bluuebunny/crossref_metadata_2025 huggingface dataset:
Características clínicas y pronóstico de los pacientes con linfoma leucemia de células t del adulto
Authors: Valdivieso Lama Natalia , Barrionuevo Cornejo Carlos , Vidal Ayllon Judith , Casanova Marquez Luis , Flores Flores Claudio , López Chavez Lourdes , Alcarraz Molina Cindy , Ruiz Mendoza Rossana , Quintana Truyenque Shirley
Published: December 2022

Introducción: El objetivo del presente estudio fue determinar las características clínicas y pronóstico de los pacientes con Leucemia/Linfoma de Células T del Adulto (ATL) en el Instituto Nacional de Enfermedades Neoplásicas (INEN) de Perú.
Metodología: Se realizó un estudio transversal, que incluyó por Se revisaron 188 historias clínicas y estudio patológico de pacientes con infección por HTLV-1 diagnosticados en el INEN durante 10 años, de quienes 150 tuvieron ATL.
Resultados: 62% de los pacientes tuvieron el subtipo ATL linfoma, 37% subtipo agudo y 1% crónico. La mediana de edad fue 53 años (20-89); 51% fueron mujeres. Dentro de las características clínicas: ECOG > o = 2 (56%); estadio clínico III-IV (80%), síntomas B (58%); incremento de la deshidrogenasa láctica, LDH, (74%); leucocitosis (50%); hipercalcemia (46%) y anemia (36%). 122 pacientes (81,3%) recibieron tratamiento, 79% con quimioterapia (QT) y 4,6% radioterapia complementaria (RT); CHOP fue el esquema de QT más frecuente (89%). De los pacientes con QT tuvieron 18% RC, 32% RP, 7% EE y 13% PE.
Conclusión: En este reporte en pacientes con ATL, la forma linfoma es el subtipo más frecuente, existe alta prevalencia de inmunofenotipo atípico y pobre respuesta al CHOP.
Potential diagnostic of lymph node metastasis and prognostic values of TM4SFs in papillary thyroid carcinoma patients
Authors: Wang Kun , Li Haomin , Zhao Junyu , Yao Jinming , Lu Yiran , Dong Jianjun , Bai Jie , Liao Lin
Published: December 2022

Background: Although the prognosis of papillary thyroid carcinoma (PTC) is relatively good, it causes around 41,000 deaths per year, which is likely related to recurrence and metastasis. Lymph node metastasis (LNM) is an important indicator of PTC recurrence and transmembrane 4 superfamily (TM4SF) proteins regulate metastasis by modulating cell adhesion, migration, tissue differentiation, and tumor invasion. However, the diagnostic and prognostic values of TM4SF in PTC remain unclear.

Methods: This study aimed to identify TM4SF genes with predictive value for LNM and prognostic value in PTC using bioinformatic analysis. We screened the differentially expressed genes (DEGs) of the TM4SF family in PTC using data from TCGA, constructed a PPI network using STRING, and evaluated the predictive role of TM4SF1 in LNM via a binary logistic regression analysis and ROC curve. We assessed the association between TM4SF1 expression and DNA methylation, and determined the functional and mechanistic role of TM4SF1 in promoting LNM via GSEA, KEGG, and GO. We estimated the relationship between each TM4SF gene and overall survival (OS, estimated by Kaplan-Meier analysis) in patients with PTC and established a predictive model of prognostic indicators using a LASSO penalized Cox analysis to identify hub genes. Finally, we explored the correlation between TM4SFs and TMB/MSI.

Results: We identified 21 DEGs from the 41 TM4SFs between N0 (without LNM) and N1 (with LNM) patients, with TM4SF1, TM4SF4, UPK1B, and CD151 being highly expressed in the N1 group; several DEGs were observed in the TNM, T, and N cancer stages. The “integrins and other cell-surface receptors” pathway was the most significantly enriched functional category related to LNM and TM4SFs. TM4SF1 was identified as an indicator of LNM (AUC= 0.702). High levels of TM4SF1 might be related to Wnt/β-catenin pathway and epithelial–mesenchymal transition (EMT) process in PTC. The higher expression of TM4SF1 was also related to DNA promoter hypomethylation. CD9, TM4SF4, TSPAN2, and TSPAN16 were associated with OS in PTC patients and TSPAN2 has great potential to become a prognostic marker of PTC progression. For the prognostic model, the riskscore = (-0.0058)*CD82+(-0.4994)*+(0.1584)*TSPAN11+(1.7597)*TSPAN19+(0.2694)*TSPAN2 (lambda.min = 0.0149). The AUCs for 3-year, 5-year, and 10-year OS were 0.81, 0.851, and 0.804. TSPAN18, TSPAN31, and TSPAN32 were associated with both TMB and MSI in PTC patients.

