bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined effects of sodium-glucose cotransporter 2 inhibitor and angiotensin receptor-neprilysin inhibitor on renal function in cardiovascular disease patients with type 2 diabetes mellitus: a retrospective cohort study
Authors: Xu Ling , Chen Bo , Zhang Hua , Zhu Dan
Published: January 2024

Background

Angiotensin receptor/neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined.

Methods

This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month.

Results

In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up.

Conclusion

In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone.

Clinical trial registration

clinicaltrials.gov, identifier NCT05922852.
Prognostic indicators in pituitary adenoma surgery: a comprehensive analysis of surgical outcomes and complications
Authors: Riley George , Scheyer Nicolas , Klein Marc , Merlot Isabelle , Guerci Bruno , Jeanbert Elodie , Demarquet Lea
Published: January 2024

Objective

The primary aim of this study was to identify predictive factors associated with onset of de-novo clinically significant pituitary insufficiencies following endoscopic endonasal surgery (EES) for pituitary adenomas. The secondary objective explored the predictive factors of surgical success

Methods

A retrospective analysis was conducted on 211 patients who underwent EES. Logistic regression models were employed for the primary and secondary objectives. Patients were stratified into specific groups based on surgical indications and prolactin levels for nuanced analysis.

Results

Significant predictors for de-novo pituitary insufficiencies included male sex (OR 3.3, CI95% 1.3-8.1, p=0.01), immediate postoperative insufficiencies (OR 5.6, CI95% 2.8-11.1, p<0.001), and HYPRONOS criteria (OR 5.7, CI95% 1.6-20.9, p=0.008). For surgical success, preoperative insufficiencies (OR 0.7, CI95% 0.5-0.9, p=0.008), repeat surgeries (OR 0.1, CI95% 0-0.4, p=0.001), and gonadotroph or somatotroph adenomas were significant. Age and adenoma size were not predictive in multivariate analysis. Furthermore, we observed a “dip and recover” effect of prolactin after surgery and lower prolactin levels at follow-up (< 3 ng/ml) are correlated with more anterior pituitary insufficiencies than normoprolactinemic patients (p = 0.004).

Conclusion

This study identifies key predictors for outcomes in pituitary surgery. Our research is the first to employ individualized success criteria for EES, challenging existing perceptions about the role of age and adenoma size. These findings open avenues for nuanced, individualized preoperative risk assessment and postoperative management.
Mechanical response analysis of the wide-chord hollow fan blade considering the fluid–structure interaction
Authors: Zhang Xinzhe , Wang Xian , Li Guoju , Zhang Yamin , Zhang Guojie
Published: January 2024

The aero-engine wide-chord hollow fan blade with a cavity stiffener structure can effectively reduce the weight and greatly increase the rotational speed. However, during the high-speed rotation process of the hollow fan, there is a strong coupling effect between the solid domain of the blade and the incoming air. This effect leads to a certain deformation of the rotor blade, which has a large impact on the structural strength of the blade. Aiming at the problem of the fluid–structure interaction in its operation, the finite-element method was used to simulate the two-layer structure of the TC4 titanium alloy wide-chord hollow fan blade. The centrifugal force and fluid–structure coupling effect were considered when carrying out the research on the structural mechanical characteristics of the blade. The results show that the maximum equivalent stress of the blade considering the fluid–structure coupling effect is 508 MPa at the rotational speed of 2,900 r/min, which is approximately 18% higher than the maximum stress when only the centrifugal force is considered. This phenomenon indicates that the effect of aerodynamic force on the blade stress cannot be ignored. The stress concentration area of the blade is located in the third stiffener from the leading edge and near the root of the blade, and the aerodynamic force has a more significant effect on the radial stress distribution of the blade. Further analysis of the equivalent stress distribution along the blade tip direction shows a trend of first increasing and then decreasing. The maximum equivalent stress appears at a distance of 30 mm up to the bottom of the stiffener.
A dual source fed eleven level switched capacitor multilevel inverter with voltage boosting capability
Authors: Hussain Md Tahmid , Tariq Mohd , Sarwar Adil , Ahmad Shafiq , Poshtan Majid , Mahmoud Haitham A.
Published: January 2024

This work introduces an 11-level switched-capacitor multilevel inverter (SCMLI) designed for solar photo-voltaic (PV) applications, capitalizing on the growing popularity of multilevel inverters due to their superior power quality. With a 1.67-times boosting capability, the proposed SCMLI employs 10 switches, 2 DC supplies, and 2 capacitors to achieve an 11-level output voltage waveform. The topology requires only seven driver circuits, incorporating 2 bidirectional switches and 3 complementary pairs of switches. The proposed inverter has intrinsic capacitor self-balancing features since the capacitors are connected across the DC voltage source at different times throughout a basic cycle to charge the capacitors at a level of input voltage. A thorough comparison between the topology and recently developed SCMLI’s has been presented. The comparison demonstrates the effectiveness in terms of switches, capacitors, sources, efficiency, total standing voltage (TSV), and boosting capacity. To experimentally validate its performance, the suggested SCMLI undergoes testing using a frequency-based switching method. The topology exhibits low total harmonic distortion (THD) of 7.65% in its output voltage waveform and 0.89% in the output current waveform.
A novel machine learning ensemble forecasting model based on mixed frequency technology and multi-objective optimization for carbon trading price
Authors: Li Zejun , Long Jun , Li Lue
Published: January 2024

