bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal Trabecular Bone Score, Lower Bone Mineral Density and Lean Mass in Young Women With Premature Ovarian Insufficiency Are Prevented by Oestrogen Replacement
Authors: Samad Navira , Nguyen Hanh H. , Hashimura Hikaru , Pasco Julie , Kotowicz Mark , Strauss Boyd J. , Ebeling Peter R. , Milat Frances , Vincent Amanda J.
Published: May 2022

Background

Low bone density (BMD) and fractures commonly affect women with premature ovarian insufficiency (POI). However, bone microarchitecture and body composition data are lacking.

Objective

To assess and characterise musculoskeletal phenotype and effects of oestrogen replacement therapy (ERT) in women with POI.

Method

Cross-sectional and longitudinal studies of 60 normal karyotype women with POI, aged 20-40 years, from 2005-2018. Dual x-ray absorptiometry (DXA)-derived spinal (LS) and femoral neck (FN) BMD, trabecular bone score (TBS), appendicular lean mass (ALM), total fat mass (TFM), and fracture prevalence were compared with 60 age-, and BMI-matched population-based controls. Longitudinal changes in bone and body composition variables and ERT effects were analysed using linear mixed models over a median duration of 6 years.

Results

Women with POI were subdivided into spontaneous (s)-POI (n=25) and iatrogenic (i)-POI (n=35). Median(range) age of POI diagnosis was 34 (10-40) years with baseline DXA performed at median 1(0-13) year post-diagnosis. ERT was used by 82% women (similar for both POI groups). FN-BMD were lowest in s-POI (p<0.002). Low TBS was more common in s-POI [(44%), p=0.03], versus other groups. LS-BMD and ALM were lower in both s-POI and i-POI groups than controls (p<0.05). Fracture prevalence was not significantly different: 20% (s-POI), 17% (i-POI), and 8% (controls) (p=0.26). Longitudinal analysis of 23 POI women showed regular ERT was associated with ALM increment of 127.05 g/year (p<0.001) and protected against bone loss. However, ERT interruption was associated with annual reductions in FN BMD and TBS of 0.020g/cm2 and 0.0070 (p<0.05), respectively.

Conclusion

Deficits in BMD, trabecular microarchitecture, and lean mass were present in women with POI. However, regular ERT protected against declines in bone variables, with an increase in ALM. Assessment of skeletal and muscle health, and advocating ERT adherence, is essential in POI to optimise musculoskeletal outcomes.
Characteristics of miRNAs Present in Bovine Sperm and Associations With Differences in Fertility
Authors: Werry Nicholas , Russell Stewart J. , Gillis Daniel J. , Miller Sarah , Hickey Katie , Larmer Steven , Lohuis Michael , Librach Clifford , LaMarre Jonathan
Published: May 2022

Small non-coding RNAs have been linked to different phenotypes in bovine sperm, however attempts to identify sperm-borne molecular biomarkers of male fertility have thus far failed to identify a robust profile of expressed miRNAs related to fertility. We hypothesized that some differences in bull fertility may be reflected in the levels of different miRNAs in sperm. To explore such differences in fertility that are not due to differences in visible metrics of sperm quality, we employed Next Generation Sequencing to compare the miRNA populations in Bos taurus sperm from bulls with comparable motility and morphology but varying Sire Conception Rates. We identified the most abundant miRNAs in both populations (miRs -34b-3p; -100-5p; -191-5p; -30d-4p; -21-5p) and evaluated differences in the overall levels and specific patterns of isomiR expression. We also explored correlations between specific pairs of miRNAs in each population and identified 10 distinct pairs of miRNAs that were positively correlated in bulls with higher fertility and negatively correlated in comparatively less fertile individuals. Furthermore, 8 additional miRNA pairs demonstrated the opposite trend; negatively correlated in high fertility animals and positively correlated in less fertile bulls. Finally, we performed pathway analysis to identify potential roles of miRNAs present in bull sperm in the regulation of specific genes that impact spermatogenesis and embryo development. Together, these results present a comprehensive picture of the bovine sperm miRNAome that suggests multiple potential roles in fertility.
Metabolic Stress Index Including Mitochondrial Biomarker for Noninvasive Diagnosis of Hepatic Steatosis
Authors: Chang Jae Seung , Ahn Jhii-Hyun , Kang Seong Hee , Koh Sang-Baek , Kim Jang-Young , Baik Soon Koo , Huh Ji Hye , Lee Samuel S. , Kim Moon Young , Park Kyu-Sang
Published: May 2022

Background

Mitochondrial dysfunction with oxidative stress contributes to nonalcoholic fatty liver disease (NAFLD) progression. We investigated the steatosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers.

Methods

Altogether, 343 subjects who underwent magnetic resonance imaging-based liver examinations from a population-based general cohort, and 41 patients enrolled in a biopsy-evaluated NAFLD cohort, participated in the development and validation groups, respectively. Serologic stress biomarkers were quantitated by enzyme-linked immunosorbent assay.