Conclusion: Our findings identified TM4SF1 as a potential diagnostic marker of LNM and TSPAN2 as a prognostic factor for patients with PTC. Our study provides a novel strategy to assess prognosis and predict effective treatments in PTC.
Blastocyst complementation and interspecies chimeras in gene edited pigs
Authors: Choe Yong-ho , Sorensen Jacob , Garry Daniel J. , Garry Mary G.
Published: December 2022

The only curative therapy for many endstage diseases is allograft organ transplantation. Due to the limited supply of donor organs, relatively few patients are recipients of a transplanted organ. Therefore, new strategies are warranted to address this unmet need. Using gene editing technologies, somatic cell nuclear transfer and human induced pluripotent stem cell technologies, interspecies chimeric organs have been pursued with promising results. In this review, we highlight the overall technical strategy, the successful early results and the hurdles that need to be addressed in order for these approaches to produce a successful organ that could be transplanted in patients with endstage diseases.
Electrical and magnetic properties of antiferromagnetic semiconductor MnSi2N4 monolayer
Authors: Chen Dongke , Jiang Zhengyu , Tang Ying , Zhou Junlei , Gu Yuzhou , He Jing-Jing , Yuan Jiaren
Published: December 2022

Two-dimensional antiferromagnetic semiconductors have triggered significant attention due to their unique physical properties and broad application. Based on first-principles calculations, a novel two-dimensional (2D) antiferromagnetic material MnSi2N4 monolayer is predicted. The calculation results show that the two-dimensional MnSi2N4 prefers an antiferromagnetic state with a small band gap of 0.26 eV. MnSi2N4 has strong antiferromagnetic coupling which can be effectively tuned under strain. Interestingly, the MnSi2N4 monolayer exhibits a half-metallic ferromagnetic properties under an external magnetic field, in which the spin-up electronic state displays a metallic property, while the spin-down electronic state exhibits a semiconducting characteristic. Therefore, 100% spin polarization can be achieved. Two-dimensional MnSi2N4 monolayer has potential application in the field of high-density information storage and spintronic devices.
Overexpression of proinflammatory cytokines in dental pulp tissue and distinct bacterial microbiota in carious teeth of Mexican Individuals
Authors: Gómez-García Ana Pamela , López-Vidal Yolanda , Pinto-Cardoso Sandra , Aguirre-García María Magdalena
Published: December 2022

The prevalence of dental caries in the Mexican adult population aged 20 to 85 years is around 93.3%, and 50% in Mexican children and adolescents. Worldwide, it is the most common non-communicable disease. One of the main etiological factors for dental caries is the oral microbiome and changes in its structure and function, with an expansion of pathogenic bacteria like Streptococcus mutans. The exposed dental pulp tissue triggers an innate immune response to counteract this bacterial invasion. The relation between oral dysbiosis and innate immune responses remains unclear. We aimed to understand the relationship between innate immune response and the oral microbiota by quantifying the expression of Toll-like receptors (TLRs) and proinflammatory markers (cytokines and a chemokine) in dental pulp tissue, either exposed or not to carious dentin, and to correlate this information with the oral microbiome found in healthy teeth and those with moderate caries. RNA was purified from pulp tissue, subjected to RT-qPCR and analysed with the ΔΔCt method. Supragingival dental plaque of non-carious teeth and dentin of carious teeth were subjected to 16S targeted sequencing. Principal coordinate analysis, permutational multivariate ANOVA, and linear discriminant analysis were used to assess differences between non-carious and carious teeth. Correlations were assessed with Spearman´s test and corrected for multiple comparisons using the FDR method. The relative abundance (RA) of Lactobacillus, Actinomyces, Prevotella, and Mitsuokella was increased in carious teeth; while the RA of Haemophilus and Porphyromonas decreased. Olsenella and Parascardovia were only detected in carious teeth. Significant overexpression of interleukin 1 beta (IL1 β), IL6, and CXCL8 was detected in pulp tissue exposed to carious dentin. IL1β correlated positively with TLR2 and Actinomyces; yet negatively with Porphyromonas. These findings suggest that immune response of pulp tissue chronically exposed to cariogenic microbiome is triggered by proinflammatory cytokines IL1β and IL6 and the chemokine CXCL8.
Risk factors, clinical features, and outcomes of patients with hypertrophic cardiomyopathy complicated by ischemic stroke: A single-center retrospective study
Authors: Lu Jian-Feng , Fan Ze-Xin , Li Ying , Wang Ze-Yi , Ma Lin , Yuan Bo-Yi , Yang Ting-Ting , Liu Pen-Ju , Liu Guang-Zhi
Published: December 2022

