bluuebunny/crossref_metadata_2025 huggingface dataset:
Profiling Genome-Wide DNA Methylation Patterns in Human Aortic and Mitral Valves
Authors: Halawa Sarah , Latif Najma , Tseng Yuan-Tsan , Ibrahim Ayman M. , Chester Adrian H. , Moustafa Ahmed , Aguib Yasmine , Yacoub Magdi H.
Published: April 2022

Cardiac valves exhibit highly complex structures and specialized functions that include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied. In this work we analyzed the differential methylation profiles of 12 non-diseased aortic and mitral valve tissue samples (in matched pairs). Analysis of methylation data [reduced representation bisulfite sequencing (RRBS)] of 16,101 promoters genome-wide revealed 584 differentially methylated (DM) promoters, of which 13 were reported in endothelial mesenchymal trans-differentiation (EMT), 37 in aortic and mitral valve disease and 7 in ECM remodeling. Both functional classification as well as network analysis showed that the genes associated with the DM promoters were enriched for WNT-, Cadherin-, Endothelin-, PDGF-, HIF-1 and VEGF- signaling implicated in valvular physiology and pathophysiology. Additional enrichment was detected for TGFB-, NOTCH- and Integrin- signaling involved in EMT as well as ECM remodeling. This data provides the first insight into differential regulation of human aortic and mitral valve tissue and identifies candidate genes linked to DM promoters. Our work will improve the understanding of valve biology, valve tissue engineering approaches and contributes to the identification of relevant drug targets.
Preclinical In Silico Evidence Indicates the Pharmacological Targets and Mechanisms of Mogroside V in Patients With Ovarian Cancer and Coronavirus Disease 2019
Authors: Li Yongming , Chen Yudong , Wei Mulan , Wei Chaohe
Published: April 2022

The borderless transmission of coronavirus remains uncontrolled globally. The uncharted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant reduces the therapeutic efficacy of vaccines against coronavirus disease 2019 (COVID-19). Clinical observations suggest that tumour cases are highly infected with coronavirus, possibly due to immunologic injury, causing a higher COVID-19-related death toll. Presently, screening of candidate medication against coronavirus is in progress. Mogroside V, a bioactive ingredient of Siraitia grosvenorii, has been reported in China to have lung-protective and anticancer effects. The current study used network pharmacology and molecular docking to unlock the potential drug targets and remedial mechanisms of mogroside V against patients with ovarian cancer with COVID-19. We identified 24 related targets of mogroside V in patients with ovarian cancer and COVID-19 and characterised another 10 core targets of mogroside V against COVID-19 ovarian cancer, including Jun, IL2, HSP90AA1, AR, PRKCB, VEGFA, TLR9, TLR7, STAT3, and PRKCA. The core targets’ biological processes and signalling pathways were revealed by enrichment analysis. Molecular docking suggested favourable docking between core target protein and mogroside V, including vascular endothelial growth factor A (VEGFA). These findings indicated that mogroside V might be a potential therapeutic agent in the mitigation of COVID-19 ovarian cancer.
Combination of Stimulated Thyroglobulin and Antithyroglobulin Antibody Predicts the Efficacy and Prognosis of 131I Therapy in Patients With Differentiated Thyroid Cancer Following Total Thyroidectomy: A Retrospective Study
Authors: Pan Mengjiao , Li Zhuyao , Jia Meng , Lu Xiubo
Published: April 2022

Background and Purpose

This study aimed to analyze the diagnostic ability of the combination of stimulated thyroglobulin (sTg) and antithyroglobulin antibody (TgAb) in predicting the efficacy and prognosis of radioactive iodine (131I) therapy (RAIT) in patients with differentiated thyroid carcinomas (DTCs) after total thyroidectomy (TT).

Methods

This retrospective study comprised 409 DTC patients who underwent131I treatment following TT in the First Affiliated Hospital of Zhengzhou University from January 2019 to August 2020, and they were followed up to November 2021. Patients were divided into the successful ablation and the unsuccessful ablation group based on the classification of the efficacy of RAIT in the 2015 American Thyroid Association guidelines. The clinical characteristics and the efficacy of the initial RAIT were evaluated. The cutoffs of preablation sTg, sTg/thyroid-stimulating hormone (TSH) ratio, and sTg×TgAb product were calculated to predict the efficacy of RAIT. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors for unsuccessful ablation. Kaplan–Meier curves were used to estimate the prognostic value of sTg×TgAb product affecting progression-free survival (PFS).

Results

The cohort consisted of 222 cases in the successful ablation group and 187 cases in the unsuccessful ablation group. Between the two groups, preablation sTg, sTg/TSH ratio, and sTg×TgAb product were significantly higher in the unsuccessful ablation group. The area under the curve (AUC) of the sTg×TgAb product was the highest among the above three factors. The cutoffs for the worse therapeutic effect of the initial RAIT in sTg, sTg/TSH ratio, and sTg×TgAb were >2.99 ng/ml, >0.029 mg/IU, and >34.18, respectively. STg >2.99 ng/ml and sTg×TgAb product >34.18 were independent risk factors for unsuccessful ablation. Patients with sTg×TgAb product >34.18 had shorter PFS than that of patients with sTg×TgAb product ≤34.18. In separate analyses of TgAb-negative and TgAb-positive subgroups, higher sTg×TgAb was both associated with a lower success rate of RAIT and a shorter PFS.