Results

Multivariate regression showed that waist-to-hip ratio, fibroblast growth factor (FGF) 21, FGF19, adiponectin-to-leptin ratio, insulin, albumin, triglyceride, total-cholesterol, and alanine-aminotransferase were independent predictors of steatosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95%CI)] of the metabolic stress index for steatosis (MSI-S) was 0.886 (0.85−0.92) and 0.825 (0.69−0.96) in development and validation groups, respectively. MSI-S had higher diagnostic accuracy (78.1%−81.1%) than other steatosis indices. MSI-S notably differentiated steatosis severities, while other indices showed less discrimination.

Conclusion

MSI-S, as a novel non-invasive index, based on mitochondrial stress biomarker FGF21 effectively predicted steatosis. Furthermore, MSI-S may increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices.
The Evolution of the Spiracular Region From Jawless Fishes to Tetrapods
Authors: Gai Zhikun , Zhu Min , Ahlberg Per E. , Donoghue Philip C. J.
Published: May 2022

The spiracular region, comprising the hyomandibular pouch together with the mandibular and hyoid arches, has a complex evolutionary history. In living vertebrates, the embryonic hyomandibular pouch may disappear in the adult, develop into a small opening between the palatoquadrate and hyomandibula containing a single gill-like pseudobranch, or create a middle ear cavity, but it never develops into a fully formed gill with two hemibranchs. The belief that a complete spiracular gill must be the ancestral condition led some 20th century researchers to search for such a gill between the mandibular and hyoid arches in early jawed vertebrates. This hypothesized ancestral state was named the aphetohyoidean condition, but so far it has not been verified in any fossil; supposed examples, such as in the acanthodian Acanthodes and symmoriid chondrichthyans, have been reinterpreted and discounted. Here we present the first confirmed example of a complete spiracular gill in any vertebrate, in the galeaspid (jawless stem gnathostome) Shuyu. Comparisons with two other groups of jawless stem gnathostomes, osteostracans and heterostracans, indicate that they also probably possessed full-sized spiracular gills and that this condition may thus be primitive for the gnathostome stem group. This contrasts with the living jawless cyclostomes, in which the mandibular and hyoid arches are strongly modified and the hyomandibular pouch is lost in the adult. While no truly aphetohyoidean spiracular gill has been found in any jawed vertebrate, the recently reported presence in acanthodians of two pseudobranchs suggests a two-step evolutionary process whereby initial miniaturization of the spiracular gill was followed, independently in chondrichthyans and osteichthyans, by the loss of the anterior pseudobranch. On the basis of these findings we present an overview of spiracular evolution among vertebrates.
Distracted when Using Driving Automation: A Quantile Regression Analysis of Driver Glances Considering the Effects of Road Alignment and Driving Experience
Authors: He Dengbo , Kanaan Dina , Donmez Birsen
Published: May 2022

Background: SAE Level 2 driving automation, the state-of-the-art in commercial vehicles, requires drivers to monitor the environment to resume vehicle control when automation limits are surpassed. However, this type of driving automation was found to increase distraction engagement. Although experienced drivers were shown to better regulate their visual engagement in distracting activities when driving with and without automation, the moderating effects of road demands (e.g., road alignment) have yet to be explored in detail, in particular, for driving with automation.

Objective: To better understand the combined effects of road alignment, driving automation, and driving experience, we investigated the effects of these factors on driver glances to a visual-manual distraction task.

Method: We present a secondary analysis, using quantile regression, of two previously reported driving simulator experiments. A total of 32 participants’ data, 16 from each experiment, were utilized. Half of these participants were novice and the other half were experienced drivers. The first experiment focused on non-automated driving, while the second focused on driving with adaptive cruise control and lane keeping assistance systems combined (i.e., SAE Level 2). The analysis reported here focuses on drivers’ visual distraction engagement in two highway drives that were identical across the two experiments.

Results: With driving automation, compared to experienced driver glances, the duration of novice driver glances to the distraction task was more variable, longer, and less sensitive to variations in road alignment.

Implications: These findings suggest that, with driving automation, novice drivers are more at risk of inappropriate engagement in distractions and do not adapt to road demands as well as experienced drivers, and thus should be supported accordingly.
Discovery and Validation of a Novel Metastasis-Related lncRNA Prognostic Signature for Colorectal Cancer
Authors: Tang Qiang , Hu Xin , Guo Qiong , Shi Yueyue , Liu Liming , Ying Guoguang
Published: May 2022

Background: Cancer metastasis-related chemoresistance and tumour progression are the leading causes of death among CRC patients. Therefore, it is urgent to identify reliable novel biomarkers for predicting the metastasis of CRC.

Methods: The gene expression and corresponding clinical data of CRC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate and multivariate analyses were performed to identify prognostic metastasis-related lncRNAs. Nomograms were constructed, and the predictive accuracy of the nomogram model was assessed by ROC curve analysis. Then, the R package “pRRophetic” was used to predict chemotherapeutic response in CRC patients. In addition, the CIBERSORT database was introduced to evaluate tumour infiltrating immune cells between the high—and low-risk groups. The potential roles of SNHG7 and ZEB1-AS1 in CRC cell lines were further confirmed by in vitro experiments.