Carbon trading prices are crucial for carbon emissions and transparent carbon market pricing. Previous studies mainly focused on data mining in the prediction direction to quantify carbon trading prices. Although the prospect of high-frequency data forecasting mechanisms is considerable, more mixed-frequency ensemble forecasting is needed for carbon trading prices. Therefore, this article designs a new type of ensemble prediction model to increase the scope of model research. The module is divided into three parts: data denoising, mixed frequency and machine learning, multi-objective optimization, and ensemble forecasting. Precisely, the data preprocessing technology enhanced by adopting a self-attention mechanism can better remove noise and extract effective features. Furthermore, mixed frequency technology is introduced into the machine learning model to achieve more comprehensive and efficient prediction, and a new evaluation criterion is proposed to measure the optimal submodel. Finally, the ensemble model based on deep learning strategy can effectively integrate the advantages of high-frequency and low-frequency data in complex datasets. At the same time, a new multi-objective optimization algorithm is proposed to optimize the parameters of the ensemble model, significantly improving the predictive ability of the integrated module. The results of four experiments and the Mean Absolute Percent Error index of the proposed model improved by 28.3526% compared to machine learning models, indicating that the ensemble model established can effectively address the time distribution characteristics and uncertainty issues predicted by carbon trading price models, which helps to mitigate climate change and develop a low-carbon economy.
Quantifying interactions in the water-energy-food nexus: data-driven analysis utilizing a causal inference method
Authors: Saed Behdad , Elshorbagy Amin , Razavi Saman
Published: January 2024

Introduction: There is a pressing need for a holistic approach to optimize water-energy-food (WEF) resources management and to address their interlinkages with other resources due to population growth, socio-economic development, and climate change. However, the structural and spatial extent of the WEF system boundaries cause exponential growth in computational complexity, making exploratory data analysis crucial to obtain insight into the system’s characteristics and focus on critical components.

Methods: This study conducts a multiscale investigation of the WEF nexus within the Canadian prairie provinces (Alberta, Saskatchewan, and Manitoba), utilizing causal-correlational analysis and the multispatial Convergence Cross Mapping (mCCM) method. Initially, we employed regression analysis to establish equations, along with their coefficients of determination (R2), to identify patterns among pairs of WEF sectors, gross domestic product (GDP), and greenhouse gas (GHG) emissions. Subsequently, we conducted a causal analysis between correlated pairs using the mCCM method to explore the cause-and-effect relationships between sector pairs within the Canadian prairie provinces; both individually and as a single unit over the period 1990-2020.

Results and discussion: Results show that energy and water are the most influential sectors on GHG emissions and GDP in the prairies as a whole. Energy has a stronger influence on GHG compared to water and food sectors, while water has the strongest causal influence on the GDP of Alberta, and food and energy do so for Saskatchewan and Manitoba, respectively. The trade-offs for improving WEF nexus security strongly depend on the scale of the system under investigation, highlighting the need for careful deliberations around boundary judgment for decision-making. This study provides a better understanding of the WEF-GDP-GHG nexus in the Canadian prairies and existing interrelationships among the aforementioned sectors, helping to build more efficient WEF nexus models for further simulation and scenario analysis.
Novel cis compound heterozygous variants in MYO6 causes early onset of non-syndromic hearing loss in a Chinese family
Authors: Ji Haiting , Zhang Lichun , Hussain Hafiz Muhammad Jafar , Aftab Ayesha , Yu Huiqian , Xiao Min
Published: January 2024

Background: Mutations in the MYO6 gene have been associated with both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL), with a cumulative identification of 125 pathogenic variants. To investigate the underlying genetic factor within a Chinese family affected with heriditary hearing loss, prompted the utilization of high-throughput sequencing.

Method: A detailed clinical investigation was performed. Genetic testing was performed by using target panel sequencing, and Sanger sequencing. Targeted sequencing identified the variants and Sanger sequencing was employed to validate segregation of the identified variants within family. Additionally, bioinformatics analysis was performed to strengthen our findings.

Results: Clinical investigation revealed the family members were affected by progressive and sensorineural hearing loss with an onset around 8–10 years old. Furthermore, genetic testing identified novel MYO6 variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn], positioned in a cis pattern, as plausible pathogenic contributors to early-onset hearing loss characterized by a severe and progressive course. Moreover, bioinformatics analysis showd disruptin in hydrogen bonding of mutant amino acids with interactive amino acids.