Objective

This study aimed to explore risk factors, clinical features, and prognosis of patients with hypertrophic cardiomyopathy (HCM) complicated by ischemic stroke (IS).

Methods

We conducted a retrospective analysis of all HCM patient data and a 1-year follow-up study.

Results

Totally, 506 patients with HCM, including 71 with IS, were enrolled. Older age (≥63 years) was associated with an increased risk of IS in HCM patients (OR = 1.045, 95% CI: 1.018–1.072, p = 0.001). Among 37 patients complicated by IS, 22 (59.5%, 22/37) manifested as cardioembolism (CE) subtype, and 13 (35.1%, 3/37) small artery occlusion (SAO) subtype, according to TOAST classification. In the acute phase, the IS patients presented with NIHSS 4 (interquartile range: 1, 10). Multi-infarction was more common than single infarction (72.7 vs. 27.3%), while cortical + subcortical infarction (CE group: 50%) or subcortical infarction (SAO group: 53.8%) constituted most IS cases. Additionally, the blood supply areas of anterior circulation (CE group: 45.5%; SAO group: 92.3%) or anterior + posterior circulation (CE group: 50%) were mainly involved. The 1-year survival rate of HCM patients with concomitant IS was 81.8%, and IS was associated with 1-year all-cause death in HCM patients (HR = 5.689, 95% CI: 1.784–18.144, p = 0.003).

Conclusion

Older age is a risk factor for IS occurrence in HCM patients. Patients with HCM complicated by IS had mild or moderate neurologic deficits at disease onset. CE and SAO subtypes predominate in patients with concomitant IS, especially the former. Multiple cortical and subcortical infarctions are their neuroimaging characteristics, mainly involving the anterior circulation or anterior + posterior circulation. Is is a risk factor for all-cause death in HCM patients within 1 year.
Enhanced neurologic concept recognition using a named entity recognition model based on transformers
Authors: Azizi Sima , Hier Daniel B. , Wunsch II Donald C.
Published: December 2022

Although deep learning has been applied to the recognition of diseases and drugs in electronic health records and the biomedical literature, relatively little study has been devoted to the utility of deep learning for the recognition of signs and symptoms. The recognition of signs and symptoms is critical to the success of deep phenotyping and precision medicine. We have developed a named entity recognition model that uses deep learning to identify text spans containing neurological signs and symptoms and then maps these text spans to the clinical concepts of a neuro-ontology. We compared a model based on convolutional neural networks to one based on bidirectional encoder representation from transformers. Models were evaluated for accuracy of text span identification on three text corpora: physician notes from an electronic health record, case histories from neurologic textbooks, and clinical synopses from an online database of genetic diseases. Both models performed best on the professionally-written clinical synopses and worst on the physician-written clinical notes. Both models performed better when signs and symptoms were represented as shorter text spans. Consistent with prior studies that examined the recognition of diseases and drugs, the model based on bidirectional encoder representations from transformers outperformed the model based on convolutional neural networks for recognizing signs and symptoms. Recall for signs and symptoms ranged from 59.5% to 82.0% and precision ranged from 61.7% to 80.4%. With further advances in NLP, fully automated recognition of signs and symptoms in electronic health records and the medical literature should be feasible.
A newly identified cryogenian (ca. 806 ma) basement tonalite gneiss from the Eastern Karakoram, NW India: Constraints from geochemistry and zircon U-Pb geochronology
Authors: Pundir Shailendra , Adlakha Vikas , Kumar Santosh , Singhal Saurabh , Das Satyabrata
Published: December 2022