Results: An 8-lncRNA (LINC00261, RP1-170O19.17, CAPN10-AS1, SNHG7, ZEB1-AS1, U47924.27, NIFK-AS1, and LINC00925) signature was constructed for CRC prognosis prediction, which stratified patients into two risk groups. Kaplan-Meier analysis revealed that patients in the higher-risk group had a lower survival probability than those in the lower-risk group [p < 0.001 (TCGA); P = 0.044 (GSE39582); and P = 0.0078 (GSE29621)] The AUCs of 1-, 3-, and 5-year survival were 0.678, 0.669, and 0.72 in TCGA; 0.58, 0.55, and 0.56 in GSE39582; and 0.75, 0.54, and 0.56 in GSE29621, respectively. In addition, the risk score was an independent risk factor for CRC patients. Nomograms were constructed, and the predictive accuracy was assessed by ROC curve analysis. This signature could effectively predict the immune status and chemotherapy response in CRC patients. Moreover, SNHG7 and ZEB1-AS1 depletion significantly suppressed the colony formation, migration, and invasion of CRC cells in vitro.

Conclusion: We constructed a signature that could predict the metastasis of CRC and provide certain theoretical guidance for novel therapeutic approaches for CRC.
Pyroptosis-Related Gene Signature Predicts the Prognosis and Immune Infiltration in Neuroblastoma
Authors: Li Wanrong , Li Xin , Xia Yuren , Wang Jian
Published: May 2022

Neuroblastoma is the most common pediatric extracranial solid tumor. The 5-year survival rate for high-risk neuroblastoma is less than 50%, despite multimodal treatment. Pyroptosis, an inflammatory type of programmed cell death, manifested pro-tumor and anti-tumor roles in the adult tumor. Thus, we aimed to elucidate the function of pyroptosis in neuroblastoma. We classified neuroblastoma patients into two clusters based on the pyroptosis gene expression. We found high pyroptosis neuroblastoma manifested favorable overall survival and more anti-tumor immune cell infiltration. Based on the results of a stepwise Cox regression analysis, we built a four-gene predictive model including NLRP3, CASP3, IL18, and GSDMB. The model showed excellent predictive performance in internal and external validation. Our findings highlight that high pyroptosis positively correlated with neuroblastoma outcomes and immune landscape, which may pave the way for further studies on inducing pyroptosis therapy in high-risk neuroblastoma treatment.
Expression Level Dominance and Homeolog Expression Bias Upon Cold Stress in the F1 Hybrid Between the Invasive Sphagneticola trilobata and the Native S. calendulacea in South China, and Implications for Its Invasiveness
Authors: Wu Wei , Guo Wei , Ni Guangyan , Wang Longyuan , Zhang Hui , Ng Wei Lun
Published: May 2022

The role of hybridization is significant in biological invasion, and thermotolerance is a trait critical to range expansions. The South American Sphagneticola trilobata is now widespread in South China, threatening the native S. calendulacea by competition and hybridization. Furthermore, upon formation, their F1 hybrid can quickly replace both parents. In this study, the three taxa were used as a model to investigate the consequences of hybridization on cold tolerance, particularly the effect of subgenome dominance in the hybrid. Upon chilling treatments, physiological responses and transcriptome profiles were compared across different temperature points to understand their differential responses to cold. While both parents showed divergent responses, the hybrid’s responses showed an overall resemblance to S. calendulacea, but the contribution of homeolog expression bias to cold stress was not readily evident in the F1 hybrid possibly due to inherent bias that comes with the sampling location. Our findings provided insights into the role of gene expression in differential cold tolerance, and further contribute to predicting the invasive potential of other hybrids between S. trilobata and its congeners around the world.
Benchmarking Low-Frequency Variant Calling With Long-Read Data on Mitochondrial DNA
Authors: Lüth Theresa , Schaake Susen , Grünewald Anne , May Patrick , Trinh Joanne , Weissensteiner Hansi
Published: May 2022

Background: Sequencing quality has improved over the last decade for long-reads, allowing for more accurate detection of somatic low-frequency variants. In this study, we used mixtures of mitochondrial samples with different haplogroups (i.e., a specific set of mitochondrial variants) to investigate the applicability of nanopore sequencing for low-frequency single nucleotide variant detection.

Methods: We investigated the impact of base-calling, alignment/mapping, quality control steps, and variant calling by comparing the results to a previously derived short-read gold standard generated on the Illumina NextSeq. For nanopore sequencing, six mixtures of four different haplotypes were prepared, allowing us to reliably check for expected variants at the predefined 5%, 2%, and 1% mixture levels. We used two different versions of Guppy for base-calling, two aligners (i.e., Minimap2 and Ngmlr), and three variant callers (i.e., Mutserve2, Freebayes, and Nanopanel2) to compare low-frequency variants. We used F1 score measurements to assess the performance of variant calling.

