mach-Tomalska Monika , Matyja-Bednarczyk Aleksandra , Milchert Marcin , Napiórkowska-Baran Katarzyna , Pieniawska-Śmiech Karolina , Pituch-Noworolska Anna , Renke Joanna , Roliński Jacek , Rywczak Iwona , Stelmach-Gołdyś Agnieszka , Strach Magdalena , Suchanek Hanna , Sulicka-Grodzicka Joanna , Szczawińska-Popłonyk Aleksandra , Tokarski Sławomir , Więsik-Szewczyk Ewa , Wolska-Kuśnierz Beata , Zeman Krzysztof , Pac Małgorzata
Published: September 2022

At the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, patients with inborn errors of immunity (IEI) appeared to be particularly vulnerable to a severe course of the disease. It quickly turned out that only some IEI groups are associated with a high risk of severe infection. However, data on the course of Coronavirus Disease 2019 (COVID-19) in patients with IEI are still insufficient, especially in children; hence, further analyses are required. The retrospective study included 155 unvaccinated people with IEI: 105 children and 50 adults (67.7% and 32.3%, respectively). Male patients dominated in the study group (94 people, 60.6%). At least two comorbidities were found in 50 patients (32.3%), significantly more often in adults (56% vs. 21%). Adult patients presented significantly more COVID-19 symptoms. Asymptomatic and mildly symptomatic course of COVID-19 was demonstrated in 74.8% of the entire group, significantly more often in children (88.6% vs. 46%). Moderate and severe courses dominated in adults (54% vs. 11.4%). Systemic antibiotic therapy was used the most frequently, especially in adults (60% vs. 14.3%). COVID-19-specific therapy was used almost exclusively in adults. In the whole group, complications occurred in 14.2% of patients, significantly more often in adults (30% vs. 6.7%). In the pediatric group, there were two cases (1.9%) of multisystem inflammatory syndrome in children. Deaths were reported only in the adult population and accounted for 3.9% of the entire study group. The death rate for all adults was 12%, 15.4% for adults diagnosed with common variable immunodeficiency, 12.5% for those with X-linked agammaglobulinemia, and 21.4% for patients with comorbidity. The results of our study imply that vaccinations against COVID-19 should be recommended both for children and adults with IEI. Postexposure prophylaxis and early antiviral and anti-SARS-CoV-2 antibody-based therapies should be considered in adults with IEI, especially in those with severe humoral immune deficiencies and comorbidity.
Highly different effects of phage therapy and antibiotic therapy on immunological responses of chickens infected with Salmonella enterica serovar Typhimurium
Authors: Grabowski Łukasz , Węgrzyn Grzegorz , Węgrzyn Alicja , Podlacha Magdalena
Published: September 2022

The appearance of bacteria resistant to most or even all known antibiotics has become a serious medical problem. One such promising and effective alternative form of therapy may be the use of phages, the administration of which is considered to be safe and highly effective, especially in animals with drug-resistant infections. Although there have been no reports to date suggesting that bacteriophages can cause any severe complications or adverse effects, we still know little about their interactions with animal organisms, especially in the context of the functioning of the immune system. Therefore, the aim of the present study was to compare the impact of the application of selected bacteriophages and antibiotics (enrofloxacin and colistin), commonly used in veterinary medicine, on immune functions in Salmonella enterica serovar Typhimurium-infected chickens. The birds were infected with S. Typhimurium and then treated with a phage cocktail (14 days), enrofloxacin (5 days), or colistin (5 days). The concentrations of a panel of pro-inflammatory cytokines (IL-1β, IL-6, IFN-γ, IL-8, and IL-12) and cytokines that reveal anti-inflammatory effects (IL-10 and IL-4), the percentage of lymphocytes, and the level of stress hormones (corticosterone and cortisol), which significantly modulate the immune responses, were determined in different variants of the experiment. The phage cocktail revealed anti-inflammatory effects when administered either 1 day after infection or 2 days after S. Typhimurium detection in feces, as measured by inhibition of the increase in levels of inflammatory response markers (IL-1β, IL-6, IFN-γ, IL-8, and IL-12). This was also confirmed by increased levels of cytokines that exert an anti-inflammatory action (IL-10 and IL-4) following phage therapy. Moreover, phages did not cause a negative effect on the number and activity of lymphocytes’ subpopulations crucial for normal immune system function. These results indicate for the first time that phage therapy not only is effective but also can be used in veterinary medicine without disturbing immune homeostasis, expressed as cytokine imbalance, disturbed percentage of key immune cell subpopulations, and stress axis hyperactivity, which were observed in our experiments as adverse effects accompanying the antibiotic therapy.
Prediction model for the pretreatment evaluation of mortality risk in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease
Authors: Gui Xianhua , Li Wangzhong , Yu Yanzhe , Zhao Tingting , Jin Ziyi , Meng Kaifang , Wang Rujia , Shi Shenyun , Yu Min , Ma Miao , Chen Lulu , Luan Wei , Xin Xiaoyan , Qiu Yuying , Qiu Xiaohua , Zhang Yingwei , Cao Min , Cao Mengshu , Dai Jinghong , Cai Hourong , Huang Mei , Xiao Yonglong
Published: September 2022

Background

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early.