The Karakoram Terrane (KT) represents the southern margin of the Eurasian Plate, mainly consisting of Late Jurassic-Early Cretaceous subduction-related granites and post-collisional Miocene leucogranites, which intrude the Late Neo-Proterozoic basement. We report for the first time the existence of the Cryogenian KT basement as recorded from the geochemistry and geochronology of tonalite gneiss (ca. 806 Ma) in the southeastern Karakoram terrane, NW India. Geochemically, the studied tonalite gneiss is slightly peraluminous (Molar Al2O3/CaO+Na2O+K2O=1.1), calc-alkaline volcanic-arc granitoid, strongly fractionated REE (LaN/YbN=33.99), and high Sr/Y =19.75, more akin to its affinity with Tonalite–trondhjemite–granodiorite (TTG)/adakite. The whole-rock elemental data suggest that tonalite gneiss is more likely sourced from ancient mafic lower crust where garnet remained in the residue. The petrogenetic modeling of REE suggests that the melt similar to the observed tonalite gneiss can be generated through ∼50% partial melting of a mafic lower crust with garnet, clinopyroxene, and amphibole assemblage. The synthesis and comparison of present and published Proterozoic magmatic records on the rocks from KT strongly dictate that the produced partial melt similar to observed tonalite gneiss most likely served as the parental melt for the development of TTGs in the Southern Pamir and more evolved granitoid in the Central Tibetan terrane. We propose that the studied tonalite gneiss from the southeast Karakoram is a product of Neoproterozoic Andean-type orogeny formed on the northwestern margin of the Rodinia supercontinent. Thus, our study favors the first time, the position of KT within the Cimmerian belt along with other East Asian continental blocks.
Risk prediction model establishment with tri-phasic CT image features for differential diagnosis of adrenal pheochromocytomas and lipid-poor adenomas: Grouping method
Authors: Niu Zhongfeng , Wang Jian , Yang Yang , He Jie , Wang Subo , Xie Zongyu , Shao Meihua , Zhu Fangmei
Published: December 2022

Objectives

The purpose of this study was to establish a risk prediction model for differential diagnosis of pheochromocytomas (PCCs) from lipid-poor adenomas (LPAs) using a grouping method based on tri-phasic CT image features.

Methods

In this retrospective study, we enrolled patients that were assigned to a training set (136 PCCs and 183 LPAs) from two medical centers, along with an external independent validation set (30 PCCs and 54 LPAs) from another center. According to the attenuation values in unenhanced CT (CTu), the lesions were divided into three groups: group 1, 10 HU < CTu ≤ 25 HU; group 2, 25 HU < CTu ≤ 40 HU; and group 3, CTu > 40 HU. Quantitative and qualitative CT imaging features were calculated and evaluated. Univariate, ROC, and binary logistic regression analyses were applied to compare these features.

Results

Cystic degeneration, CTu, and the peak value of enhancement in the arterial and venous phase (DEpeak) were independent risk factors for differential diagnosis of adrenal PCCs from LPAs. In all subjects (groups 1, 2, and 3), the model formula for the differentiation of PCCs was as follows: Y = -7.709 + 3.617*(cystic degeneration) + 0.175*(CTu ≥ 35.55 HU) + 0.068*(DEpeak ≥ 51.35 HU). ROC curves were drawn with an AUC of 0.95 (95% CI: 0.927–0.973) in the training set and 0.91 (95% CI: 0.860–0.929) in the external validation set.

Conclusion

A reliable and practical prediction model for differential diagnosis of adrenal PCCs and LPAs was established using a grouping method.
Green finance and industrial pollution: Empirical research based on spatial perspective
Authors: Zhang Lechao , Mei Zihan
Published: December 2022

Green finance is an important means to promote industrial pollution reduction. This paper uses the entropy method and the TOPSIS model to calculate the green finance development index and industrial pollution index of 30 provinces in China from 2011 to 2019, and further uses the panel regression model and SDM model to test the impact of green finance on industrial pollution. The study found that there is a significant positive spatial correlation between green finance and industrial pollution; At the same time, green finance generally inhibits industrial pollution. The effect decomposition results show that the former has a significant negative direct effect and spatial spillover effect on the latter.
The rocky desertification management in Guizhou province under the localized governance system
Authors: Yuan Liang , Liu Wendao , Su Shan , Chen Zhuo
Published: December 2022