Results: We observed a mean read length of 11 kb and a mean overall read quality of 15. Ngmlr showed not only higher F1 scores but also higher allele frequencies (AF) of false-positive calls across the mixtures (mean F1 score = 0.83; false-positive allele frequencies < 0.17) compared to Minimap2 (mean F1 score = 0.82; false-positive AF < 0.06). Mutserve2 had the highest F1 scores (5% level: F1 score >0.99, 2% level: F1 score >0.54, and 1% level: F1 score >0.70) across all callers and mixture levels.

Conclusion: We here present the benchmarking for low-frequency variant calling with nanopore sequencing by identifying current limitations.
Family Planning Experiences and Needs of Young Women Living With and Without HIV Accessing an Integrated HIV and SRH Intervention in Zimbabwe-An Exploratory Qualitative Study
Authors: Mavodza Constancia V. , Busza Joanna , Mackworth-Young Constance R. S. , Nyamwanza Rangarirai , Nzombe Portia , Dauya Ethel , Dziva Chikwari Chido , Tembo Mandikudza , Simms Victoria , Mugurungi Owen , Apollo Tsitsi , Madzima Bernard , Ferrand Rashida A. , Bernays Sarah
Published: May 2022

Background

People living with HIV have higher unmet family planning needs compared to those without HIV. This is heightened for young people. However, the provision of family planning for young people within HIV programmes is uncommon. We investigated family planning uptake, acceptability of, and engagement with a service offering integrated HIV and sexual and reproductive health services for youth in a community-based setting in Zimbabwe.

Methods

CHIEDZA, a community-based intervention offering integrated HIV and sexual and reproductive health services to young people aged 16–24 years, is being trialed in Zimbabwe. This exploratory qualitative study was nested within an ongoing study process evaluation. Data was collected between March-May 2021 with two sets of interviews conducted: I) twelve semi-structured interviews with young women living with HIV aged 17–25 years and II) fifteen interviews conducted with young women without HIV aged between 20 and 25 years who used a contraceptive method. A thematic analysis approach was used.

Results

Before engaging with CHIEDZA, young women had experienced judgmental providers, on account of their age, and received misinformation about contraceptive use and inadequate information about ART-contraceptive interactions. These presented as barriers to uptake and engagement. Upon attending CHIEDZA, all the young women reported receiving non-judgmental care. For those living with HIV, they were able to access integrated HIV and family planning services that supported them having broader sexual and reproductive needs beyond their HIV diagnosis. The family planning preference of young women living with HIV included medium to long-acting contraceptives to minimize adherence challenges, and desired partner involvement in dual protection to prevent HIV transmission. CHIEDZA's ability to meet these preferences shaped uptake, acceptability, and engagement with integrated HIV and family services.

Conclusions

Recommendations for an HIV and family planning integrated service for young people living with HIV include: offering a range of services (including method-mix contraceptives) to choose from; supporting their agency to engage with the services which are most acceptable to them; and providing trained, supportive, knowledgeable, and non-judgmental health providers who can provide accurate information and counsel. We recommend youth-friendly, differentiated, person-centered care that recognize the multiple and intersecting needs of young people living with HIV.
How Should Public Administrations Foster the Ethical Development and Use of Artificial Intelligence? A Review of Proposals for Developing Governance of AI
Authors: Sigfrids Anton , Nieminen Mika , Leikas Jaana , Pikkuaho Pietari
Published: May 2022

Recent advances in AI raise questions about its social impacts and implementation. In response, governments and public administrations seek to develop adequate governance frameworks to mitigate risks and maximize the potential of AI development and use. Such work largely deals with questions of how challenges and risks should be managed, which values and goals should be pursued, and through which institutional mechanisms and principles these goals could be achieved. In this paper, we conduct a systematic review of the existing literature on the development of AI governance for public administration. The article describes principles and means by which public administrations could guide and steer AI developers and users in adopting ethical and responsible practices. The reviewed literature indicates a need for public administrations to move away from top-down hierarchical governance principles and adopt forms of inclusive policy-making to ensure the actionability of ethical and responsibility principles in the successful governance of AI development and use. By combining the results, we propose a CIIA (Comprehensive, Inclusive, Institutionalized, and Actionable) framework that integrates the key aspects of the proposed development solutions into an ideal typical and comprehensive model for AI governance.
Di-(2-ethylhexyl) Phthalate Promotes Allergic Lung Inflammation by Modulating CD8α+ Dendritic Cell Differentiation via Metabolite MEHP-PPARγ Axis
Authors: Tseng Hsin-Han , Li Chia-Yang , Wu Shin-Ting , Su Hsiang-Han , Wong Tzu-Hsuan , Wu Hsin-En , Chang Yu-Wei , Huang Shau-Ku , Tsai Eing Mei , Suen Jau-Ling
Published: May 2022