Conclusion: Our research uncovered a relationship between mutations in the MYO6 gene and non-syndromic hearing loss. We identified two variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn] in MYO6 as strong candidates responsible for the observed progressive hereditary hearing loss. This study not only adds to our knowledge about hearing problems related to MYO6 but also reveals the presence of monogenic compound heterozygosity. Our study will provide a new sight for genetic diagnosis in such patients and their management for future use.
Diversity of antibiotic resistance gene variants at subsequent stages of the wastewater treatment process revealed by a metagenomic analysis of PCR amplicons
Authors: Gorecki Adrian , Ostapczuk Piotr , Dziewit Lukasz
Published: January 2024

Wastewater treatment plants have been recognised as point sources of various antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARG) which are considered recently emerging biological contaminants. So far, culture-based and molecular-based methods have been successfully applied to monitor antimicrobial resistance (AMR) in WWTPs. However, the methods applied do not permit the comprehensive identification of the true diversity of ARGs. In this study we applied next-generation sequencing for a metagenomic analysis of PCR amplicons of ARGs from the subsequent stages of the analysed WWTP. The presence of 14 genes conferring resistance to different antibiotic families was screened by PCR. In the next step, three genes were selected for detailed analysis of changes of the profile of ARG variants along the process. A relative abundance of 79 variants was analysed. The highest diversity was revealed in the ermF gene, with 52 variants. The relative abundance of some variants changed along the purification process, and some ARG variants might be present in novel hosts for which they were currently unassigned. Additionally, we identified a pool of novel ARG variants present in the studied WWTP. Overall, the results obtained indicated that the applied method is sufficient for analysing ARG variant diversity.
Establishing wildflower meadows in anthropogenic landscapes
Authors: Bretzel Francesca , Vannucchi Francesca , Pezzarossa Beatrice , Paraskevopoulou Angeliki , Romano Daniela
Published: January 2024

In anthropized sites, the establishment and management of sustainable and nature-based wildflower meadow solutions exclude fertilization, weeding, and watering, and reduce the frequency of mowing. Once such inputs have been reduced, the ecosystem services generated by the vegetation result in an increase in biodiversity in terms of plant and animal species, an improvement in soil quality and biota, the mitigation of air pollutants and carbon sequestration, as well as a reduction in soil temperature. Environmental education and citizen science are also some of the benefits of this type of vegetation, especially in urban areas. Herbaceous meadow-like communities, which are composed of forbs only or a combination of graminoid and forb species, are usually established by sowing. The seeds are available for purchase from specialized seed producers as single species or in a mix, some companies offer mixes composed of garden species with botanical species. Donor meadows are the sources of the genetic material and the template to reproduce the meadow herbaceous community at different sites through seed harvest, hay harvest, and the displacement of soil with its seed bank. Management techniques, such as soil preparation, determining the appropriate sowing and mowing time, can help in establishing and maintaining the most desirable species. The suspension of urban turf mowing allows the growth of the natural seed bank, which in unproductive soils facilitates the appearance of many pollinator-friendly herbaceous species. With the appropriate pedological conditions and management, the natural urban herbaceous vegetation thus provides beautiful and rich plant communities, which are also easy to maintain. This review identifies the best practices through a qualitative selection of case studies related to the various methods to establish wildflower meadows in the urban infrastructure and the main constraints such as the lack of a suitable seed market.
Circulating microbiome analysis in patients with perioperative anaphylaxis
Authors: de Chaisemartin Luc , Ciocan Dragos , Gouel-Chéron Aurélie , Granger Vanessa , Longrois Dan , Montravers Philippe , Cassard Anne-Marie , Chollet-Martin Sylvie
Published: January 2024

Background

Perioperative anaphylaxis is a rare and acute systemic manifestation of drug-induced hypersensitivity reactions that occurs following anesthesia induction; the two main classes of drugs responsible for these reactions being neuromuscular blocking agents (NMBA) and antibiotics. The sensitization mechanisms to the drugs are not precisely known, and few risk factors have been described. A growing body of evidence underlines a link between occurrence of allergy and microbiota composition. However, no data exist on microbiota in perioperative anaphylaxis. The aim of this study was to compare circulating microbiota richness and composition between perioperative anaphylaxis patients and matched controls.

Methods

Circulating 16s rDNA was quantified and sequenced in serum samples from 20 individuals with fully characterized IgE-mediated NMBA-related anaphylaxis and 20 controls matched on sex, age, NMBA received, type of surgery and infectious status. Microbiota composition was analyzed with a published bioinformatic pipeline and links with patients clinical and biological data investigated.

Results

Analysis of microbiota diversity showed that anaphylaxis patients seem to have a richer circulating microbiota than controls, but no major differences of composition could be detected with global diversity indexes. Pairwise comparison showed a difference in relative abundance between patients and controls for Saprospiraceae, Enterobacteriaceae, Veillonellaceae, Escherichia-Shigella, Pseudarcicella, Rhodoferax, and Lewinella. Some taxa were associated with concentrations of mast cell tryptase and specific IgE.