Conclusion

STg×TgAb product predicted the efficacy and prognosis of131I therapy for both TgAb-negative and TgAb-positive DTC patients before the initial131I treatment following TT. Thus, it can be used as a clinical reference indicator for the surveillance of DTC patients.
Changes in Landscape Pattern and an Ecological Risk Assessment of the Changshagongma Wetland Nature Reserve
Authors: Yang Cai , Deng Wei , Yuan Quanzhi , Zhang Shaoyao
Published: April 2022

The Changshagongma wetlands is the Chinese National Nature Reserve were listed as a Ramsar Wetland of International Importance in 2018. Here, we examined four periods (1992, 2002, 2013, and 2020) of remote sensing image data to analyze the changes in wetland landscape patterns and the ecological risk in Changshagongma Wetland Nature Reserve over the past 30 years. The results showed that wetlands account for approximately 30% of the study area, and swamp meadows were the main type of wetland, accounting for approximately 95% of the total wetland area. In terms of landscape patterns, wetland fragmentation declined, wetland patch shapes became less complicated, and spatial connectivity increased. The landscape fragmentation of non-wetland alpine meadows was reduced. The patches of sandy grasslands tended to be regular, and their spatial connectivity was reduced. The wetland regions of high ecological risk are concentrated in the central and southern parts of the Changshagongma Wetland Nature Reserve. Low-risk regions are mainly concentrated in the contiguous swamp meadows in the northwest and wetlands in the southwest. From 1992 to 2020, the level of ecological risk of the Changshagongma Wetland Nature Reserve showed a “∧”-shaped trend, with the highest risk in 2002 and the lowest risk in 2020. Among the selected indicators, climate conditions constituted the main factor affecting the ecological risk of the Changshagongma Wetland Nature Reserve, followed by topographical conditions, and human activities were the least influential. Over the past 30 years, the temperature and precipitation in the study area increased significantly. The climate in the study area can be roughly divided into two periods bounding 2002, and the climate has been changing from cold and dry to warm and wet. The ecological environment of the study area is affected by natural and human activities. Cold and dry climatic conditions and uncontrolled grazing accelerate the destruction of the wetland ecological environment, and warm and wet climatic conditions and ecological conservation policies are conducive to the ecological restoration of wetlands. In general, the wetland landscape structure in the study area has become less complex, landscape heterogeneity has decreased, and ecological quality has improved.
Single Stranded Fully Modified-Phosphorothioate Oligonucleotides can Induce Structured Nuclear Inclusions, Alter Nuclear Protein Localization and Disturb the Transcriptome In Vitro
Authors: Flynn Loren L. , Li Ruohan , Pitout Ianthe L. , Aung-Htut May T. , Larcher Leon M. , Cooper Jack A. L. , Greer Kane L. , Hubbard Alysia , Griffiths Lisa , Bond Charles S. , Wilton Steve D. , Fox Archa H. , Fletcher Sue
Published: April 2022

Oligonucleotides and nucleic acid analogues that alter gene expression are now showing therapeutic promise in human disease. Whilst the modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, such modifications may also confer unexpected physicochemical and biological properties. Gapmer mixed-modified and DNA oligonucleotides on a phosphorothioate backbone can bind non-specifically to intracellular proteins to form a variety of toxic inclusions, driven by the phosphorothioate linkages, but also influenced by the oligonucleotide sequence. Recently, the non-antisense or other off-target effects of 2′ O- fully modified phosphorothioate linkage oligonucleotides are becoming better understood. Here, we report chemistry-specific effects of oligonucleotides composed of modified or unmodified bases, with phosphorothioate linkages, on subnuclear organelles and show altered distribution of nuclear proteins, the appearance of highly stable and strikingly structured nuclear inclusions, and disturbed RNA processing in primary human fibroblasts and other cultured cells. Phosphodiester, phosphorodiamidate morpholino oligomers, and annealed complimentary phosphorothioate oligomer duplexes elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of transfected fibroblasts exhibiting such disruption. Our data add to the growing body of evidence of off-target effects of some phosphorothioate nucleic acid drugs in primary cells and suggest alternative approaches to mitigate these effects.
Phthalate Exposure, PPARα Variants, and Neurocognitive Development of Children at Two Years
Authors: Yu Ling , Zhang Hongling , Zheng Tongzhang , Liu Juan , Fang Xingjie , Cao Shuting , Xia Wei , Xu Shunqing , Li Yuanyuan
Published: April 2022

Background: The PPARα gene may be crucial to the neurotoxic effect of phthalates. However, epidemiological studies considering the neurodevelopmental influence of phthalates interacting with genetic susceptibility are limited. We hypothesized phthalates could interact with the PPARα gene, synergistically affecting neurocognitive development.