Di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is a ubiquitous environmental pollutant that can disrupt endocrine function. Epidemiological studies suggest that chronic exposure to DEHP in the environment is associated with the prevalence of childhood allergic diseases; however, the underlying causal relationship and immunological mechanism remain unclear. This study explored the immunomodulatory effect of DEHP on allergic lung inflammation, while particularly focusing on the impact of DEHP and its metabolite on dendritic cell differentiation and activity of peroxisome proliferator-activated receptor gamma (PPARγ). The results showed that exposure to DEHP at a human tolerable daily intake dose exacerbated allergic lung inflammation in mice. Ex vivo flow cytometric analysis revealed that DEHP-exposed mice displayed a significantly decreased number of CD8α+ dendritic cells (DCs) in spleens and DC progenitors in the bone marrow, as well as, less interleukin-12 production in splenic DCs and increased T helper 2 polarization. Pharmacological experiments showed that mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP, significantly hampered the differentiation of CD8α+ DCs from Fms-like tyrosine kinase 3 ligand-differentiated bone marrow culture, by modulating PPARγ activity. These results suggested that chronic exposure to DEHP at environmentally relevant levels, promotes allergic lung inflammation, at least in part, by altering DC differentiation through the MEHP-PPARγ axis. This study has crucial implications for the interaction(s) between environmental pollutants and innate immunity, with respect to the development of allergic asthma.
Danggui-Shaoyao-San Attenuates Cognitive Impairment via the Microbiota–Gut–Brain Axis With Regulation of Lipid Metabolism in Scopolamine-Induced Amnesia
Authors: Liu Piaoxue , Zhou Xun , Zhang Haoran , Wang Rui , Wu Xiaolang , Jian Wenxuan , Li Weirong , Yuan Dongsheng , Wang Qi , Zhao Wei
Published: May 2022

Danggui-Shaoyao-San (DSS) has a long history of being used as a traditional medicine (TCM) and has been reported to show therapeutic effects in alleviating the symptoms of cognitive impairment. The purpose of this study was to investigate whether DSS treatment attenuates cognitive impairment via the microbiota–gut–brain axis in scopolamine-induced amnesia. In this work, we first performed the Morris water maze (MWM) test and novel object recognition (NOR) test to evaluate the memory function of treated C57BL/6N mice. Then we evaluated 16S rRNA for gut microbiota analysis, as well as assessment of blood–brain barrier function and intestinal barrier function and lipid metabolism analysis on tissues from different groups. We hypothesised that DSS may affect brain function and behavior through the gut–brain axis in a bidirectional interplay with both top-down and bottom-up regulation. Furthermore, in order to confirm whether intestinal flora plays a crucial role in scopolamine-induced amnesia, C57BL/6N mice were treated with fecal microbial transplantation (FMT), and then behavioral tests were performed. The mice’s feces were simultaneously evaluated by 16S rRNA analysis. The result supported that the FMT-induced improvement in cognitive function highlights the role of the gut microbiota–brain axis to mediate cognitive function and behavior. Besides theses works, more findings indicated that DSS altered lipid metabolism by activating LXR-PPAR-γ and repaired mucosal barrier dysfunction assessed with a broad range of techniques, which attenuated cognitive impairment via the microbiota–gut–brain axis.
Estrogen Acts Through Estrogen Receptor-β to Promote Mannan-Induced Psoriasis-Like Skin Inflammation
Authors: Wu Huimei , Zeng Longhui , Ou Jiaxin , Wang Tingting , Chen Yong , Nandakumar Kutty Selva
Published: May 2022

Sex-bias is more obvious in several autoimmune disorders, but not in psoriasis. However, estrogen levels fluctuate during puberty, menstrual cycle, pregnancy, and menopause, which are related to variations in psoriasis symptoms observed in female patients. Estrogen has disease promoting or ameliorating functions based on the type of immune responses and tissues involved. To investigate the effects of estrogen on psoriasis, at first, we developed an innate immunity dependent mannan-induced psoriasis model, which showed a clear female preponderance in disease severity in several mouse strains. Next, we investigated the effects of endogenous and exogenous estrogen using ovariectomy and sham operated mice. 17-β-estradiol (E2) alone promoted the skin inflammation and it also significantly enhanced mannan-induced skin inflammation. We also observed a prominent estrogen receptor-β (ER-β) expression in the skin samples, especially on keratinocytes. Subsequently, we confirmed the effects of E2 on psoriasis using ER-β antagonist (PHTPP) and agonist (DPN). In addition, estrogen was found to affect the expression of certain genes (vgll3 and cebpb), microRNAs (miR146a and miR21), and immune cells (DCs and γδ T cells) as well as chemokines (CCL5 and CXCL10) and cytokines (TNF-α, IL-6, IL-22, IL-23, and IL-17 family), which promoted the skin inflammation. Thus, we demonstrate a pathogenic role for 17-β-estradiol in promoting skin inflammation, which should be considered while designing new treatment strategies for psoriasis patients.
Platelet-to-Albumin Ratio: A Novel IgA Nephropathy Prognosis Predictor
Authors: Tan Jiaxing , Song Guojiao , Wang Siqing , Dong Lingqiu , Liu Xiang , Jiang Zheng , Qin Aiya , Tang Yi , Qin Wei
Published: May 2022

Background

Chronic inflammation is related to the development of IgA nephropathy (IgAN). Emerging studies have reported that platelet-related parameters including platelet (PLT), platelet-to-albumin ratio (PAR), and platelet-to-lymphocyte ratio (PLR) are proved to be novel prognostic indicators for several inflammatory diseases. Whether platelet-related parameters could serve as predictors for IgAN remains unknown.