Guizhou Province has shown remarkable rocky desertification management results in this century. However, under the localized governance system, the division of Guizhou’s rocky desertification management zoning map has also shown its drawbacks. The conflicts arising from the localized governance system in China and rocky desertification management in Guizhou are mainly demonstrated by the following manifestations: 1) areas originally required for integrated governance are divided by different municipal administrative affiliations, resulting in the inability to coordinate governance; 2) the same administrative affiliation of the counties is divided into different areas of governance. The key factor is the differentiation of governance due to administrative division, including constraints such as differences in the focus of governance, governance tools and governance philosophy. Based on this, it is recommended that local governance focus on cross-administrative cooperation as well as the reasonable adjusting and promoting of governance boundaries.
The evolution of public sentiment toward government management of emergencies: Social media analytics
Authors: Pi Zhongxu , Feng Hao
Published: December 2022

At present, social media have become the main media of network public opinion (PO) dissemination. By analyzing the trend of emotional development in public emergencies, we can explore the evolution law of PO and identify potential risks, which provide decision support for the guidance and control of government management. First, based on the concept of critical points in the complex system, this study established a public sentiment (PS) evolution model under public emergencies and proposed an algorithm to identify the critical points in PS based on microblog data analysis. In addition, the BC-BIRCH algorithm was used to construct a topic clustering model for public emergencies, which improved the effect of topic discovery by merging multiple topic clusters. The evolution of public emergencies was analyzed by calculating the emotional heat value of different topic events. Finally, experimental results showed that the emotion of netizens' fluctuates greatly in the initial stage of PO under different themes. The method used in this paper achieved good results in topic clustering, critical point prediction, and PO evolution analysis of public emergencies. The main contribution of this paper is to analyze the evolution of the internal mechanism of PS and to identify and predict key nodes such as the outbreak and extinction of netizens' sentiment based on data-driven methods so as to provide the basis and support to the government and related media as the main body of prevention and control to respond in advance and guide in time.
Pre-but not post-meiotic senescence affects sperm quality and reproductive success in the North African houbara bustard
Authors: Meunier Léna , Sorci Gabriele , Abi Hussein Hiba , Hingrat Yves , Rehspringer Noé , Saint-Jalme Michel , Lesobre Loïc , Torres Carreira Janaina
Published: December 2022

Age-dependent reduction in reproductive success can arise due to multiple factors including a deterioration of reproductive physiology. Senescing males have been shown to produce ejaculates with poor sperm quality, which impinges on male reproductive success. In addition to individual age, gamete age can also affect male reproductive success. Accordingly, variance in male reproductive success can be due to pre-meiotic (referring to individual age) and post-meiotic senescence (sperm age). Here, we tested whether male senescence and sperm cell aging have additive or interactive effects on male reproductive success in a bird with a promiscuous mating system, the North African houbara bustard. To assess the effect of pre-meiotic aging, we compared male reproductive success between two age classes (3-6- and 12–16-year-old). To infer the effect of post-meiotic aging, male ejaculates were collected at three-time intervals following a common initial collection (day 1, 5, and 10). Therefore, day 1 ejaculates are supposed to contain younger sperm than day 5 and 10 ejaculates. Following controlled artificial inseminations, reproductive success was assessed using three fitness-linked traits (hatching success, chick growth rate and survival). In addition to reproductive output, we also assessed whether pre- and post-meiotic aging affected a wide range of sperm and ejaculate traits. In agreement with previous reports, we found that males in the older age class produced less sperm with poorer motility compared to young individuals. However, contrary to the prediction, we found that ejaculates collected at day 5 and 10 tended to have better sperm traits such as motility and velocity. The results on sperm traits were generally mirrored in the effect on reproductive success since young males produced offspring that grew faster and had better survival during the first month of life, and eggs fertilized by sperm collected at day 5 had the highest hatching success. In any of the models, there was evidence for interactive effects of male and sperm age. Overall, these results confirm the role of pre-meiotic aging on male reproductive success. The lack of evidence for sperm aging could come from the experimental design but might also reflect the pattern of mating frequency in a species with a lek-based mating system.
Segawa syndrome caused by TH gene mutation and its mechanism
Authors: Wang Yilin , Wang Chunmei , Liu Meiyan , Xu Wuhen , Wang Simei , Yuan Fang , Luo Xiaona , Xu Quanmei , Yin Rongrong , Wang Anqi , Guo Miao , Lin Longlong , Wang Chao , Cheng Hongyi , Liu Zhiping , Zhang Yuanfeng , Zeng Fanyi , Yan Jingbin , Chen Yucai
Published: December 2022