Methods: A total of 961 mother-infant pairs were involved in this study. The concentrations of phthalate metabolites in maternal urine during pregnancy were detected. Children’s neurocognitive development was estimated with the Bailey Infant Development Inventory (BSID). Genetic variations in PPARα were genotyped with the Illumina Asian Screening Array. We applied generalized linear regression models to estimate genotypes and phthalate metabolites’ association with children’s neurocognitive development.

Results: After adjusting for potential confounders, the mono-n-butyl phthalate (MnBP) concentration was negatively associated with Psychomotor Development Index (PDI) (β = −0.86, 95% CI: −1.67, −0.04). The associations between MnBP and neurocognitive development might be modified by PPARα rs1800246. Compared with low-MnBP individuals carrying rs1800246 GG genotypes, high-MnBP individuals with the AG + AA genotype had a higher risk of neurocognitive developmental delay, with the odds ratio of 2.76 (95% CI:1.14, 6.24).

Conclusions: Our current study revealed that prenatal exposure to MnBP was negatively correlated with children’s neurocognitive development, and PPARα rs1800246 might modify the association.
Lactobacillus spp. for Gastrointestinal Health: Current and Future Perspectives
Authors: Dempsey Elaine , Corr Sinéad C.
Published: April 2022

In recent decades, probiotic bacteria have become increasingly popular as a result of mounting scientific evidence to indicate their beneficial role in modulating human health. Although there is strong evidence associating various Lactobacillus probiotics to various health benefits, further research is needed, in particular to determine the various mechanisms by which probiotics may exert these effects and indeed to gauge inter-individual value one can expect from consuming these products. One must take into consideration the differences in individual and combination strains, and conditions which create difficulty in making direct comparisons. The aim of this paper is to review the current understanding of the means by which Lactobacillus species stand to benefit our gastrointestinal health.
Advances in the Immune Regulatory Role of Non-Coding RNAs (miRNAs and lncRNAs) in Insect-Pathogen Interactions
Authors: Moure Ulrich Aymard Ekomi , Tan Tingshan , Sha Lin , Lu Xiaoqin , Shao Zhi , Yang Guang , Wang Yi , Cui Hongjuan
Published: April 2022

Insects are by far the most abundant and diverse living organisms on earth and are frequently prone to microbial attacks. In other to counteract and overcome microbial invasions, insects have in an evolutionary way conserved and developed immune defense mechanisms such as Toll, immune deficiency (Imd), and JAK/STAT signaling pathways leading to the expression of antimicrobial peptides. These pathways have accessory immune effector mechanisms, such as phagocytosis, encapsulation, melanization, nodulation, RNA interference (RNAi), lysis, autophagy, and apoptosis. However, pathogens evolved strategies that circumvent host immune response following infections, which may have helped insects further sophisticate their immune response mechanisms. The involvement of ncRNAs in insect immunity is undeniable, and several excellent studies or reviews have investigated and described their roles in various insects. However, the functional analyses of ncRNAs in insects upon pathogen attacks are not exhaustive as novel ncRNAs are being increasingly discovered in those organisms. This article gives an overview of the main insect signaling pathways and effector mechanisms activated by pathogen invaders and summarizes the latest findings of the immune modulation role of both insect- and pathogen-encoded ncRNAs, especially miRNAs and lncRNAs during insect–pathogen crosstalk.
Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats
Authors: Patel Nikita M. , Yamada Noriaki , Oliveira Filipe R. M. B. , Stiehler Lara , Zechendorf Elisabeth , Hinkelmann Daniel , Kraemer Sandra , Stoppe Christian , Collino Massimo , Collotta Debora , Alves Gustavo Ferreira , Ramos Hanna Pillmann , Sordi Regina , Marzi Ingo , Relja Borna , Marx Gernot , Martin Lukas , Thiemermann Christoph
Published: April 2022

Objective

The aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS.

Background

The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown.

Methods

The MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver.

Results

We demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver.

Conclusion

Our results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage.
Inflammatory Response to Regulated Cell Death in Gout and Its Functional Implications
Authors: Zhao Jianan , Wei Kai , Jiang Ping , Chang Cen , Xu Lingxia , Xu Linshuai , Shi Yiming , Guo Shicheng , Xue Yu , He Dongyi
Published: April 2022