Conclusion

We did not find a global difference in terms of microbiota composition between anaphylaxis patient and controls. However, several taxa were associated with anaphylaxis patients and with their biological data. These findings must be further confirmed in different settings to broaden our understanding of drug anaphylaxis pathophysiology and identify predisposition markers.
Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment
Authors: Nguyen William Q. , Chrisman Lauren P. , Enriquez Gail L. , Hooper Madeline J. , Griffin Teresa L. , Ahmad Merjaan , Rahman Sophia , Green Stefan J. , Seed Patrick C. , Guitart Joan , Burns Michael B. , Zhou Xiaolong A.
Published: January 2024

Recent studies have shown a close relationship between cutaneous T-cell lymphoma (CTCL) and its microbiome. CTCL disease progression is associated with gut dysbiosis and alterations in bacterial taxa parallel those observed in immunologically similar atopic dermatitis. Moreover, the microbial profile of lesional skin may predict response to narrowband ultraviolet B (nbUVB), a common skin-directed therapy. However, the relationship between the gut microbiome, an immunologically vital niche, and nbUVB remains unexplored in CTCL. Herein, we performed 16S rRNA sequencing and PICRUSt2 predictive metagenomics on DNA extracted from stool swabs of 13 CTCL patients treated with nbUVB, 8 non-treated patients, and 13 healthy controls. Disease response was assessed with modified Severity Weighted Assessment Tool (mSWAT); of nbUVB-treated patients, 6 improved (decreased mSWAT), 2 remained stable, and 5 worsened (increased mSWAT). Protective commensal bacteria including Lactobacillaceae and Erysipelatoclostridiaceae were significantly less abundant in CTCL patients compared to controls. With treatment, the CTCL gut microbiome exhibited decreased phylogenetic diversity and lower relative abundance of pro-inflammatory Sutterellaceae. Sutterellaceae was also significantly more abundant in patients who worsened, and Eggerthellaceae and Erysipelotrichaceae trended higher in patients who improved. Finally, PICRUSt2 functional predictions based on shifts in abundance of bacterial sequences repeatedly identified alterations in inositol degradation, which plays a key role in host immunomodulation, including inositol phospholipid signaling relevant to T-cell survival and proliferation. Our results bolster the paradigm of gut dysbiosis in CTCL and its functional implications in disease pathogenesis, and further delineate bacterial taxa associated with nbUVB response and with nbUVB treatment itself.
Exposure to common infections may shape basal immunity and potentially HIV-1 acquisition amongst a high-risk population in Coastal Kenya
Authors: Fwambah Lynn , Andisi Cheryl , Streatfield Claire , Bromell Rachel , Hare Jonathan , Esbjörnsson Joakim , Ndung’u Thumbi , Sanders Eduard J. , Hassan Amin S. , Nduati Eunice
Published: January 2024

Introduction

The impact of exposure to endemic infections on basal immunity and susceptibility to HIV-1 acquisition remains uncertain. We hypothesized that exposure to infections such as cytomegalovirus (CMV), malaria and sexually transmitted infections (STIs) in high-risk individuals may modulate immunity and subsequently increase susceptibility to HIV-1 acquisition.

Methods

A case-control study nested in an HIV-1 negative high-risk cohort from Coastal Kenya was used. Cases were defined as volunteers who tested HIV-1 positive during follow-up and had a plasma sample collected 3 ± 2 months prior to the estimated date of HIV-1 infection. Controls were individuals who remained HIV-1 negative during the follow-up and were matched 2:1 to cases by sex, age, risk group and follow-up time. STI screening was performed using microscopic and serologic tests. HIV-1 pre-infection plasma samples were used to determined exposure to CMV and malaria using enzyme-linked immunosorbent assays and to quantify forty-one cytokines and soluble factors using multiplexing assays. Multiplexing data were analyzed using principal component analysis. Associations between cytokines and soluble factors with subsequent HIV-1 acquisition were determined using conditional logistic regression models.

Results and discussion

Overall, samples from 47 cases and 94 controls were analyzed. While exposure to malaria (p=0.675) and CMV (p=0.470) were not associated with HIV-1 acquisition, exposure to STIs was (48% [95% CI, 33.3 – 63] vs. 26% [95% CI, 17.3 – 35.9]. Ten analytes were significantly altered in cases compared to controls and were clustered into four principal components: PC1 (VEGF, MIP-1β, VEGF-C and IL-4), PC2 (MCP-1, IL-2 and IL-12p70), PC3 (VEGF-D) and PC4 (Eotaxin-3). PC1, which is suggestive of a Th2-modulatory pathway, was significantly associated with HIV-1 acquisition after controlling for STIs (adjusted odds ratio, (95% CI), p-value: 1.51 [1.14 – 2.00], p=0.004). Elevation of Th2-associated pathways may dampen responses involved in viral immunity, leading to enhanced susceptibility to HIV-1 acquisition. Immunomodulatory interventions aimed at inhibiting activation of Th2-associated pathways may be an additional strategy to STI control for HIV-1 prevention and may reduce dampening of immune responses to vaccination.
Sublethal heat treatment enhances lactic acid uptake in macrophages via MCT1, leading to reduced paraspeckle formation and a subsequent decrease in macrophage pyroptosis
Authors: Fan Zhuoyang , Yang Guowei , Luo Rongkui , Qu Xudong , Ye Xiaodan , Wang Jianhua , Yan Zhiping , Shu Minfeng , Zhang Wei , Liu Rong
Published: January 2024

Introduction

Heat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment.

