bluuebunny/crossref_metadata_2025 huggingface dataset:
Left atrial appendage exclusion in atrial fibrillation
Authors: Rozen Guy , Margolis Gilad , Marai Ibrahim , Roguin Ariel , Rahamim Eldad , Planer David , Heist Edwin Kevin , Amir Offer , Tahiroglu Ilgar , Ruskin Jeremy , Mansour Moussa , Elbaz-Greener Gabby
Published: September 2022

Although oral anticoagulants (OACs) are first-line therapy for stroke prevention in patients with atrial fibrillation (AF), some patients cannot be treated with OACs due to absolute or relative contraindications. Left atrial appendage (LAA) exclusion techniques have been developed over the years as a therapeutic alternative for stroke prevention. In this paper, we review the evolution of surgical techniques, employed as an adjunct to cardiac surgery or as a stand-alone procedure, as well as the recently introduced and widely utilized percutaneous LAA occlusion techniques. Until recently, data on surgical LAAO were limited and based on non-randomized studies. We focus on recently published randomized data which strongly support an add-on surgical LAAO in eligible patients during cardiac surgery and could potentially change current practice guidelines. In recent years, the trans-catheter techniques for LAA occlusion have emerged as another, less invasive alternative for patients who cannot tolerate oral anticoagulation. We review the growing body of evidence from prospective studies and registries, focusing on the two systems which are in widespread clinical use nowadays: the Watchman and Amulet type devices. These data show favorable results for both Watchman and Amulet devices, setting them as an important tool in our arsenal for stroke reduction in AF patients, especially in those who have contraindications for OACs. A better understanding of the different therapeutic alternatives, their specific benefits, and downfalls in different patient populations can guide us in tailoring the optimal therapeutic approach for stroke reduction in our AF patients.
Reference values of normal abdominal aortic areas in Chinese population measured by contrast-enhanced computed tomography
Authors: Wang Xiang , Jin Shasha , Wang Qing , Liu Jiawei , Li Fei , Chu Haiwei , Zheng Dexing , Zhang Xiaolong , Ding Jianrong , Pan Jingli , Zhao Wenjun
Published: September 2022

Objective

To generate reference values of the normal areas of the abdominal aorta at various levels among Chinese people and to explore the factors that may promote the expansion of the abdominal aorta.

Methods

The areas of normal abdominal aortas were gauged at various levels based on inner-to-inner measurements in 1,066 Chinese adult patients (>18 years) without the abdominal aortic disease. The areas of subphrenic abdominal, suprarenal abdominal, infrarenal abdominal, and distal abdominal aortas were measured. The demographic and clinical characteristics were collected into a specifically designed electronic database. Multivariable linear regression was used to analyze the potential risk factors promoting the expansion of the abdominal aorta.

Results

In males, the median areas of the subphrenic abdominal aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and distal abdominal aorta were 412.1, 308.0, 242.2, and 202.2 mm2, respectively. In females, the median areas of the subphrenic abdominal aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and distal abdominal aorta were 327.7, 243.4, 185.4, and 159.6 mm2, respectively. The areas of the abdominal aorta at different levels were larger in males than in females and increased with age. Multiple linear stepwise regression analysis showed that the subphrenic abdominal aortic area was significantly related to age (β = 0.544, p < 0.001), sex (β = 0.359, p < 0.001), and hypertension (β = 0.107, p < 0.001). Suprarenal abdominal aortic area was related to age (β = 0.398, p < 0.001), sex (β = 0.383, p < 0.001), history of smoking (β = 0.074, p = 0.005), and hypertension (β = 0.111, p < 0.001). The infrarenal abdominal aortic area was correlated with age (β = 0.420, p < 0.001), sex (β = 0.407, p < 0.001), and history of smoking (β = 0.055, p = 0.036). The distal abdominal aortic area was correlated with age (β = 0.463, p < 0.001), sex (β = 0.253, p < 0.001), and hypertension (β = 0.073, p = 0.013).

Conclusion

The abdominal aortic areas at different levels were larger in males than in females. Aging, hypertension, and smoking prompt the expansion of abdominal aorta.
Macrophage-extracellular matrix interactions: Perspectives for tissue engineered heart valve remodeling
Authors: Poulis Nikolaos , Martin Marcy , Hoerstrup Simon P. , Emmert Maximilian Y. , Fioretta Emanuela S.
Published: September 2022