Gout, a chronic inflammatory arthritis disease, is characterized by hyperuricemia and caused by interactions between genetic, epigenetic, and metabolic factors. Acute gout symptoms are triggered by the inflammatory response to monosodium urate crystals, which is mediated by the innate immune system and immune cells (e.g., macrophages and neutrophils), the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pro-inflammatory cytokine (e.g., IL-1β) release. Recent studies have indicated that the multiple programmed cell death pathways involved in the inflammatory response include pyroptosis, NETosis, necroptosis, and apoptosis, which initiate inflammatory reactions. In this review, we explore the correlation and interactions among these factors and their roles in the pathogenesis of gout to provide future research directions and possibilities for identifying potential novel therapeutic targets and enhancing our understanding of gout pathogenesis.
Regional Analgesia in Video-Assisted Thoracic Surgery: A Bayesian Network Meta-Analysis
Authors: Lin Jingfang , Liao Yanling , Gong Cansheng , Yu Lizhu , Gao Fei , Yu Jing , Chen Jianghu , Chen Xiaohui , Zheng Ting , Zheng Xiaochun
Published: April 2022

Background

A variety of regional analgesia methods are used during video-assisted thoracic surgery (VATS). Our network meta-analysis (NMA) sought to evaluate the advantages of various methods of localized postoperative pain management in VATS patients.

Methods

PubMed, the Cochrane Library, and EMBASE were searched from their date of inception to May 2021 for randomized controlled trials (RCTs) comparing two or more types of locoregional analgesia in adults using any standardized clinical criteria. This was done using Bayesian NMA.

Results

A total of 3,563 studies were initially identified, and 16 RCTs with a total of 1,144 participants were ultimately included. These studies, which spanned the years 2014 to 2021 and included data from eight different countries, presented new information. There were a variety of regional analgesia techniques used, and in terms of analgesic effect, thoracic epidural anesthesia (TEA) [SMD (standard mean difference) = 1.12, CrI (Credible interval): (−0.08 to −2.33)], thoracic paravertebral block (TPVB) (SMD = 0.67, CrI: (−0.25 to 1.60) and erector spinae plane block (ESPB) (SMD = 0.34, CrI: (−0.5 to 1.17) were better than other regional analgesia methods.

Conclusion

Overall, these findings show that TEA, TPVB and ESPB may be effective forms of regional analgesia in VATS. This research could be a valuable resource for future efforts regarding the use of thoracic regional analgesia and enhanced recovery after surgery.

Systematic Review Registration

Identifier [PROSPERO CRD42021253218].
Rapid and Accurate Detection of SARS Coronavirus 2 by Nanopore Amplicon Sequencing
Authors: Li Xiao-xiao , Li Chao , Du Peng-cheng , Li Shao-yun , Yu Le , Zhao Zhi-qiang , Liu Ting-ting , Zhang Cong-kai , Zhang Sen-chao , Zhuang Yu , Dong Chao-ran , Ge Qing-gang
Published: April 2022

Objective

We aimed to evaluate the performance of nanopore amplicon sequencing detection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples.

Method

We carried out a single-center, prospective cohort study in a Wuhan hospital and collected a total of 86 clinical samples, including 54 pharyngeal swabs, 31 sputum samples, and 1 fecal sample, from 86 patients with coronavirus disease 2019 (COVID-19) from Feb 20 to May 15, 2020. We performed parallel detection with nanopore-based genome amplification and sequencing (NAS) on the Oxford Nanopore Technologies (ONT) minION platform and routine reverse transcription quantitative polymerase chain reaction (RT-qPCR). In addition, 27 negative control samples were detected using the two methods. The sensitivity and specificity of NAS were evaluated and compared with those of RT-qPCR.

Results

The viral read number and reference genome coverage were both significantly different between the two groups of samples, and the latter was a better indicator for SARS-CoV-2 detection. Based on the reference genome coverage, NAS revealed both high sensitivity (96.5%) and specificity (100%) compared with RT-qPCR (80.2 and 96.3%, respectively), although the samples had been stored for half a year before the detection. The total time cost was less than 15 h, which was acceptable compared with that of RT-qPCR (∼2.5 h). In addition, the reference genome coverage of the viral reads was in line with the cycle threshold value of RT-qPCR, indicating that this number could also be used as an indicator of the viral load in a sample. The viral load in sputum might be related to the severity of the infection, particularly in patients within 4 weeks after onset of clinical manifestations, which could be used to evaluate the infection.

Conclusion

Our results showed the high sensitivity and specificity of the NAS method for SARS-CoV-2 detection compared with RT-qPCR. The sequencing results were also used as an indicator of the viral load to display the viral dynamics during infection. This study proved the wide application prospect of nanopore sequencing detection for SARS-CoV-2 and may more knowledge about the clinical characteristics of COVID-19.
Prospective Comparison Between Shotgun Metagenomics and Sanger Sequencing of the 16S rRNA Gene for the Etiological Diagnosis of Infections
Authors: Lamoureux Claudie , Surgers Laure , Fihman Vincent , Gricourt Guillaume , Demontant Vanessa , Trawinski Elisabeth , N’Debi Melissa , Gomart Camille , Royer Guilhem , Launay Nathalie , Le Glaunec Jeanne-Marie , Wemmert Charlotte , La Martire Giulia , Rossi Geoffrey , Lepeule Raphaël , Pawlotsky Jean-Michel , Rodriguez Christophe , Woerther Paul-Louis
Published: April 2022