Methods

We observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production. The study focused on how this pH shift, crucial in tumor progression and resistance, influences macrophage polarization, especially towards the M2 phenotype known for tumor-promoting functions. We also examined the upregulation of MCT1 expression post sublethal heat treatment and its primary role in lactic acid transport.

Results

Notably, the study found minimal disparity in MCT1 expression between hepatocellular carcinoma patients and healthy liver tissues, highlighting the complexity of cancer biology. The research further revealed an intricate relationship between lactic acid, MCT1, and the inhibition of macrophage pyroptosis, offering significant insights for therapeutic strategies targeting the tumor immune environment. Post sublethal heat treatment, a reduction in paraspeckle under lactic acid exposure was observed, indicating diverse cellular impacts. Additionally, PKM2 was identified as a key molecule in this context, with decreased levels after sublethal heat treatment in the presence of lactic acid.

Discussion

Collectively, these findings illuminate the intertwined mechanisms of sublethal heat treatments, metabolic alterations, and immune modulation in the tumor milieu, providing a deeper understanding of the complex interplay in cancer biology and treatment.
Ankylosing spondylitis: acute/subacute vs. chronic iridocyclitis - a bidirectional two-sample Mendelian randomization study
Authors: Li Hui , Xu Yingying , Guo Qin , Zhang Tiantian , Zhou Shufen , Wu Meimei , Cheng Yuanxiong , Guo Chengshan
Published: January 2024

Background

Observational studies found associations between ankylosing spondylitis (AS) and iridocyclitis (IC), but the causality remained unconfirmed.

Methods

We employed two-sample Mendelian randomization (MR) to investigate the bidirectional causal relationships between AS and IC. Single-nucleotide polymorphisms (SNPs) were chosen from the FinnGen database’s genome-wide association studies (GWAS) following a rigorous evaluation of the studies’ quality. Sensitivity analysis was performed to assess the potential influence of pleiotropy and heterogeneity on the MR findings.

Results

Elevated genetic risk for AS showed positive causal effects on IC and its subtypes (IC, OR = 1.094, 95% CI = 1.035-1.157, P = 0.00156; Acute/Subacute IC, OR = 1.327, 95% CI = 1.266-1.392, P = 8.73×10-32; Chronic IC, OR = 1.454, 95% CI = 1.308-1.618, P = 5.19×10-12). Significant causal association was specifically observed between Acute/Subacute IC and AS (OR = 1.944, 95% CI = 1.316-2.873, P = 8.38×10-4). Sensitivity analysis suggested that horizontal pleiotropy was unlikely to influence the causality, and the leave-one-out analysis confirmed that a single SNP did not drive the observed associations.

Conclusion

Our findings provide new proof of a positive causal relationship between AS and IC in the European population. Notably, it is Acute/Subacute IC, rather than IC as a whole or Chronic IC, that is associated with an elevated risk of AS. These results emphasize the significance of considering AS characteristics in the diagnosis of Acute/Subacute IC.
Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19
Authors: Yatsenko Tetiana , Rios Ricardo , Nogueira Tatiane , Salama Yousef , Takahashi Satoshi , Tabe Yoko , Naito Toshio , Takahashi Kazuhisa , Hattori Koichi , Heissig Beate
Published: January 2024

Patients with coronavirus disease-2019 (COVID-19) have an increased risk of thrombosis and acute respiratory distress syndrome (ARDS). Thrombosis is often attributed to increases in plasminogen activator inhibitor-1 (PAI-1) and a shut-down of fibrinolysis (blood clot dissolution). Decreased urokinase-type plasminogen activator (uPA), a protease necessary for cell-associated plasmin generation, and increased tissue-type plasminogen activator (tPA) and PAI-1 levels have been reported in COVID-19 patients. Because these factors can occur in free and complexed forms with differences in their biological functions, we examined the predictive impact of uPA, tPA, and PAI-1 in their free forms and complexes as a biomarker for COVID-19 severity and the development of ARDS. In this retrospective study of 69 Japanese adults hospitalized with COVID-19 and 20 healthy donors, we found elevated free, non-complexed PAI-1 antigen, low circulating uPA, and uPA/PAI-1 but not tPA/PAI-1 complex levels to be associated with COVID-19 severity and ARDS development. This biomarker profile was typical for patients in the complicated phase. Lack of PAI-1 activity in circulation despite free, non-complexed PAI-1 protein and plasmin/α2anti-plasmin complex correlated with suPAR and sVCAM levels, markers indicating endothelial dysfunction. Furthermore, uPA/PAI-1 complex levels positively correlated with TNFα, a cytokine reported to trigger inflammatory cell death and tissue damage. Those levels also positively correlated with lymphopenia and the pro-inflammatory factors interleukin1β (IL1β), IL6, and C-reactive protein, markers associated with the anti-viral inflammatory response. These findings argue for using uPA and uPA/PAI-1 as novel biomarkers to detect patients at risk of developing severe COVID-19, including ARDS.
Characterizing ligand-receptor interactions and unveiling the pro-tumorigenic role of CCL16-CCR1 axis in the microenvironment of hepatocellular carcinoma
Authors: Dai Zongbo , Wang Yu , Sun Ning , Zhang Chengshuo
Published: January 2024