In situ heart valve tissue engineering approaches have been proposed as promising strategies to overcome the limitations of current heart valve replacements. Tissue engineered heart valves (TEHVs) generated from in vitro grown tissue engineered matrices (TEMs) aim at mimicking the microenvironmental cues from the extracellular matrix (ECM) to favor integration and remodeling of the implant. A key role of the ECM is to provide mechanical support to and attract host cells into the construct. Additionally, each ECM component plays a critical role in regulating cell adhesion, growth, migration, and differentiation potential. Importantly, the immune response to the implanted TEHV is also modulated biophysically via macrophage-ECM protein interactions. Therefore, the aim of this review is to summarize what is currently known about the interactions and signaling networks occurring between ECM proteins and macrophages, and how these interactions may impact the long-term in situ remodeling outcomes of TEMs. First, we provide an overview of in situ tissue engineering approaches and their clinical relevance, followed by a discussion on the fundamentals of the remodeling cascades. We then focus on the role of circulation-derived and resident tissue macrophages, with particular emphasis on the ramifications that ECM proteins and peptides may have in regulating the host immune response. Finally, the relevance of these findings for heart valve tissue engineering applications is discussed.
Comparative effects of different types of cardioplegia in cardiac surgery: A network meta-analysis
Authors: Tan Jia , Bi Siwei , Li Jingyi , Gu Jun , Wang Yishun , Xiong Jiyue , Yu Xiang , Du Lei
Published: September 2022

Objective

To compare the outcomes of four types of cardioplegia during cardiac surgery: del Nido (DN), blood cardioplegia (BC), histidine-tryptophan-ketoglutarate (HTK) and St. Thomas.

Methods

Randomized controlled trials (RCTs) and observational cohort studies from 2005 to 2021 were identified in PubMed, Embase, and Cochrane databases. Data were extracted for the primary endpoint of perioperative mortality as well as the following secondary endpoints: atrial fibrillation, renal failure, stroke, use of an intra-aortic balloon pump, re-exploration, intensive care unit stay and hospital stay. A network meta-analysis comparing all four types of cardioplegia was performed, as well as direct meta-analysis comparing pairs of cardioplegia types.

Results

Data were extracted from 18 RCTs and 49 observational cohort studies involving 18,191 adult patients (55 studies) and 1,634 children (12 studies). Among adult patients, risk of mortality was significantly higher for HTK (1.89, 95% CI 1.10, 3.52) and BC (RR 1.73, 95% CI 1.22, 2.79) than for DN. Risk of atrial fibrillation was significantly higher for BC (RR 1.41, 95% CI 1.09, 1.86) and DN (RR 1.51, 95% CI 1.15, 2.03) than for HTK. Among pediatric patients, no significant differences in endpoints were observed among the four types of cardioplegia.

Conclusions

This network meta-analysis suggests that among adult patients undergoing cardiac surgery, DN may be associated with lower perioperative mortality than HTK or BC, while risk of atrial fibrillation may be lower with HTK than with BC or DN.
Anomaly identification of monitoring data and safety evaluation method of tailings dam
Authors: Dong Kai , Yang Dewei , Yan Jihao , Sheng Jinbao , Mi Zhankuan , Lu Xiang , Peng Xuehui
Published: September 2022

The seepage field of tailings dam is closely related to the safety state. Real-time evaluation of seepage field safety based on monitoring data is of great significance to ensure the safe operation of tailings pond. The premise of accurately evaluating the safety status is to ensure reliability of the data, and it is necessary to identify the anomalies of the monitoring data. Because of the complex influence factors of seepage field of tailings dam, the traditional anomaly identification method based on regression model fails due to its low fitting accuracy. Therefore, a novel abnormal identification method of monitoring data based on improved cloud model and radial basis function neural network model, which can accurately identify anomaly data and distinguish the environmental quantity response. Based on the coupling relationship between the seepage field and the slope stability, the surrogate model between the depth of saturation line and the safety factor of slope stability is constructed, and the real-time safety evaluation method of seepage field is put forward. The proposed methods are applied to an engineering example. The misjudgment rates of the abnormal data identification method are less than 5%, and it has better applicability than the traditional regression model. The constructed real-time safety evaluation model accurately reflected the health status of the seepage field, and realized the quantitative assessment of the safety of tailings dam. This provides reliable data support for the operation management and the risk control of tailings pond.
Hydrocarbon detection based on empirical mode decomposition, teager-kaiser energy, and the cepstrum
Authors: Jiang Xudong , Cao Junxing , Su Zhaodong , Fu Jingcheng , Shi Shaochen
Published: September 2022

Seismic waves produce anomalies when they pass through hydrocarbons; these anomalies, which are commonly used to detect hydrocarbons, are manifested differently in different domains. Here, we propose a novel hydrocarbon detection method that combines Empirical Mode Decomposition (EMD), the Teager-Kaiser energy operator (TKEO), and the cepstrum. This method utilizes EMD’s ability to adaptively decompose signals, benefits from the TKEO’s superior performance regarding the focusing of instantaneous energy, and uses the sensitivity of cepstrum domain parameters to hydrocarbons. Here, applying the developed EMD-TKE-Cepstrum method to the Marmousi2 example revealed that it could describe the position and extent of hydrocarbons more clearly than the synchronous compression wavelet transform (SCWT) method. Applying the EMD-TKE-Cepstrum algorithm to field data further confirmed its potential regarding the identification of anomalies associated with hydrocarbon reservoirs.
Prior land surface reflectance-based sandstorm detection from space using deep learning
Authors: Qu Yu , Sun Lin , Su Qing hua , Ma Nan , Wang Zhi hui , Liu Xi rong
Published: September 2022