Bacteriological diagnosis is traditionally based on culture. However, this method may be limited by the difficulty of cultivating certain species or by prior exposure to antibiotics, which justifies the resort to molecular methods, such as Sanger sequencing of the 16S rRNA gene (Sanger 16S). Recently, shotgun metagenomics (SMg) has emerged as a powerful tool to identify a wide range of pathogenic microorganisms in numerous clinical contexts. In this study, we compared the performance of SMg to Sanger 16S for bacterial detection and identification. All patients’ samples for which Sanger 16S was requested between November 2019 and April 2020 in our institution were prospectively included. The corresponding samples were tested with a commercial 16S semi-automated method and a semi-quantitative pan-microorganism DNA- and RNA-based SMg method. Sixty-seven samples from 64 patients were analyzed. Overall, SMg was able to identify a bacterial etiology in 46.3% of cases (31/67) vs. 38.8% (26/67) with Sanger 16S. This difference reached significance when only the results obtained at the species level were compared (28/67 vs. 13/67). This study provides one of the first evidence of a significantly better performance of SMg than Sanger 16S for bacterial detection at the species level in patients with infectious diseases for whom culture-based methods have failed. This technology has the potential to replace Sanger 16S in routine practice for infectious disease diagnosis.
Physical Disturbance Reduces Cyanobacterial Relative Abundance and Substrate Metabolism Potential of Biological Soil Crusts on a Gold Mine Tailing of Central China
Authors: Xiao Jingshang , Lan Shubin , Zhang Zulin , Yang Lie , Qian Long , Xia Ling , Song Shaoxian , Farías María E. , Torres Rosa María , Wu Li
Published: April 2022

As the critical ecological engineers, biological soil crusts (biocrusts) are considered to play essential roles in improving substrate conditions during ecological rehabilitation processes. Physical disturbance, however, often leads to the degradation of biocrusts, and it remains unclear how the physical disturbance affects biocrust microorganisms and their related metabolism. In this study, the photosynthetic biomass (indicated by chlorophyll a), nutrients, enzyme activities, and bacterial communities of biocrusts were investigated in a gold mine tailing of Central China to evaluate the impact of physical disturbance on biocrusts during the rehabilitation process of gold mine tailings. The results show that physical disturbance significantly reduced the photosynthetic biomass, nutrient contents (organic carbon, ammonium nitrogen, nitrate nitrogen, and total phosphorus), and enzyme activities (β-glucosidase, sucrase, nitrogenase, neutral phosphatase, and urease) of biocrusts in the mine tailings. Furthermore, 16S rDNA sequencing showed that physical disturbance strongly changed the composition, structure, and interactions of the bacterial community, leading to a shift from a cyanobacteria dominated community to a heterotrophic bacteria (proteobacteria, actinobacteria, and acidobacteria) dominated community and a more complex bacterial network (higher complexity, nodes, and edges). Altogether, our results show that the biocrusts dominated by cyanobacteria could also develop in the tailings of humid region, and the dominants (e.g., Microcoleus) were the same as those from dryland biocrusts; nevertheless, physical disturbance significantly reduced cyanobacterial relative abundance in biocrusts. Based on our findings, we propose the future work on cyanobacterial inoculation (e.g., Microcoleus), which is expected to promote substrate metabolism and accumulation, ultimately accelerating the development of biocrusts and the subsequent ecological restoration of tailings.
Saturated Dissolved Oxygen Concentration in in situ Fragmentation Bioleaching of Copper Sulfide Ores
Authors: Huang Ming-Qing , Zhang Ming , Zhan Shu-Lin , Chen Lin , Xue Zhen-Lin
Published: April 2022

In situ fragmentation bioleaching is a promising way to perform deep mining safely, economically, and in an environmentally friendly manner, where oxygen plays a critical role in microbial growth and mineral dissolution. However, the lack of oxygen limits the implementation of in-situ fragmentation bioleaching. To overcome this limitation, aeration was proposed, with saturated dissolved oxygen concentration as an important indicator. Orthogonal experiments were conducted to measure saturated dissolved oxygen concentration at various temperature, pH, and electrolyte (ferrous sulfate, ferric sulfate, copper sulfate, and sulfuric acid) concentration conditions. Experimental data were analyzed by Python programming language and least squares method to obtain a saturated dissolved oxygen concentration model. Results showed that temperature had the most significant effect on oxygen solubility, which was concluded by comparing the results of surface fitting based on the least squares method. At 30–40°C, the saturated dissolved oxygen concentration decreased faster as metal ions concentration increased. The conjoint effect of the five variables on oxygen solubility showed that pH was linearly negatively related to oxygen solubility. Additionally, a mathematical model was also proposed to predict the saturated dissolved oxygen concentration in in situ fragmentation bioleaching of copper sulfide ores. This work enables bioleaching processes to be modeled and controlled more effectively.
Development and Validation of Novel Prognostic Models for Immune-Related Genes in Osteosarcoma
Authors: Li Junqing , Su Li , Xiao Xing , Wu Feiran , Du Guijuan , Guo Xinjun , Kong Fanguo , Yao Jie , Zhu Huimin
Published: April 2022