Background

The heterogeneity of the tumor microenvironment significantly influences the prognosis of hepatocellular carcinoma (HCC) patients, with cell communication through ligand-receptor complexes playing a central role.

Methods

We conducted single-cell transcriptomic analysis on ten HCC tissues to identify ligand-receptor genes involved in malignant HCC cell communication using CellChat. Leveraging RNA-Seq data from the TCGA Liver Cancer (TCGA-LIHC) and Liver Cancer - RIKEN, JP (LIRI-JP) cohorts, we employed Cox regression analysis to screen for prognosis-related genes. Prognostic risk models were constructed through unsupervised clustering and differential gene expression analysis. Subsequently, a co-culture system involving tumor cells and macrophages was established. A series of experiments, including Transwell assays, immunofluorescence staining, immunoprecipitation, flow cytometry, and immunohistochemistry, were conducted to elucidate the mechanism through which HCC cells recruit macrophages via the CCL16-CCR1 axis.

Results

Single-cell analysis unveiled significant interactions between malignant HCC cells and macrophages, identifying 76 related ligand-receptor genes. Patients were classified into three subtypes based on the expression patterns of eight prognosis-related ligand-receptor genes. The subtype with the worst prognosis exhibited reduced infiltration of T cell-related immune cells, downregulation of immune checkpoint genes, and increased M2-like tumor-associated macrophage scores. In vitro experiments confirmed the pivotal role of the CCL16-CCR1 axis in the recruitment and M2 polarization of tumor-associated macrophages. Clinical samples demonstrated a significant association between CCL16 protein expression levels and advanced stage, lymph node metastasis, and distant metastasis. Immunohistochemistry and immunofluorescence staining further confirmed the correlation between CCL16 and CCR1, CD68, and CD206, as well as CD68+CCR1+ macrophage infiltration.

Conclusions

Our study identified molecular subtypes, a prognostic model, and immune microenvironment features based on ligand-receptor interactions in malignant HCC cell communication. Moreover, we revealed the pro-tumorigenic role of HCC cells in recruiting M2-like tumor-associated macrophages through the CCL16-CCR1 axis.
Myeloid cell MHC I expression drives CD8+ T cell activation in nonalcoholic steatohepatitis
Authors: Adams Victoria R. , Collins Leonard B. , Williams Taufika Islam , Holmes Jennifer , Hess Paul , Atkins Hannah M. , Scheidemantle Grace , Liu Xiaojing , Lodge Mareca , Johnson Aaron J. , Kennedy Arion
Published: January 2024

Background & aims

Activated CD8+ T cells are elevated in Nonalcoholic steatohepatitis (NASH) and are important for driving fibrosis and inflammation. Despite this, mechanisms of CD8+ T cell activation in NASH are largely limited. Specific CD8+ T cell subsets may become activated through metabolic signals or cytokines. However, studies in NASH have not evaluated the impact of antigen presentation or the involvement of specific antigens. Therefore, we determined if activated CD8+ T cells are dependent on MHC class I expression in NASH to regulate fibrosis and inflammation.

Methods

We used H2Kb and H2Db deficient (MHC I KO), Kb transgenic mice, and myeloid cell Kb deficient mice (LysM Kb KO) to investigate how MHC class I impacts CD8+ T cell function and NASH. Flow cytometry, gene expression, and histology were used to examine hepatic inflammation and fibrosis. The hepatic class I immunopeptidome was evaluated by mass spectrometry.

Results

In NASH, MHC class I isoform H2Kb was upregulated in myeloid cells. MHC I KO demonstrated protective effects against NASH-induced inflammation and fibrosis. Kb mice exhibited increased fibrosis in the absence of H2Db while LysM Kb KO mice showed protection against fibrosis but not inflammation. H2Kb restricted peptides identified a unique NASH peptide Ncf2 capable of CD8+ T cell activation in vitro. The Ncf2 peptide was not detected during fibrosis resolution.