Traditional sandstorm detection methods use radiation differences among dust, underlying surface, and cloud to distinguish them by setting appropriate thresholds. Owing to the complex structure of the underlying surface, dust, and cloud, it is difficult to set a uniform threshold to achieve high-precision separation. Deep learning (DL) has powerful information mining capabilities and can fully use spectral differences between dust, land surface, and clouds. However, under the limited band information provided by satellite sensors, DL cannot easily distinguish highly heterogeneous land surfaces from multi-modal dust and cloud. This study proposes a sandstorm detection algorithm with DL supported by a land surface reflectance (LSR) dataset. The clear sky LSR dataset was obtained based on the MOD09A1 product. Based on the dataset, the difference between the reflectance observed by the satellite and the corresponding LSR is generated, which is used as a characteristic parameter of sandstorm detection with the deep learning method. The sandstorm detection of MODIS data is realized using multi-band radiation and radiation difference with DL. Results showed that the sandstorm detection algorithm used in this study was consistent with the OMI AI product with a detection accuracy of 84.6%. Compared with the detection results without the LSR dataset, this method effectively improves the accuracy of sandstorm identification.
Inclusion of technology affinity in self scale–Development and evaluation of a single item measurement instrument for technology affinity
Authors: Henrich Marvin , Kleespies Matthias Winfried , Dierkes Paul Wilhelm , Formella-Zimmermann Sandra
Published: September 2022

The success of the increasing use of technology in education is highly dependent on learner acceptance. Although the Technology Acceptance Model (TAM) is dominant in research for surveying acceptance of technology, it does not allow the prediction of a successful first time use of technology. The successful first time use can be determined with the survey of technology affinity, as it corresponds to the expression of certain personality traits of users and is thus detached from the specific technology. Since there are no measurement instruments for the educational sector so far and existing instruments for measuring technology affinity do not meet the specific requirements for use in the educational context (e.g., limited time for questioning), we present the single item Inclusion of Technology Affinity in Self-Scale (ITAS). In study 1 we provide evidence of convergent and discriminant validity within the general population so that a generalization of its applicability is possible. In study 2 we subsequently tested ITAS in the actual target group, the educational sector. The high correlations of the ITAS with the ATI and the control instrument TA-EG (ranging from rs = 0.679 to rs = 0.440) show that ITAS is suitable for use in research. Furthermore, the newly developed instrument convinces with its low complexity, the graphical component, which requires little text understanding and the high time saving. This research thus can contribute to the investigation of technology affinity in the educational sector helping educators to conduct technical activities with their learning group, to predict possible difficulties and adjust their planning accordingly.
Cooperative trading strategy of carbon emitting power generation units participating in carbon and electricity markets
Authors: Yang Yuyan , Liu Jichun , Xu Xiao , Xie Kangmin , Lai Zhenming , Xue Yulin , Yang Bingquan
Published: September 2022

Energy-saving and emission reduction will become the focus of the energy industry in the future. The coordination of the carbon and electricity markets can help achieve the goals of carbon reduction. With the establishment of the carbon market, carbon emitting power generation units (CEPGU) need to consider the trading strategy and comprehensive benefits in the electricity and carbon markets. To further explore the mechanism and interaction process of electricity price and carbon price, the day-ahead electricity market model and carbon market trading model are developed in this study. Based on the deviation between the bid-winning power output in the electricity market and the quota plan in the carbon market, the generation cost model and the carbon quota trading decision model of the units are constructed. Finally, a case study is provided to simulate the coordinated trading process of the carbon and electricity markets. The transaction time scales of the two markets are matched. The results prove that the generation plan of the units can coordinate with the carbon quota level and provide a trading strategy for the power generation enterprises.
Effects of aquatic heavy metal intoxication on the level of hematocrit and hemoglobin in fishes: A review
Authors: Ahmed Imtiaz , Zakiya Archo , Fazio Francesco
Published: September 2022

Environmental pollution caused due to the presence of heavy metals has become a great concern as it has an adverse effect on almost all types of ecosystem. In this sense, these pollutants have a tendency to pollute the aquatic ecosystem, thus badly affecting the health of aquatic organisms. As a result, toxicological studies believe them to be the most harmful pollutants in the aquatic environment. Among all the aquatic organisms, fish—being a chief organism in this system—become the easiest victim of these pollutants. Heavy metals enter fish bodies through the alimentary system by consumption of polluted food, or through the gills, and skin. They are finally delivered by the bloodstream to the organs and tissues where they accumulate after absorption. Ultimately, in this way heavy metals make their way into humans through the food chain. The fluctuations in the hematological values may serve as an initial indicator of the toxicant’s impact on fish health. It has been observed that when pollutants impact the quality of the aquatic medium, the first consequence is apparent in the form of physiological changes in fish, which are reflected in one or more hematological parameters, such as hemoglobin, hematocrit, red blood cell count, white blood cell count, etc. As a result of these alterations, fish become weak, anemic, and more susceptible to diseases. Over the past several decades, a vast number of studies have been reported on the qualitative and quantitative variations in hematological parameters due to the presence of heavy metal intoxication. Heavy metal contamination of water resources not only degrades the water quality but also negatively impacts the quality of food in the form of fish proteins. Therefore, this article sheds light on the effects of heavy metals on hemoglobin and hematocrit of fish hematology and calls for more attention to the protection and preservation of aquatic ecosystems, particularly those contaminated with heavy metals.
Interacting municipal-level anthropogenic and ecological disturbances drive changes in Neotropical forest carbon storage
Authors: Toro Giselle , Otero Maria Paula , Clerici Nicola , Szantoi Zoltan , González-González Andrés , Escobedo Francisco J.
Published: September 2022