Methods

A total of 966 IgAN patients were enrolled in this retrospective study and were divided into several groups based on the optimal cut-off value of the platelet-related parameters. End-stage renal disease was used as the renal endpoint. A 1:2 propensity score (PS) match was then carried out to eliminate significant differences at baseline. The area under the receiver operating characteristic curve (AUROC), Kaplan–Meier (K-M) curve, and Cox proportional hazards analyses were performed to evaluate their predictive effect.

Results

Without considering the effect of covariates, the K-M curve showed that PLT, PLR, and PAR were strongly correlated with the renal outcomes of IgAN. However, the AUROC revealed that the PAR and PLR had better predictive power than the PLT. Multivariate Cox regression adjusting for demographic data, pathological findings, treatment, and laboratory results indicated that compared with PLR, albumin and PLT, PAR seemed to be a better marker of adverse renal outcome, implying that PAR was the only platelet-related parameter that could be used as an independent risk factor. Notably, high PAR patients seemed to have more severe clinical manifestations and pathological lesions. However, after eliminating the influence of different baselines on outcome variables, the PAR could still predict the poor prognosis of IgAN. To more accurately evaluate the predictive power of the PAR, we analyzed the predictive effect of the PAR on patients with different clinicopathological characteristics through subgroup analysis. It was indicated that the PAR might better predict the prognosis and outcome of patients whose disease was already very severe.

Conclusion

PAR might be used as an independent risk factor for IgAN progression.
The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer’s Disease
Authors: Qin Qi , Wang Meng , Yin Yunsi , Tang Yi
Published: May 2022

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Synaptic dysfunction is an integral feature of AD pathophysiology and a significant factor in early cognitive impairment in AD. Microglia, which are intrinsic immune cells in the central nervous system, play important regulatory roles in the process of synapse formation. Microglia can refine synaptic connections through synaptic clearance to ensure accurate synaptic transmission. Synaptic clearance is not only existed during central nervous system development but also aberrantly activated during AD pathology. However, the mechanisms of synaptic clearance in AD remain to be investigated. TREM2 is involved in the synaptic clearance of microglia, acting alone or with other molecules, such as apolipoprotein E (APOE). In addition, C1q is essential for microglia-mediated synaptic clearance. In this review, we systematically summarized the potential mechanisms of microglia involved in synaptic clearance, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.
Evaluating the Immune Response in Treatment-Naive Hospitalised Patients With Influenza and COVID-19
Authors: Legebeke Jelmer , Lord Jenny , Penrice-Randal Rebekah , Vallejo Andres F. , Poole Stephen , Brendish Nathan J. , Dong Xiaofeng , Hartley Catherine , Holloway John W. , Lucas Jane S. , Williams Anthony P. , Wheway Gabrielle , Strazzeri Fabio , Gardner Aaron , Schofield James P. R. , Skipp Paul J. , Hiscox Julian A. , Polak Marta E. , Clark Tristan W. , Baralle Diana
Published: May 2022

The worldwide COVID-19 pandemic has claimed millions of lives and has had a profound effect on global life. Understanding the body’s immune response to SARS-CoV-2 infection is crucial in improving patient management and prognosis. In this study we compared influenza and SARS-CoV-2 infected patient cohorts to identify distinct blood transcript abundances and cellular composition to better understand the natural immune response associated with COVID-19, compared to another viral infection being influenza, and identify a prognostic signature of COVID-19 patient outcome. Clinical characteristics and peripheral blood were acquired upon hospital admission from two well characterised cohorts, a cohort of 88 patients infected with influenza and a cohort of 80 patients infected with SARS-CoV-2 during the first wave of the pandemic and prior to availability of COVID-19 treatments and vaccines. Gene transcript abundances, enriched pathways and cellular composition were compared between cohorts using RNA-seq. A genetic signature between COVID-19 survivors and non-survivors was assessed as a prognostic predictor of COVID-19 outcome. Contrasting immune responses were detected with an innate response elevated in influenza and an adaptive response elevated in COVID-19. Additionally ribosomal, mitochondrial oxidative stress and interferon signalling pathways differentiated the cohorts. An adaptive immune response was associated with COVID-19 survival, while an inflammatory response predicted death. A prognostic transcript signature, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, was able to stratify COVID-19 patients likely to survive or die. This study provides a unique insight into the immune responses of treatment naïve patients with influenza or COVID-19. The comparison of immune response between COVID-19 survivors and non-survivors enables prognostication of COVID-19 patients and may suggest potential therapeutic strategies to improve survival.
Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis
Authors: Shao Bo , Qin Ya-fei , Ren Shao-hua , Peng Qiu-feng , Qin Hong , Wang Zhao-bo , Wang Hong-da , Li Guang-ming , Zhu Yang-lin , Sun Cheng-lu , Zhang Jing-yi , Li Xiang , Wang Hao
Published: May 2022

Background

Mesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics.

Methods

The articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer.