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.
A pan-cancer analysis of the prognostic value of long non-coding RNA LINC00662 in human cancers
Authors: Zhang Guangming , Wu Bin , Fu Liangyin , Liu Bin , Han Xiaoyong , Wang Jie , Zhang Yipeng , Yu Miao , Ma Haizhong , Ma Shixun , Cai Hui
Published: December 2022

Background: Numerous studies have revealed that the long non-coding RNA LINC00662 is irregularly expressed in various cancers, as well as is correlated with cancer development and progression. Nevertheless, the clinical value of LINC00662 remains controversial. Hence, we explored the correlation of LINC00662 with cancer prognosis through meta-analysis and bioinformatics analysis.

Methods: From the beginning through 12 March 2022, we searched for correlational studies on Web of Science, Embase, PubMed and The Cochrane Library. We used pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) to determine the significance of studies on survival outcomes and clinicopathological aspects in human cancers. Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) database was employed to confirm our findings.

Results: Our meta-analysis of 14 studies comprising a total of 960 cancer patients revealed that LINC00662 overexpression was correlated with poor overall survival (HR = 1.91, 95% CI 1.49–2.45, p < 0.001) in cancer patients and relapse-free survival (HR = 2.12, 95% CI 1.19–3.76, p = 0.010) in hepatocellular carcinoma patients. The correlation between LINC00662 and OS was further supported by the results of subgroup analyses according to cancer type, follow-up time, HR availability, and NOS score. In addition, LINC00662 overexpression predicted advanced tumor stage (OR = 4.23, 95% CI 2.50–7.17, p < 0.001), larger tumor size (OR = 1.49, 95% CI 1.11–1.99, p = 0.008), earlier lymph node metastasis (OR = 2.40, 95% CI 1.25–4.59, p = 0.008), and earlier distant metastasis (OR = 4.78, 95% CI 2.57–8.88, p < 0.001). However, there were no statistically significant differences in age (OR = 1.16, 95% CI 0.90–1.51, p = 0.246), gender (OR = 1.10, 95% CI 0.79–1.53, p = 0.578), or differentiation grade (OR = 1.53, 95% CI 0.71–3.33, p = 0.280).

Conclusion: LINC00662 expression upregulation is associated with poor prognosis and advanced clinicopathological features in patients with multiple tumors. LINC00662 may serve as a biomarker for the diagnosis and treatment of patients with tumors.
Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications
Authors: Luo Liping , Zheng Qiaoyun , Chen Zhenyu , Huang Meijuan , Fu Lin , Hu Jianda , Shi Qizhen , Chen Yingyu
Published: December 2022

The development of coagulation factor VIII (FVIII) inhibitory antibodies is a serious complication in hemophilia A (HA) patients after FVIII replacement therapy. Inhibitors render regular prophylaxis ineffective and increase the risk of morbidity and mortality. Immune tolerance induction (ITI) regimens have become the only clinically proven therapy for eradicating these inhibitors. However, this is a lengthy and costly strategy. For HA patients with high titer inhibitors, bypassing or new hemostatic agents must be used in clinical prophylaxis due to the ineffective ITI regimens. Since multiple genetic and environmental factors are involved in the pathogenesis of inhibitor generation, understanding the mechanisms by which inhibitors develop could help identify critical targets that can be exploited to prevent or eradicate inhibitors. In this review, we provide a comprehensive overview of the recent advances related to mechanistic insights into anti-FVIII antibody development and discuss novel therapeutic approaches for HA patients with inhibitors.
Parasite infections, neuroinflammation, and potential contributions of gut microbiota
Authors: Alloo Jérémy , Leleu Ines , Grangette Corinne , Pied Sylviane
Published: December 2022