Deforestation is a documented driver of biodiversity loss and ecosystem services in the tropics. However, less is known on how interacting regional and local-level anthropogenic and ecological disturbances such as land use activities, human populations, and armed conflict affect carbon storage and emissions in Neotropical forests. Therefore, we explored how local-scale, socio-ecological drivers affect carbon dynamics across space and time in a region in Colombia characterized by deforestation, land use cover (LULC) changes, and armed conflict. Specifically, using available municipal level data from a period of armed conflict (2009–2012), spatiotemporal analyses, and multivariate models, we analyzed the effects of a suite of socio-ecological drivers (e.g., armed conflict, illicit crops, human population, agriculture, etc.) on deforestation and carbon storage-emission dynamics. We found that about 0.4% of the initial forest cover area was converted to other LULC types, particularly pastures and crops. Gross C storage emissions were 4.14 Mt C, while gross carbon sequestration was 1.43 Mt C; primarily due to forest regeneration. We found that livestock ranching, illegal crop cultivation, and rural population were significant drivers of deforestation and carbon storage changes, while the influential role of armed conflict was less clear. However, temporal dynamics affected the magnitude of LULC effects and deforestation on carbon storage and emissions. The approach and findings can be used to better inform medium to long-term local and regional planning and decision-making related to forest conservation and ecosystem service policies in Neotropical forests experiencing disturbances related to global change and socio-political events like armed conflict.
Characterization of PM2.5-bound trace elements, source apportionment, and assessment of associated human health risks during summer and winter in Greater Noida, the National Capital Region of India
Authors: Kumar Vishnu , Yadav Mudit , Behera Sailesh N.
Published: September 2022

To examine the trends of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) and its elemental constituents during two distinct seasons at a site away from the city center of Delhi and the National Capital Region (Delhi-NCR) of India, this unique study aimed at the development of source-receptor-effect linkages. This research paper presents results of occurrence, long-range transport (LRT), source apportionment, and human health impact assessment of 24 PM2.5-bound trace elements (Al, Ba, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ga, K, Li, Mg, Mn, Na, Ni, Pb, S, Se, Si, Te, Tl, Zn, and Zr). The concentration of PM2.5 during winter (296 ± 45 μg/m3) was significantly higher than in summer (114 ± 48 μg/m3) and exceeded 24 h Indian standard on most of the measurement days. The seasonal concentration ratios (winter/summer) of individual elements varied from 1.7 (Si) to 5.9 (Tl). The backward trajectory of air masses showed that transboundary transport of pollutants occurred in the downwind direction during winter, indicating that this remote site was affected by transported particulates and local activities. The principal component analysis–absolute principal component score (PCA-APCS) model confirmed five significant sources, vehicles (22.3%), soil/road dust (23.1%), coal combustion (20.9%), open burning (13.8%), and other industries (10.2%) responsible for particulate emission. The results from the multiple path particle dosimetry model (MPPD) showed higher deposition of particulates in the human respiratory system occurred during winter (44%) than in summer (40%). The elements with crustal sources of origin had a higher deposition fraction in the head region (0.27 for Si) compared to elements of anthropogenic sources (0.13 for Li). The excess lifetime carcinogenic risk (ELCR) under winter episodic events increased significantly at 128 × 10−6 compared to the summer non-episodic period at 41 × 10−6.
What causes the spatiotemporal disparities in greenway use intensity? evidence from the central urban area of Beijing, China
Authors: Qiu Cailin , Qiu Ning , Zhang Tianjie
Published: September 2022