Results

A total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords “machine perfusion”, “liver transplantation”, and “microRNAs” also may be the focus of new trends and future research.

Conclusions

In this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.
The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer
Authors: Wang Bin , Liu Jie , Han Yin , Deng Yaotiao , Li Jinze , Jiang Yu
Published: May 2022

Background

Tertiary lymphoid structures (TLSs) have been proven to be predictive biomarkers of favorable clinical outcomes and response to immunotherapies in several solid malignancies. Nevertheless, the effect of TLSs in patients with breast cancer (BC) remains controversial. The objective of the current study is to investigate the clinicopathological and prognostic significance of TLSs in BC. Given the unique difficulties for detecting and quantifying TLSs, a TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) BC cohort was used to validate and supplement our results.

Methods

Electronic platforms (PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and Wanfang) were searched systematically to identify relevant studies as of January 11, 2022. We calculated combined odds ratios (ORs) with 95% confidence intervals (CIs) to determine the relationship between clinicopathological parameters and TLSs. The pooled hazard ratios (HRs) and 95% CIs were also calculated to evaluate the prognostic significance of TLSs. The TLS signature based on the TCGA BC cohort was applied to validate and supplement our results.

Results

Fifteen studies with 3,898 patients were eligible for enrollment in our study. The combined analysis indicated that the presence of TLSs was related to improved disease-free survival (DFS) (HR = 0.61, 95% CI: 0.41–0.90, p < 0.05) and overall survival (OS) (HR = 1.66, 95% CI: 1.26–2.20, p < 0.001). Additionally, the presence of TLSs was positively correlated with early tumor TNM stage and high tumor-infiltrating lymphocytes. TLS presence was positively related to human epidermal growth factor receptor 2 (HER-2) and Ki-67 but inversely correlated with the status of estrogen and progesterone receptor. Simultaneously, our study found that tumor immune microenvironment was more favorable in the high-TLS signature group than in the low-TLS signature group. Consistently, BC patients in the high-TLS signature group exhibited better survival outcomes compared to those in the low-TLS signature group, suggesting that TLSs might be favorable prognostic biomarkers.

Conclusions

TLS presence provides new insight into the clinicopathological features and prognosis of patients with BC, whereas the factors discussed limited the evidence quality of this study. We look forward to consistent methods to define and characterize TLSs, and more high-quality prospective clinical trials designed to validate the value of TLSs alone or in combination with other markers.
Tumor-Resident T Cells, Associated With Tertiary Lymphoid Structure Maturity, Improve Survival in Patients With Stage III Lung Adenocarcinoma
Authors: Zhao Hua , Wang Hao , Zhao Yu , Sun Qian , Ren Xiubao
Published: May 2022

Tertiary lymphoid structure (TLS) and tumor-resident memory T cells (TRM) play crucial roles in the anti-tumor immune response, facilitating a good prognosis in patients with cancer. However, there have been no reports on the relationship between TRM and TLS maturity. In this study, we detected TRM and the maturity of TLS by immunofluorescence staining and analyzed the relationship between their distribution and proportion in patients with lung adenocarcinoma (LUAD). The proportion of TRM within TLSs was significantly higher than that outside and was positively correlated with the survival of patients. In addition, the proportions of CD4+CD103+ TRM and CD8+CD103+ TRM were significantly increased with the gradually maturation of TLSs. We divided the patients into three levels (grade 1, grade 2, and grade 3) according to the presence of increasing maturation of TLSs. The proportion of CD103+ TRM in grade 3 patients was significantly higher than that in grade 1 and grade 2 patients, suggesting a close relationship between CD103+ TRM and TLS maturity. Furthermore, positive prognosis was associated with grade 3 patients that exhibited CD103+TRMHigh phenotype.
Predicting Pathological Complete Response in Neoadjuvant Dual Blockade With Trastuzumab and Pertuzumab in HER2 Gene Amplified Breast Cancer
Authors: Xiao Yi , Ding Jiahan , Ma Dachang , Chen Sheng , Li Xun , Yu Keda
Published: May 2022

Background

Dual-targeted therapy is the standard treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and effective biomarkers to predict the response to neoadjuvant trastuzumab and pertuzumab treatment need further investigation. Here, we developed a predictive model to evaluate the dual-targeted neoadjuvant treatment efficacy in HER2 gene-amplified breast cancer.

Method

This retrospective study included 159 HER2-amplified patients with locally advanced breast cancer who received neoadjuvant trastuzumab, pertuzumab, and chemotherapy. The correlation between clinicopathological factors and pathological complete response (pCR, in the breast and axilla) was evaluated. Patients were randomly assigned into the training set (n=110) and the testing set (n=49). We used an independent cohort (n=65) for external validation. We constructed our predictive nomogram model with the results of risk variables associated with pCR identified in the multivariate logistic analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, decision curve analysis, and calibration curves were employed to assess the nomogram’s performance.