Immunotherapy has shown excellent therapeutic effects on various malignant tumors; however, to date, immunotherapy for osteosarcoma is still suboptimal. In this study, we performed comprehensive bioinformatic analysis of immune-related genes (IRGs) and tumor-infiltrating immune cells (TIICs). Datasets of differentially expressed IRGs were extracted from the GEO database (GSE16088). The functions and prognostic values of these differentially expressed IRGs were systematically investigated using a series of bioinformatics methods. In addition, CCK8 and plate clone formation assays were used to explore the effect of PGF on osteosarcoma cells, and twenty-nine differentially expressed IRGs were identified, of which 95 were upregulated and 34 were downregulated. Next, PPI was established for Identifying Hub genes and biology networks by Cytoscape. Six IRGs (APLNR, TPM2, PGF, CD86, PROCR, and SEMA4D) were used to develop an overall survival (OS) prediction model, and two IRGs (HLA-B and PGF) were used to develop a relapse-free survival (RFS) prediction model. Compared with the low-risk patients in the training cohort (GSE39058) and TARGET validation cohorts, high-risk patients had poorer OS and RFS. Using these identified IRGs, we used OS and RFS prediction nomograms to generate a clinical utility model. The risk scores of the two prediction models were associated with the infiltration proportions of some TIICs, and the activation of memory CD4 T-cells was associated with OS and RFS. CD86 was associated with CTLA4 and CD28 and influenced the infiltration of different TIICs. In vitro experiments showed that the knockdown of PGF inhibited the proliferation and viability of osteosarcoma cells. In conclusion, these findings help us better understand the prognostic roles of IRGs and TIICs in osteosarcoma, and CD86 and PGF may serve as specific immune targets.
Novel PANK2 Mutations in Patients With Pantothenate Kinase-Associated Neurodegeneration and the Genotype–Phenotype Correlation
Authors: Li Wen-Bin , Shen Nan-Xiang , Zhang Chao , Xie Huan-Cheng , Li Zong-Yan , Cao Li , Chen Li-Zhi , Zeng Yuan-jin , Fan Cui-Xia , Chen Qian , Shi Yi-Wu , Song Xing-Wang
Published: April 2022

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder caused by mutations in the mitochondrial pantothenate kinase 2 (PANK2) gene and displays an inherited autosomal recessive pattern. In this study, we identified eight PANK2 mutations, including three novel mutations (c.1103A > G/p.D368G, c.1696C > G/p.L566V, and c.1470delC/p.R490fs494X), in seven unrelated families with PKAN. All the patients showed an eye-of-the-tiger sign on the MRI, six of seven patients had dystonia, and two of seven patients had Parkinsonism. Biallelic mutations of PANK2 decreased PANK2 protein expression and reduced mitochondrial membrane potential in human embryonic kidney (HEK) 293T cells. The biallelic mutations from patients with early-onset PKAN, a severity phenotype, showed decreased mitochondrial membrane potential more than that from late-onset patients. We systematically reviewed all the reported patients with PKAN with PANK2 mutations. The results indicated that the early-onset patients carried a significantly higher frequency of biallelic loss-of-function (LoF) mutations compared to late-onset patients. In general, patients with LoF mutations showed more severe phenotypes, including earlier onset age and loss of gait. Although there was no significant difference in the frequency of biallelic missense mutations between the early-onset and late-onset patients, we found that patients with missense mutations in the mitochondrial trafficking domain (transit peptide/mitochondrial domain) of PANK2 exhibited the earliest onset age when compared to patients with mutations in the other two domains. Taken together, this study reports three novel mutations and indicates a correlation between the phenotype and mitochondrial dysfunction. This provides new insight for evaluating the clinical severity of patients based on the degree of mitochondrial dysfunction and suggests genetic counseling not just generalized identification of mutated PANK2 in clinics.
Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus
Authors: Eide Per Kristian , Lashkarivand Aslan , Hagen-Kersten Åsmund Aleksander , Gjertsen Øivind , Nedregaard Bård , Sletteberg Ruth , Løvland Grethe , Vatnehol Svein Are Sirirud , Pripp Are Hugo , Valnes Lars Magnus , Ringstad Geir
Published: April 2022

Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.
Single-Cell Profiling of Tumor Microenvironment Heterogeneity in Osteosarcoma Identifies a Highly Invasive Subcluster for Predicting Prognosis
Authors: Guo Junfeng , Tang Hong , Huang Pan , Guo Junfeng , Shi Youxing , Yuan Chengsong , Liang Taotao , Tang Kanglai
Published: April 2022