The reasonable layout of green sports space has positive significance for promoting residents’ outdoor sports. Existing studies rarely use large-scale trajectory data to analyze urban greenway physical activity; they mostly use on-site research and questionnaires to conduct research. This study, using central Beijing as a case study, identified the spatiotemporal relationships of greenway use intensity with the social, economic, and built environment. A multiscale geographically weighted regression (MGWR) model was used to explore the temporal heterogeneity of the factors, compensating for the lack of cross-sectional data in existing studies. The results demonstrated significant differences in the spatiotemporal patterns among the core, central and inner suburban areas, and they revealed residents’ preferences in different periods. The MGWR model indicated that there were obvious scale differences and spatial heterogeneity in the greenway use intensity among social, economic, and built environment factors. Housing prices, residential density, historical resource density, and greening quality of greenways contributed to greenway use intensity, which was weak in the core area and strong in the inner suburban area. The reason for the difference in the temporal dimension was related to commuting and the separation of workplaces and residences. The layout of the greenway should be combined with rivers, historical resources, and green space to improve its attractiveness. This paper improved the spatial awareness of greenway use and facilitated the ability of urban planners to generate appropriate strategies to improve land use efficiency in different regions and promote green spatial justice to meet the needs of green, healthy cities.
Investigating the effect of government subsidies on enterprise research and development
Authors: Wu Guangliang , Buravleva Yana , Wu Jing , Li Yi , Tang Decai , Bethel Brandon J.
Published: September 2022

Governments design and implement policies to achieve various goals. Still, perhaps none are as pressing as shifting national economies away from non-renewable fuels and towards more sustainable, environmentally-friendly technologies. To incentivize such transitions, governments provide subsidies to private and public companies to innovate, i.e., to engage in research and development (R&D). However, it can be asked if companies are using government subsidies (GS) actually to perform R&D, and the answer will determine the effectiveness of government policies. This paper seeks to answer this question by investigating Chinese lithium-ion battery (LiB) firms and the GS they receive. Hausman tests, fixed- and random-effects models, and Generalized Method of Moments confirmed a positive but weak correlation between GS and R&D as determined by patent output (PO). Interestingly, observations of information flow suggested that GS also affected other variables such as net profit and main business income. This suggests that firms are awarded GS for higher PO, but a corresponding increase in R&D and its expected growth in company performance is not occurring. It is suggested that performance indicators other than PO be used as Chinese firms may use this metric to apply for more GS, rather than performing R&D that leads to technological breakthroughs.
Development of an exosome-related and immune microenvironment prognostic signature in colon adenocarcinoma
Authors: Cui Guoliang , Wang Can , Liu Jinhui , Shon Kinyu , Gu Renjun , Chang Cheng , Ren Lang , Wei Fei , Sun Zhiguang
Published: September 2022

Background: The correlation between exosomes and the tumor immune microenvironment has been proved to affect tumorigenesis and progression of colon adenocarcinoma (COAD). However, it remained unclear whether exosomes had an impact on the prognostic indications of COAD patients.

Methods: Expression of exosome-related genes (ERGs) and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The ERGs associated with prognosis were identified and exosome-related prognostic signature was constructed. Patients in two risk groups were classified according to the risk score calculation formula: Risk score = 1.0132 * CCKBR + 0.2416 * HOXC6 + 0.7618 * POU4F1. The expression of three ERGs was investigated by qRT-PCR. After that, we developed a nomogram predicting the likelihood of survival and verified its predictive efficiency. The differences of tumor immune microenvironment, immune cell infiltration, immune checkpoint and sensitivity to drugs in two risk groups were analyzed.

Results: A prognostic signature was established based on the three ERGs (CCKBR, HOXC6, and POU4F1) and patients with different risk group were distinguished. Survival analysis revealed the negative associated of risk score and prognosis, ROC curve analyses showed the accuracy of this signature. Three ERGs expression was investigated by qRT-PCR in three colorectal cancer cell lines. Moreover, risk score was positively correlated with tumor mutational burden (TMB), immune activities, microsatellite instability level, the expression of immune checkpoint genes. Meanwhile, the expression level of three ERGs and the risk score were markedly related with the sensitive response to chemotherapy.

Conclusion: The novel signature composed of three ERGs with precise predictive capabilities can be used to predict prognosis and provide a promising therapeutic target for improving the efficacy of immunotherapy.
Case report: Novel treatment regimen for enterovirus encephalitis in SCID
Authors: Chetty Kritika , Cheng Iek , Kaliakatsos Marios , Gonzalez-Granado Luis Ignacio , Klapsa Dimitra , Martin Javier , Bamford Alasdair , Breuer Judith , Booth Claire
Published: September 2022

Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post–gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.
HLAII peptide presentation of infliximab increases when complexed with TNF
Authors: Casasola-LaMacchia Andrea , Seward Robert Joseph , Tourdot Sophie , Willetts Matthew , Kruppa Gary , Agostino Michael J. , Bergeron Gabrielle , Ahyi-Amendah Nathalie , Ciarla Andrew , Lu Zhaojiang , Kim Hai-Young , Hickling Timothy P. , Neubert Hendrik
Published: September 2022