Many parasitic diseases (including cerebral malaria, human African trypanosomiasis, cerebral toxoplasmosis, neurocysticercosis and neuroschistosomiasis) feature acute or chronic brain inflammation processes, which are often associated with deregulation of glial cell activity and disruption of the brain blood barrier’s intactness. The inflammatory responses of astrocytes and microglia during parasite infection are strongly influenced by a variety of environmental factors. Although it has recently been shown that the gut microbiota influences the physiology and immunomodulation of the central nervous system in neurodegenerative diseases like Alzheimer’s disease and Parkinson’s, the putative link in parasite-induced neuroinflammatory diseases has not been well characterized. Likewise, the central nervous system can influence the gut microbiota. In parasite infections, the gut microbiota is strongly perturbed and might influence the severity of the central nervous system inflammation response through changes in the production of bacterial metabolites. Here, we review the roles of astrocytes and microglial cells in the neuropathophysiological processes induced by parasite infections and their possible regulation by the gut microbiota.
Identification of immune microenvironment subtypes and signature genes for Alzheimer’s disease diagnosis and risk prediction based on explainable machine learning
Authors: Lai Yongxing , Lin Peiqiang , Lin Fan , Chen Manli , Lin Chunjin , Lin Xing , Wu Lijuan , Zheng Mouwei , Chen Jianhao
Published: December 2022

Background

Using interpretable machine learning, we sought to define the immune microenvironment subtypes and distinctive genes in AD.

Methods

ssGSEA, LASSO regression, and WGCNA algorithms were used to evaluate immune state in AD patients. To predict the fate of AD and identify distinctive genes, six machine learning algorithms were developed. The output of machine learning models was interpreted using the SHAP and LIME algorithms. For external validation, four separate GEO databases were used. We estimated the subgroups of the immunological microenvironment using unsupervised clustering. Further research was done on the variations in immunological microenvironment, enhanced functions and pathways, and therapeutic medicines between these subtypes. Finally, the expression of characteristic genes was verified using the AlzData and pan-cancer databases and RT-PCR analysis.

Results

It was determined that AD is connected to changes in the immunological microenvironment. WGCNA revealed 31 potential immune genes, of which the greenyellow and blue modules were shown to be most associated with infiltrated immune cells. In the testing set, the XGBoost algorithm had the best performance with an AUC of 0.86 and a P-R value of 0.83. Following the screening of the testing set by machine learning algorithms and the verification of independent datasets, five genes (CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12) that were closely associated with AD pathological biomarkers and allowed for the accurate prediction of AD progression were found to be immune microenvironment-related genes. The feature gene-based nomogram may provide clinical advantages to patients. Two immune microenvironment subgroups for AD patients were identified, subtype2 was linked to a metabolic phenotype, subtype1 belonged to the immune-active kind. MK-866 and arachidonyltrifluoromethane were identified as the top treatment agents for subtypes 1 and 2, respectively. These five distinguishing genes were found to be intimately linked to the development of the disease, according to the Alzdata database, pan-cancer research, and RT-PCR analysis.

Conclusion

The hub genes associated with the immune microenvironment that are most strongly associated with the progression of pathology in AD are CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12. The hypothesized molecular subgroups might offer novel perceptions for individualized AD treatment.
Increased formation of neutrophil extracellular traps in patients with anti-N-methyl-d-aspartate receptor encephalitis
Authors: Qiao Shan , Sun Quan-ye , Zhou Peng , Zhang Shan-chao , Wang Zhi-hao , Li Hai-yun , Wang Ai-hua , Liu Xue-wu , Xin Tao
Published: December 2022

Background

Neutrophil extracellular traps (NETs) have been found to play an important role in several nervous system diseases. However, their role in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remains unclear. The purpose of this study was to examine the possible role of NETs in anti-NMDAR encephalitis.

Materials and methods

Eleven patients with anti-NMDAR encephalitis and ten healthy participants were enrolled. Plasma NETs levels were detected using an immunofluorescence assay and enzyme-linked immunosorbent assay. Additionally, we examined 10 plasma cytokines in patients with anti-NMDAR encephalitis and analyzed the correlation between citrullinated histone 3 levels and cytokine release.

Results

Peripheral blood neutrophils from patients with anti-NMDAR encephalitis were more susceptible to NET generation. When compared with controls, cases of anti-NMDAR encephalitis showed elevated levels of IL-1 α, IL-6, IL-8, IL-13, MCP-1, and TNF-α (p < 0.05). Moreover, IL-6, IL-8, and TNF-α levels were positively correlated with H3Cit levels.