Osteosarcoma is the most common malignant bone tumor in adolescents, and metastasis is the key reason for treatment failure and poor prognosis. Once metastasis occurs, the 5-year survival rate is only approximately 20%, and assessing and predicting the risk of osteosarcoma metastasis are still difficult tasks. In this study, cellular communication between tumor cells and nontumor cells was identified through comprehensive analysis of osteosarcoma single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, illustrating the complex regulatory network in the osteosarcoma microenvironment. In line with the heterogeneity of osteosarcoma, we found subpopulations of osteosarcoma cells that highly expressed COL6A1, COL6A3 and MIF and were closely associated with lung metastasis. Then, BCDEG, a reliable risk regression model that could accurately assess the metastasis risk and prognosis of patients, was established, providing a new strategy for the diagnosis and treatment of osteosarcoma.
Gynecologic Oncology and Inclusion of Women Into the Surgical Workforce: The Canary in This Coal Mine
Authors: Hong Linda J. , Rubinsak Lisa , Benoit Michelle F. , Teoh Deanna , Chandavarkar Uma , Brockmeyer Amy , Stevens Erin , Ioffe Yevgeniya , Temkin Sarah M.
Published: April 2022

Objective

Women make up a majority of the gynecologic oncology workforce. Increasing the numbers of women in leadership has been proposed as a path towards professional gender equity. This study examined whether leadership gender and departmental infrastructure impact the work environment for women gynecologic oncologists.

Methods

Members of a 472-member private Facebook group “Women of Gynecologic Oncology” (WGO) who self-identified as women gynecologic oncologists provided demographics, practice infrastructure, personal experience with workplace bullying, gender discrimination, microaggressions using a REDcap survey platform.

Results

Of 250 (53%) respondents to this survey, most were younger than age 50 years (93.6%); White (82.2%) and non-Hispanic (94.3%); married (84.7%); and parenting (75.2%). Practice environments included academic (n=152, 61.0%), hospital employed (n=57, 22.9%), and private practice (n=31, 12.4%), and 89.9% supervised trainees. A significant percent of respondents had experienced bullying (52.8%), gender discrimination (57%) and microaggressions (83%). Age, race, ethnicity, practice setting, or mentorship were not statistically significantly associated with these experiences. Reported perpetrators were varied and included colleagues (84%), patients (44%), staff (41%), administrators (18%), and trainees (16%). Prevalence of bullying (55.0 vs 47.7%, p=0.33), gender discrimination (59.1 vs 52.3%, p=0.33) and microaggressions (83.3 vs 83.0%, p=1.00) were similar irrespective of departmental leadership gender.

Conclusions

Women gynecologic oncologists report a high prevalence of workplace bullying, gender discrimination and microaggressions regardless of the gender of their immediate leadership. Proactive and deliberate structural interventions to improve the work environment for surgeons who are women are urgently needed.
Mitochondria Dysfunction-Mediated Molecular Subtypes and Gene Prognostic Index for Prostate Cancer Patients Undergoing Radical Prostatectomy or Radiotherapy
Authors: Feng Dechao , Shi Xu , Zhang Facai , Xiong Qiao , Wei Qiang , Yang Lu
Published: April 2022

Background

Given the age relevance of prostate cancer (PCa) and the role of mitochondrial dysfunction (MIDS) in aging, we orchestrated molecular subtypes and identified key genes for PCa from the perspective of MIDS.

Methods

Cluster analysis, COX regression analysis, function analysis, and tumor immune environment were conducted. We performed all analyses using software R 3.6.3 and its suitable packages.

Results

CXCL14, SFRP4, and CD38 were eventually identified to classify the PCa patients in The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) dataset into two distinct clusters. Patients in the cluster 2 had shorter BCR-free survival than those in the cluster 1 in terms of both TCGA database and GEO dataset. We divided the patients from the TCGA database and the GEO dataset into high- and low-risk groups according to the median of MIDS-related genetic prognostic index. For patients in the TCGA database, the biochemical recurrence (BCR) risk in high-risk group was 2.34 times higher than that in low-risk group. Similarly, for patients in the GEO dataset, the risk of BCR and metastasis in high-risk group was 2.35 and 3.04 times higher than that in low-risk group, respectively. Cluster 2 was closely associated with advanced T stage and higher Gleason score for patients undergoing radical prostatectomy or radiotherapy. For patients undergoing radical prostatectomy, the number of CD8+ T cells was significantly lower in cluster 2 than in cluster 1, while cluster 2 had significantly higher stromal score than cluster 1. For patients undergoing radical radiotherapy, cluster 2 had significantly higher level of CD8+ T cells, neutrophils, macrophages, dendritic cells, stromal score, immune score, and estimate score, but showed lower level of tumor purity than cluster 1.