CD4+ T-cell activation through recognition of Human Leukocyte Antigen II (HLAII)-presented peptides is a key step in the development of unwanted immune response against biotherapeutics, such as the generation of anti-drug antibodies (ADA). Therefore, the identification of HLAII-presented peptides derived from biotherapeutics is a crucial part of immunogenicity risk assessment and mitigation strategies during drug development. To date, numerous CD4+ T-cell epitopes have been identified by HLAII immunopeptidomics in antibody-based biotherapeutics using either their native or aggregated form. Antibody-target immune complexes have been detected in patients with ADA and are thought to play a role in ADA development by enhancing the presentation of CD4+ T-cell epitopes at the surface of antigen presenting cells (APCs). The aim of this study was to investigate the effect of biotherapeutic antibody-target immune complexes on the HLAII peptide presentation of biotherapeutics in human primary monocyte-derived dendritic cells (DCs). The trimeric tumor necrosis factor (TNF) and its biotherapeutic antagonists infliximab (INFL), adalimumab (ADAL), and a single armed Fab’ were used as a model system. The HLAII immunopeptidome of DCs loaded with antagonists or their immune complexes with TNF was analyzed by trapped ion mobility time-of-flight mass spectrometry (timsTOF MS) leading to the identification of ~ 12,000 unique HLAII-associated peptides per preparation. Anti-TNF sequences were detected at a median of 0.3% of the total immunopeptidome, against a majority background of peptides from endogenous and media-derived proteins. TNF antagonist presentation spanned the variable and constant regions in a widespread manner in both light and heavy chains, consistent with previously discovered HLAII peptides. This investigation extends the collection of observed HLAII peptides from anti-TNF biotherapeutics to include sequences that at least partially span the complementary determining regions (CDRs), such as the LCDR1 for both INFL and ADAL. Although antagonist presentation varied significantly across donors, peptides from both bivalent antagonists INFL and ADAL were more highly presented relative to the Fab’. While TNF immune complexes did not alter overall HLAII presentation, a moderate increase in presentation of a subset of peptide clusters was observed in the case of INFL-TNF, which included HCDR2, HCDR3 and LCDR2 sequences.
The pyroptosis-related gene signature predicts prognosis and indicates the immune microenvironment status of chronic lymphocytic leukemia
Authors: Sha Yeqin , Jiang Rui , Miao Yi , Qin Shuchao , Wu Wei , Xia Yi , Wang Li , Fan Lei , Jin Hui , Xu Wei , Li Jianyong , Zhu Huayuan
Published: September 2022

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with great heterogeneity. Pyroptosis has recently been recognized as an inflammatory form of programmed cell death (PCD) and shares a close relationship with apoptosis. Although the role of apoptosis in CLL was comprehensively studied and successfully applied in clinical treatment, the relationship between pyroptosis genes and CLL remained largely unknown. In this study, eight differentially expressed pyroptosis-related genes (PRGs) were identified between CLL and normal B cells. In order to screen out the prognostic value of differentially expressed PRGs, univariate and multivariate Cox regression analyses were conducted and a risk model with three PRG signatures (GSDME, NLRP3, and PLCG1) was constructed. All CLL samples were stratified into high- and low-risk subgroups according to risk scores. The risk model showed high efficacy in predicting both overall survival (OS) and time to first treatment (TTFT). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) showed the dysregulation of immune and inflammatory response in the high-risk group. Single-sample GSEA (ssGSEA) of immune cell infiltration and the activity of immune-related pathways also displayed decreased antitumor immunity in the high-risk group. In conclusion, PRGs are of prognostic value in CLL and may play important roles in tumor immunity, and the underlying relationship between PRGs and CLL needs to be explored further.
Antitumor effects of fecal microbiota transplantation: Implications for microbiome modulation in cancer treatment
Authors: Xu Hui , Cao Chenxi , Ren Yuqing , Weng Siyuan , Liu Long , Guo Chunguang , Wang Libo , Han Xinwei , Ren Jianzhuang , Liu Zaoqu
Published: September 2022

Fecal microbiome transplantation (FMT) from healthy donors is one of the techniques for restoration of the dysbiotic gut, which is increasingly being used to treat various diseases. Notably, mounting evidence in recent years revealed that FMT has made a breakthrough in the oncology treatment area, especially by improving immunotherapy efficacy to achieve antitumor effects. However, the mechanism of FMT in enhancing antitumor effects of immune checkpoint blockers (ICBs) has not yet been fully elucidated. This review systematically summarizes the role of microbes and their metabolites in the regulation of tumor immunity. We highlight the mechanism of action of FMT in the treatment of refractory tumors as well as in improving the efficacy of immunotherapy. Furthermore, we summarize ongoing clinical trials combining FMT with immunotherapy and further focus on refined protocols for the practice of FMT in cancer treatment, which could guide future directions and priorities of FMT scientific development.
Diet, microbiota, and the mucus layer: The guardians of our health
Authors: Suriano Francesco , Nyström Elisabeth E. L. , Sergi Domenico , Gustafsson Jenny K.
Published: September 2022

The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and high-fat diets in shaping intestinal homeostasis by modulating the gut microbiota.
Benzophenone-3 and antinuclear antibodies in U.S. adolescents and adults ages 12-39 years
Authors: Parks Christine G. , Meier Helen C. S. , Jusko Todd A. , Wilkerson Jesse , Miller Frederick W. , Sandler Dale P.
Published: September 2022

Background

Between 1988 and 2012, prevalence of antinuclear antibodies (ANA) increased in the U.S., especially in adolescents and non-Hispanic Whites. Female predominance of ANA suggests a role for hormonal factors, including xenobiotic exposures that may disrupt endocrine signaling. Benzophenone-3 (BP-3) is one such chemical with increasing exposure through sunscreen use. We investigated whether urinary BP-3 levels were related to ANA in adolescents and young adults.