Conclusion

These results suggest that activated hepatic CD8+ T cells are dependent on myeloid cell MHC class I expression in diet induced NASH to promote inflammation and fibrosis. Additionally, our studies suggest a role of NADPH oxidase in the production of Ncf2 peptide generation.
Immunogenicity and reactogenicity of repeated intradermal mRNA COVID-19 vaccines administered as a second booster dose in a Thai geriatric population
Authors: Assantachai Prasert , Niyomnaitham Suvimol , Toh Zheng Quan , Thammasalee Monthira , Pengsorn Napaporn , Monklang Wiyachatr , Licciardi Paul V. , Chokephaibulkit Kulkanya
Published: January 2024

Background

Geriatric populations are at an increased risk of severe presentations, hospitalization, and loss of life from COVID-19. Few studies have explored vaccination regimens in adults >65 years old. Repeated booster vaccination is required for high-risk populations as COVID-19 vaccine efficacy is short-lived. We compared the immunogenicity and reactogenicity of second intradermal (ID) COVID-19 booster vaccination with second intramuscular (IM) vaccination in older adults.

Methods

This single-center, open-labeled, prospective, cohort study conducted at Siriraj Hospital enrolled older adults ≥65 years old who previously received a first booster (third dose) mRNA vaccine (mRNA-1273 or BNT162b2) via ID or IM administration. Participants were allocated to receive a second booster of the same vaccine type and route as their first booster 16–17 weeks thereafter. Anti-SARS-CoV-2 receptor binding domain IgG and neutralizing antibody titers against Wuhan and Omicron subvariants (BA.1, BA.2, and BA.4/5) were measured 2 weeks after vaccination.

Results

Of 91 enrolled participants, 72.5% were women, with a median age of 75 years. Forty-nine participants (53.8%) received a second ID booster, and 42 (46.2%) received a second IM booster. Two weeks after the second booster, all groups generated anamnestic IgG antibody responses that were 5.41- to 10.00-fold higher than at baseline. Overall, higher antibody GMTs against Wuhan and Omicron subvariants were observed in IM compared with ID regimens. ID mRNA-1273 induced similar GMTs to IM BNT162b2 2 weeks after the second booster against Wuhan (486.77 [321.48, 737.05] vs. 472.63 [291.24, 767.01], respectively; p = 0.072). Higher GMTs against Omicron BA.1 (GMR [95% CI], 1.71 [1.39, 2.11]; p = 0.023), BA.2 (1.34 [1.11, 1.62]; p = 0.845), and BA.4/5 (1.10 [0.92, 1.33]; p = 0.531) were seen in all groups at 2 weeks after the second booster compared with 2–4 weeks after the first booster. Both local and systemic AEs were less frequent after the second than after the first booster, regardless of administrative route and vaccine type. Local AEs were significantly more frequent in ID mRNA-1273 arms than their respective BNT162b2 arms 2 weeks after the second booster (ID-mRNA-1273 vs. ID-BNT162b2: p ≤ 0.001).

Conclusion

Repeated fractional ID vaccination may be an alternative booster vaccination strategy for geriatric populations.
Rational use of eculizumab in secondary atypical hemolytic uremic syndrome
Authors: Cordero Lucía , Cavero Teresa , Gutiérrez Eduardo , Trujillo Hernando , Sandino Justo , Auñón Pilar , Rivero Marta , Morales Enrique
Published: January 2024

Background

Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in secondary aHUS, since the two main series that investigated this subject showed discrepant results. Our work aims to reassess the efficacy of eculizumab in treating secondary aHUS.

Methods

Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 23 patients diagnosed with secondary aHUS who received treatment with eculizumab and compared them with a control cohort of 14 patients. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets.

Results

We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 52.3% of patients and partial in 23.8%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (90.9% in the eculizumab cohort and 85.7% in the control cohort).

Conclusion

Early and short-term use of eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, assuring better renal recovery compared to patients who do not receive complement blockade.
HLA-DPB1 genotype variants predict DP molecule cell surface expression and DP donor specific antibody binding capacity
Authors: Yin Yuxin , Soe Nwe Nwe , Valenzuela Nicole M. , Reed Elaine F. , Zhang Qiuheng
Published: January 2024