Conclusions

We proposed distinctly prognosis-related molecular subtypes at genetic level and related formula for PCa patients undergoing radical prostatectomy or radiotherapy, mainly to provide a roadmap for precision medicine.
Variations in Circulating Levels of Angiopoietin-2 Over Time Are Predictive of Ramucirumab–Paclitaxel Therapy Outcome in Advanced Gastric Cancer: Results of Prospective Study
Authors: D’Alessandro Rosalba , Refolo Maria Grazia , Schirizzi Annalisa , De Leonardis Giampiero , Donghia Rossella , Guerra Vito , Giannelli Gianluigi , Lolli Ivan Roberto , Laterza Maria Maddalena , De Vita Ferdinando , Messa Caterina , Lotesoriere Claudio
Published: April 2022

The combination of paclitaxel and ramucirumab is the second-line therapy of choice in the treatment of advanced gastric cancer. To date, no biomarkers are available in gastric cancer to predict the outcome of antiangiogenic therapy. The present prospective study included 35 patients undergoing second-line therapy with ramucirumab and paclitaxel. Serum samples were systematically collected from the beginning of therapy and at each cycle until disease progression. Multiplex analysis of a panel of angiogenic factors identified markers for which the changes at defined time intervals were significantly different in patients with progression-free survival ≤3 (Rapid Progression Group) compared to those with progression-free survival >3 (Control Disease Group). Comparative analysis revealed significantly different results in the two groups of patients for VEGFC and Angiopoietin-2, both involved in angiogenesis and lymphangiogenesis. VEGFC increased in the progressive-disease group, while it decreased in the control-disease group. This decrease persisted beyond the third cycle, and it was statistically significant compared to the basal level in patients with longer progression-free survival. Angiopoietin-2 decreased significantly after 2 months of therapy. At progression time, there was a significant increase in VEGFC and Angiopoietin-2, suggesting the activation pathways counteracting the blockade of VEGFR2 by ramucirumab. Overall results showed that a greater change in VEGFC and Angiopoietin-2 levels measured at the beginning of the third cycle of therapy corresponded to a lower risk of progression and thus to longer progression-free survival.
The Transition From Ambrisentan to Macitentan in Patients With Pulmonary Arterial Hypertension: A Real-word Prospective Study
Authors: Chen Yusi , Luo Jun , Chen Jingyuan , Kotlyar Eugene , Li Zilu , Chen Wenjie , Li Jiang
Published: April 2022

Background: In a long-term event-driven trial, macitentan has demonstrated beneficial time to clinical worsening in patients with pulmonary arterial hypertension (PAH) and reduced PAH-related hospitalization rates compared with placebo. Macitentan is the most recently approved endothelin receptor antagonist (ERA) and is the first ERA that has shown efficacy for morbidity and mortality in PAH patients; therefore, patients and physicians may consider converting treatment from ambrisentan to macitentan. Our study evaluated the safety, efficacy, and quality of life in PAH patients transitioning from ambrisentan to macitentan.

Methods: This was a real-world, prospective study with a 12-month follow-up. PAH patients who had received stable doses of ambrisentan for over 3 months, were within the World Health Organization Functional Class II/III, and 6-min walk distance ≥ of 250 m were enrolled. The study included a screening period, followed by a transition phase, after which patients entered the long-term follow-up. Clinical data and treatment satisfaction outcomes were collected to assess and monitor the safety and efficacy of the transition. The trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; No. ChiCTR2000034898).

Results: One hundred and fifty-seven enrolled PAH patients completed the transition. All criteria for continuous treatment transition were met by 145 patients (92.4%). Results showed improvements in exercise capacity, cardiac function, and hemodynamics compared with baseline. During the process, 4 patients discontinued macitentan due to adverse events. There was no statistical difference in the overall incidence of adverse events before and after the transition.

Conclusion: Transition to macitentan from ambrisentan was successful and well-tolerated by PAH patients, and was associated with greater efficacy and satisfaction.
The Role of Flavonoids in the Osteogenic Differentiation of Mesenchymal Stem Cells
Authors: Zhang Jinli , Liu Zhihe , Luo Yang , Li Xiaojian , Huang Guowei , Chen Huan , Li Aiguo , Qin Shengnan
Published: April 2022

Mesenchymal stem cells (MSCs) play an important role in developing bone tissue engineered constructs due to their osteogenic and chondrogenic differentiation potential. MSC-based tissue engineered constructs are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and directional differentiation. Flavonoids are a secondary metabolite, widely existed in nature and have many biological activities. For a long time, researchers have confirmed the anti-osteoporosis effect of flavonoids through in vitro cell experiments, animal studies. In recent years the regulatory effects of flavonoids on mesenchymal stem cells (MSCs) differentiation have been received increasingly attention. Recent studies revealed flavonoids possess the ability to modulate self-renewal and differentiation potential of MSCs. In order to facilitate further research on MSCs osteogenic differentiation of flavonoids, we surveyed the literature published on the use of flavonoids in osteogenic differentiation of MSCs, and summarized their pharmacological activities as well as the underlying mechanisms, aimed to explore their promising therapeutic application in bone disorders and bone tissue engineered constructs.