Methods

In a sample of 1,785 individuals ages 12-39 years in the National Health and Nutrition Examination Survey (NHANES; 2003-4, 2011-12), we examined cross-sectional associations of ANA (N=192; 3+ or 4+ at the 1:80 dilution, measured by HEp-2 immunofluorescence) with urinary BP-3, and other phenols bisphenol-A, triclosan, and parabens. Adjusted prevalence odds ratios (POR) were calculated in season-stratified models [winter (November-April) and summer (May-October)], given differences in sunscreen use and BP-3 concentrations.

Results

BP-3 concentrations (detected in >98.5% of individuals) did not differ by ANA positivity in the summer (geometric mean, GM 30.6 ng/ml ANA-positive vs. 35.3 ANA-negative; GM ratio 1.15), but in winter were higher among ANA-positives (50.2 vs. 20.1 ANA-negative; GM ratio 2.50). ANA was associated with log10BP-3 in winter (POR 1.57; 95%CI 1.07-2.30 per unit increase) but not summer (0.94; 0.61, 1.44; interaction p=0.09). Triclosan, parabens, and bisphenol-A levels were unrelated to ANA overall or by season (ORs 0.64 to 1.33).

Conclusions

The association of urinary BP-3 with ANA in the winter may reflect different exposure patterns or unmeasured confounders. Findings warrant replication in prospective studies and including past and year-round exposures.
Efficacy, immunogenicity and safety of COVID-19 vaccines in older adults: a systematic review and meta-analysis
Authors: Li Zejun , Liu Shouhuan , Li Fengming , Li Yifeng , Li Yilin , Peng Pu , Li Sai , He Li , Liu Tieqiao
Published: September 2022

Background

Older adults are more susceptible to severe health outcomes for coronavirus disease 2019 (COVID-19). Universal vaccination has become a trend, but there are still doubts and research gaps regarding the COVID-19 vaccination in the elderly. This study aimed to investigate the efficacy, immunogenicity, and safety of COVID-19 vaccines in older people aged ≥ 55 years and their influencing factors.

Methods

Randomized controlled trials from inception to April 9, 2022, were systematically searched in PubMed, EMBASE, the Cochrane Library, and Web of Science. We estimated summary relative risk (RR), rates, or standardized mean difference (SMD) with 95% confidence interval (CI) using random-effects meta-analysis. This study was registered with PROSPERO (CRD42022314456).

Results

Of the 32 eligible studies, 9, 21, and 25 were analyzed for efficacy, immunogenicity, and safety, respectively. In older adults, vaccination was efficacious against COVID-19 (79.49%, 95% CI: 60.55−89.34), with excellent seroconversion rate (92.64%, 95% CI: 86.77−96.91) and geometric mean titer (GMT) (SMD 3.56, 95% CI: 2.80−4.31) of neutralizing antibodies, and provided a significant protection rate against severe disease (87.01%, 50.80−96.57). Subgroup and meta-regression analyses consistently found vaccine types and the number of doses to be primary influencing factors for efficacy and immunogenicity. Specifically, mRNA vaccines showed the best efficacy (90.72%, 95% CI: 86.82−93.46), consistent with its highest seroconversion rate (98.52%, 95% CI: 93.45−99.98) and GMT (SMD 6.20, 95% CI: 2.02−10.39). Compared to the control groups, vaccination significantly increased the incidence of total adverse events (AEs) (RR 1.59, 95% CI: 1.38−1.83), including most local and systemic AEs, such as pain, fever, chill, etc. For inactivated and DNA vaccines, the incidence of any AEs was similar between vaccination and control groups (p > 0.1), while mRNA vaccines had the highest risk of most AEs (RR range from 1.74 to 7.22).