Methods

This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model’s performance was assessed in terms of discrimination, calibration, and clinical usefulness.

Results

This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846–0.957), good calibration (Hosmer–Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001).

Conclusions

We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.
Herpes simplex virus type 2 inhibits TNF-α-induced NF-κB activation through viral protein ICP22-mediated interaction with p65
Authors: Hu Huimin , Fu Ming , Li Chuntian , Zhang Binman , Li Yuncheng , Hu Qinxue , Zhang Mudan
Published: September 2022

Herpes simplex virus type 2 (HSV-2) is a prevalent human pathogen and the main cause of genital herpes. After initial infection, HSV-2 can establish lifelong latency within dorsal root ganglia by evading the innate immunity of the host. NF-κB has a crucial role in regulating cell proliferation, inflammation, apoptosis, and immune responses. It is known that inhibition of NF-κB activation by a virus could facilitate it to establish infection in the host. In the current study, we found that HSV-2 inhibited TNF-α-induced activation of NF-κB-responsive promoter in a dose-dependent manner, while UV-inactivated HSV-2 did not have such capability. We further identified the immediate early protein ICP22 of HSV-2 as a vital viral element in inhibiting the activation of NF-κB-responsive promoter. The role of ICP22 was confirmed in human cervical cell line HeLa and primary cervical fibroblasts in the context of HSV-2 infection, showing that ICP22 deficient HSV-2 largely lost the capability in suppressing NF-κB activation. HSV-2 ICP22 was further shown to suppress the activity of TNF receptor-associated factor 2 (TRAF2)-, IκB kinase α (IKK α)-, IKK β-, IKK γ-, or p65-induced activation of NF-κB-responsive promoter. Mechanistically, HSV-2 ICP22 inhibited the phosphorylation and nuclear translocation of p65 by directly interacting with p65, resulting in the blockade of NF-κB activation. Furthermore, ICP22 from several alpha-herpesviruses could also inhibit NF-κB activation, suggesting the significance of ICP22 in herpesvirus immune evasion. Findings in this study highlight the importance of ICP22 in inhibiting NF-κB activation, revealing a novel mechanism by which HSV-2 evades the host antiviral responses.
Construction and validation of nomograms based on the log odds of positive lymph nodes to predict the prognosis of lung neuroendocrine tumors
Authors: Wang Suyu , Wei Juan , Guo Yibin , Xu Qiumeng , Lv Xin , Yu Yue , Liu Meiyun
Published: September 2022

Background

This research aimed to investigate the predictive performance of log odds of positive lymph nodes (LODDS) for the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs).

Methods

We collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The study cohort was split into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed based on the derivation cohort and validated using the external validation cohort to predict the 1-, 3-, and 5-year cancer-specific survival (CSS) and overall survival (OS) of patients with LNETs. The accuracy and clinical practicability of nomograms were tested by Harrell’s concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses.

Results

The Cox proportional-hazards model showed the high LODDS group (-0.79≤LODDS) had significantly higher mortality compared to those in the low LODDS group (LODDS<-0.79) for both CSS and OS. In addition, age at diagnosis, sex, histotype, type of surgery, radiotherapy, and chemotherapy were also chosen as predictors in Cox regression analyses using stepwise Akaike information criterion method and included in the nomograms. The values of C-index, NRI, and IDI proved that the established nomograms were better than the conventional eighth edition of the TNM staging system. The calibration plots for predictions of the 1-, 3-, and 5-year CSS/OS were in excellent agreement. Decision curve analyses showed that the nomograms had value in terms of clinical application.

Conclusions

We created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to bring individually tailored risk assessment and therapy.
Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension
Authors: Didriksen Henriette , Molberg Øyvind , Mehta Adi , Jordan Suzana , Palchevskiy Vyacheslav , Fretheim Håvard , Gude Einar , Ueland Thor , Brunborg Cathrine , Garen Torhild , Midtvedt Øyvind , Andreassen Arne K. , Lund-Johansen Fridtjof , Distler Oliver , Belperio John , Hoffmann-Vold Anna-Maria
Published: September 2022

Introduction

Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21.

Materials and methods

To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS).

Results

By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail.

Conclusion

This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.