Results

We revealed that the HER2/CEP17 ratio (p=0.001), CD8 levels (p=0.005), and histological grade (p=0.007) were independent indicators for pCR in dual-targeted neoadjuvant treatment after multivariate adjustment. The combined prediction efficacy of the three indicators was significantly higher than that of each single indicator alone. The AUCs were 0.819, 0.773, and 0.744 in the training, testing, and external validation sets, respectively.

Conclusions

The HER2/CEP17 ratio, CD8 levels, and histological grade were significantly correlated with pCR in dual-targeted neoadjuvant treatment. The combined model using these three markers provided a better predictive value for pCR than the HER2/CEP17 ratio, CD8 levels, and the histological grade alone, which showed that an immunological effect partially mediates the predictive impact of neoadjuvant treatment.
Multimericity Amplifies the Synergy of BCR and TLR4 for B Cell Activation and Antibody Class Switching
Authors: Pone Egest J. , Hernandez-Davies Jenny E. , Jan Sharon , Silzel Emily , Felgner Philip L. , Davies D. Huw
Published: May 2022

Sustained signaling through the B cell antigen receptor (BCR) is thought to occur only when antigen(s) crosslink or disperse multiple BCR units, such as by multimeric antigens found on the surfaces of viruses or bacteria. B cell-intrinsic Toll-like receptor (TLR) signaling synergizes with the BCR to induce and shape antibody production, hallmarked by immunoglobulin (Ig) class switch recombination (CSR) of constant heavy chains from IgM/IgD to IgG, IgA or IgE isotypes, and somatic hypermutation (SHM) of variable heavy and light chains. Full B cell differentiation is essential for protective immunity, where class switched high affinity antibodies neutralize present pathogens, memory B cells are held in reserve for future encounters, and activated B cells also serve as semi-professional APCs for T cells. But the rules that fine-tune B cell differentiation remain partially understood, despite their being essential for naturally acquired immunity and for guiding vaccine development. To address this in part, we have developed a cell culture system using splenic B cells from naive mice stimulated with several biotinylated ligands and antibodies crosslinked by streptavidin reagents. In particular, biotinylated lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, and biotinylated anti-IgM were pre-assembled (multimerized) using streptavidin, or immobilized on nanoparticles coated with streptavidin, and used to active B cells in this precisely controlled, high throughput assay. Using B cell proliferation and Ig class switching as metrics for successful B cell activation, we show that the stimuli are both synergistic and dose-dependent. Crucially, the multimerized immunoconjugates are most active over a narrow concentration range. These data suggest that multimericity is an essential requirement for B cell BCR/TLRs ligands, and clarify basic rules for B cell activation. Such studies highlight the importance in determining the choice of single vs multimeric formats of antigen and PAMP agonists during vaccine design and development.
CD11c+ T-bet+ CD21hi B Cells Are Negatively Associated With Renal Impairment in Systemic Lupus Erythematosus and Act as a Marker for Nephritis Remission
Authors: Sosa-Hernández Víctor A. , Romero-Ramírez Sandra , Cervantes-Díaz Rodrigo , Carrillo-Vázquez Daniel A. , Navarro-Hernandez Itze C. , Whittall-García Laura P. , Absalón-Aguilar Abdiel , Vargas-Castro Ana S. , Reyes-Huerta Raúl F. , Juárez-Vega Guillermo , Meza-Sánchez David E. , Ortiz-Navarrete Vianney , Torres-Ruiz Jiram , Mejía-Domínguez Nancy R. , Gómez-Martín Diana , Maravillas-Montero José L.
Published: May 2022

Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), characterized by abnormal B cell activation and differentiation to memory or plasma effector cells. However, the role of these cells in the pathogenesis of LN is not fully understood, as well as the effect of induction therapy on B cell subsets, possibly associated with this manifestation, like aged-associated B cells (ABCs). Consequently, we analyzed the molecules defining the ABCs subpopulation (CD11c, T-bet, and CD21) through flow cytometry of blood samples from patients with lupus presenting or not LN, following up a small sub-cohort after six months of induction therapy. The frequency of ABCs resulted higher in LN patients compared to healthy subjects. Unexpectedly, we identified a robust reduction of a CD21hi subset that was almost specific to LN patients. Moreover, several clinical and laboratory lupus features showed strong and significant correlations with this undefined B cell subpopulation. Finally, it was observed that the induction therapy affected not only the frequencies of ABCs and CD21hi subsets but also the phenotype of the CD21hi subset that expressed a higher density of CXCR5. Collectively, our results suggest that ABCs, and more importantly the CD21hi subset, may work to assess therapeutic response since the reduced frequency of CD21hi cells could be associated with the onset of LN.
Sirolimus Restores Erythropoiesis and Controls Immune Dysregulation in a Child With Cartilage-Hair Hypoplasia: A Case Report
Authors: Del Borrello Giovanni , Miano Maurizio , Micalizzi Concetta , Lupia Michela , Ceccherini Isabella , Grossi Alice , Cavalli Andrea , Gustincich Stefano , Rusmini Marta , Faraci Maura , Dell’Orso Gianluca , Ramenghi Ugo , Mesini Alessio , Ricci Erica , Schiavone Maurizio , Di Iorgi Natascia , Dufour Carlo
Published: May 2022

Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.