Conclusion

COVID-19 vaccines showed acceptable efficacy, immunogenicity and safety in older people, especially providing a high protection rate against severe disease. The mRNA vaccine was the most efficacious, but it is worth surveillance for some AEs it caused. Increased booster coverage in older adults is warranted, and additional studies are urgently required for longer follow-up periods and variant strains.
The emerging roles of piezo1 channels in animal models of multiple sclerosis
Authors: Yang Kai , He Xueai , Wu Zhengqi , Yin Yimeng , Pan Hanyu , Zhao Xinyue , Sun Taolei
Published: September 2022

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative disease in the central nervous system (CNS). Its pathogenesis is quite complex: Accumulated evidence suggests that biochemical signals as well as mechanical stimuli play important roles in MS. In both patients and animal models of MS, brain viscoelasticity is reduced during disease progression. Piezo mechanosensitive channels are recently discovered, and their three-dimensional structure has been solved. Both the membrane dome mechanism and the membrane footprint hypothesis have been proposed to explain their mechanosensitivity. While membrane-mediated forces alone appear to be sufficient to induce Piezo gating, tethers attached to the membrane or to the channel itself also seem to play a role. Current research indicates that Piezo1 channels play a key role in multiple aspects of MS pathogenesis. Activation of Piezo1 channels in axon negatively regulates CNS myelination. in addition, the inhibition of Piezo1 in CD4+ T cells and/or T regulatory cells (Treg) attenuates experimental autoimmune encephalitis (EAE) symptoms. Although more work has to be done to clarify the roles of Piezo1 channels in MS, they might be a promising future drug target for MS treatment.
Identification of cuproptosis-related subtypes, cuproptosis-related gene prognostic index in hepatocellular carcinoma
Authors: Ding Lei , Li Wei , Tu Jili , Cao Zhixing , Li Jizheng , Cao Haiming , Liang Junjie , Liang Yiming , Yu Qiangfeng , Li Gencong
Published: September 2022

Cuproptosis is a novel form of cell death, correlated with the tricarboxylic acid (TCA) cycle. However, the metabolic features and the benefit of immune checkpoint inhibitor (ICI) therapy based on cuproptosis have not yet been elucidated in Hepatocellular carcinoma (HCC). First, we identified and validated three cuproptosis subtypes based on 10 cuproptosis-related genes (CRGs) in HCC patients. We explored the correlation between three cuproptosis subtypes and metabolism-related pathways. Besides, a comprehensive immune analysis of three cuproptosis subtypes was performed. Then, we calculated the cuproptosis-related gene prognostic index (CRGPI) score for predicting prognosis and validated its predictive capability by Decision curve analysis (DCA). We as well explored the benefit of ICI therapy of different CRGPI subgroups in two anti-PD1/PD-L1 therapy cohorts (IMvigor210 cohort and GSE176307). Finally, we performed the ridge regression algorithm to calculate the IC50 value for drug sensitivity and Gene set enrichment analysis (GSEA) analysis to explore the potential mechanism. We found that cluster A presented a higher expression of FDX1 and was correlated with metabolism, glycolysis, and TCA cycle pathways, compared with the other two clusters. HCC patients with high CRGPI scores had a worse OS probability, and we further found that the CRGPI-high group had high expression of PD1/PDL1, TMB, and better response (PR/CR) to immunotherapy in the IMvigor210 cohort and GSE176307. These findings highlight the importance of CRGPI serving as a potential biomarker for both prognostic and immunotherapy for HCC patients. Generally, our results provide novel insights about cuproptosis into immune therapeutic strategies.
Plasma-derived exosomal mRNA profiles associated with type 1 diabetes mellitus
Authors: Fan Wenqi , Pang Haipeng , Shi Xiajie , Li Jiaqi , Wang Yimeng , Luo Shuoming , Lin Jian , Yu Haibo , Xiao Yang , Li Xia , Huang Gan , Xie Zhiguo , Zhou Zhiguang
Published: September 2022

Background

Exosomes carry various types of transcripts, such as messenger RNAs (mRNAs), and play an important role in mediating cell-to-cell communication, thus influencing multiple physiological and pathological processes. However, the role of exosomal mRNAs in T1DM is largely unknown. Here, we aimed to identify the plasma-derived exosomal mRNA expression profiles in T1DM and to explore their potential biological functions in T1DM.

Materials and Methods

Plasma-derived exosomes were isolated from 10 patients with T1DM and 10 age- and sex-matched control subjects by size exclusion chromatography methods. Transmission electron microscopy, nanoparticle tracking analysis, and western blot analysis confirmed the presence of exosomes. The exosomal mRNAs were analyzed using the Illumina HiSeq platform. Six differentially expressed mRNAs (DEMs) were randomly selected to determine the expression level by quantitative real-time PCR (qRT−PCR) in a larger cohort (T1DM subjects N=40; control subjects N=40). The biological functions of DEMs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein−protein interaction networks were constructed to explore the potential associations among DEMs.

Results

In total, 112 DEMs were identified in T1DM, among which 66 mRNAs were upregulated and 46 mRNAs were downregulated. Four of six candidate exosomal mRNAs were successfully validated by qRT−PCR. Bioinformatics analysis indicated that these mRNAs were most significantly involved in positive regulation by host viral transcription (GO enrichment analysis) and oxidative phosphorylation (KEGG pathway analysis).

Conclusions

Our study reported the plasma-derived exosomal mRNA expression profiles of T1DM for the first time. The identified DEMs might be associated with the pathogenesis of T1DM, and some DEMs have the potential to serve as biomarkers and therapeutic targets for T1DM.