The contribution of alloresponses to mismatched HLA-DP in solid organ transplantation and hematopoietic stem cell transplantation (HCT) has been well documented. Exploring the regulatory mechanisms of DPB1 alleles has become an important question to be answered. In this study, our initial investigation focused on examining the correlation between the rs9277534G/A SNP and DPB1 mRNA expression. The result showed that there was a significant increase in DPB1 mRNA expression in B lymphoblastoid cell lines (BLCLs) with the rs9277534GG genotype compared to rs9277534AA genotype. In addition, B cells with the rs9277534GG exhibited significantly higher DP protein expression than those carrying the rs9277534AA genotype in primary B cells. Furthermore, we observed a significant upregulation of DP expression in B cells following treatment with Interleukin 13 (IL-13) compared to untreated B cells carrying rs9277534GG-linked DPB1 alleles. Fluorescence in situ hybridization (FISH) analysis of DPB1 in BLCL demonstrated significant differences in both the cytoplasmic (p=0.0003) and nuclear (p=0.0001) localization of DP mRNA expression comparing DPB1*04:01 (rs9277534AA) and DPB1*05:01 (rs9277534GG) homozygous cells. The study of the correlation between differential DPB1 expression and long non-coding RNAs (lncRNAs) showed that lnc-HLA-DPB1-13:1 is strongly associated with DP expression (r=0.85), suggesting the potential involvement of lncRNA in regulating DP expression. The correlation of DP donor specific antibody (DSA) with B cell flow crossmatch (B-FCXM) results showed a better linear correlation of DP DSA against GG and AG donor cells (R2 = 0.4243, p=0.0025 and R2 = 0.6172, p=0.0003, respectively), compared to DSA against AA donor cells (R2 = 0.0649, p=0.4244). This explained why strong DP DSA with a low expression DP leads to negative B-FCXM. In conclusion, this study provides evidence supporting the involvement of lncRNA in modulating HLA-DP expression, shedding lights on the intricate regulatory mechanisms of DP, particularly under inflammatory conditions in transplantation.
Cell-free chromatin particles released from dying cancer cells activate immune checkpoints in human lymphocytes: implications for cancer therapy
Authors: Shabrish Snehal , Pal Kavita , Khare Naveen Kumar , Satsangi Dharana , Pilankar Aishwarya , Jadhav Vishalkumar , Shinde Sushma , Raphael Nimisha , Sriram Gaurav , Lopes Relestina , Raghuram Gorantla V. , Tandel Harshali , Mittra Indraneel
Published: January 2024

Immune checkpoint blockade is the exciting breakthrough in cancer, but how immune checkpoints are activated is unknown. We have earlier reported that cell-free chromatin particles (cfChPs) that circulate in blood of cancer patients, or those that are released locally from dying cancer cells, are readily internalized by healthy cells with biological consequences. Here we report that treatment of human lymphocytes with cfChPs isolated from sera of cancer patients led to marked activation of the immune checkpoints PD-1, CTLA-4, LAG-3, NKG2A, and TIM-3. This finding was corroborated in vivo in splenocytes of mice when cfChPs were injected intravenously. Significant upregulation of immune checkpoint was also observed when isolated lymphocytes were exposed to conditioned medium containing cfChPs released from hypoxia-induced dying HeLa cells. Immune checkpoint activation could be down-regulated by pre-treating the conditioned media with three different cfChPs deactivating agents. Down-regulation of immune checkpoints by cfChPs deactivating agents may herald a novel form of immunotherapy of cancer.
Macrophage plasticity and function in cancer and pregnancy
Authors: Yin Tingxuan , Li Xinyi , Li Yanhong , Zang Xingxing , Liu Lu , Du Meirong
Published: January 2024

As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.
Single cell sequencing revealed the mechanism of CRYAB in glioma and its diagnostic and prognostic value
Authors: Cai Hua-Bao , Zhao Meng-Yu , Li Xin-Han , Li Yu-Qing , Yu Tian-Hang , Wang Cun-Zhi , Wang Li-Na , Xu Wan-Yan , Liang Bo , Cai Yong-Ping , Zhang Fang , Hong Wen-Ming
Published: January 2024

Background

We explored the characteristics of single-cell differentiation data in glioblastoma and established prognostic markers based on CRYAB to predict the prognosis of glioblastoma patients. Aberrant expression of CRYAB is associated with invasive behavior in various tumors, including glioblastoma. However, the specific role and mechanisms of CRYAB in glioblastoma are still unclear.

Methods

We assessed RNA-seq and microarray data from TCGA and GEO databases, combined with scRNA-seq data on glioma patients from GEO. Utilizing the Seurat R package, we identified distinct survival-related gene clusters in the scRNA-seq data. Prognostic pivotal genes were discovered through single-factor Cox analysis, and a prognostic model was established using LASSO and stepwise regression algorithms. Moreover, we investigated the predictive potential of these genes in the immune microenvironment and their applicability in immunotherapy. Finally, in vitro experiments confirmed the functional significance of the high-risk gene CRYAB.

Results

By analyzing the ScRNA-seq data, we identified 28 cell clusters representing seven cell types. After dimensionality reduction and clustering analysis, we obtained four subpopulations within the oligodendrocyte lineage based on their differentiation trajectory. Using CRYAB as a marker gene for the terminal-stage subpopulation, we found that its expression was associated with poor prognosis. In vitro experiments demonstrated that knocking out CRYAB in U87 and LN229 cells reduced cell viability, proliferation, and invasiveness.

Conclusion

The risk model based on CRYAB holds promise in accurately predicting glioblastoma. A comprehensive study of the specific mechanisms of CRYAB in glioblastoma would contribute to understanding its response to immunotherapy. Targeting the CRYAB gene may be beneficial for glioblastoma patients.