Conclusion

We provide evidence that NETs may play a role in anti-NMDAR encephalitis, providing clues for elucidation of the pathogenesis of this disease.
A potential antibody repertoire diversification mechanism through tyrosine sulfation for biotherapeutics engineering and production
Authors: Zhong Xiaotian , D’Antona Aaron M.
Published: December 2022

The diversity of three hypervariable loops in antibody heavy chain and light chain, termed the complementarity-determining regions (CDRs), defines antibody’s binding affinity and specificity owing to the direct contact between the CDRs and antigens. These CDR regions typically contain tyrosine (Tyr) residues that are known to engage in both nonpolar and pi stacking interaction with antigens through their complementary aromatic ring side chains. Nearly two decades ago, sulfotyrosine residue (sTyr), a negatively charged Tyr formed by Golgi-localized membrane-bound tyrosylprotein sulfotransferases during protein trafficking, were also found in the CDR regions and shown to play an important role in modulating antibody-antigen interaction. This breakthrough finding demonstrated that antibody repertoire could be further diversified through post-translational modifications, in addition to the conventional genetic recombination. This review article summarizes the current advances in the understanding of the Tyr-sulfation modification mechanism and its application in potentiating protein-protein interaction for antibody engineering and production. Challenges and opportunities are also discussed.
Tartrate resistant acid phosphatase 5 (TRAP5) mediates immune cell recruitment in a murine model of pulmonary bacterial infection
Authors: Tanner Lloyd , Bergwik Jesper , Bhongir Ravi K. V. , Puthia Manoj , Lång Pernilla , Ali Mohamad N. , Welinder Charlotte , Önnerfjord Patrik , Erjefält Jonas S. , Palmberg Lena , Andersson Göran , Egesten Arne
Published: December 2022

Introduction

During airway infection, upregulation of proinflammatory cytokines and subsequent immune cell recruitment is essential to mitigate bacterial infection. Conversely, during prolonged and non-resolving airway inflammation, neutrophils contribute to tissue damage and remodeling. This occurs during diseases including cystic fibrosis (CF) and COPD where bacterial pathogens, not least Pseudomonas aeruginosa, contribute to disease progression through long-lasting infections. Tartrate-resistant acid phosphatase (TRAP) 5 is a metalloenzyme expressed by alveolar macrophages and one of its target substrates is the phosphoglycoprotein osteopontin (OPN).

Methods

We used a knockout mouse strain (Trap5-/-) and BALB/c-Tg (Rela-luc)31Xen mice paired with siRNA administration or functional protein add-back to elucidate the role of Trap5 during bacterial infection. In a series of experiments, Trap5-/- and wild-type control mice received intratracheal administration of P.aerugniosa (Xen41) or LPS, with mice monitored using intravital imaging (IVIS). In addition, multiplex cytokine immunoassays, flow cytometry, multispectral analyses, histological staining were performed.

Results

In this study, we found that Trap5-/- mice had impaired clearance of P. aeruginosa airway infection and reduced recruitment of immune cells (i.e. neutrophils and inflammatory macrophages). Trap5 knockdown using siRNA resulted in a decreased activation of the proinflammatory transcription factor NF-κB in reporter mice and a subsequent decrease of proinflammatory gene expression. Add-back experiments of enzymatically active TRAP5 to Trap5-/- mice restored immune cell recruitment and bacterial killing. In human CF lung tissue, TRAP5 of alveolar macrophages was detected in proximity to OPN to a higher degree than in normal lung tissue, indicating possible interactions.

Discussion

Taken together, the findings of this study suggest a key role for TRAP5 in modulating airway inflammation. This could have bearing in diseases such as CF and COPD where excessive neutrophilic inflammation could be targeted by pharmacological inhibitors of TRAP5.
How should international judicial bodies constituted under UNCLOS determine if they have jurisdiction over disputes involving territorial sovereignty?
Authors: Liu Chenhong
Published: December 2022

For the international judicial bodies constituted under the United Nations Convention on the Law of the Sea (UNCLOS), there are mainly three conditions which limit their jurisdiction to extend to disputes pertaining to the interpretation and application of UNCLOS which involve sovereignty issue: firstly, if the nature of the dispute is deemed as a sovereignty dispute; secondly, if the prerequisite to adjudicate/arbitrate the dispute is to resolve the sovereignty dispute; and thirdly, if the adjudication/arbitration of the dispute will advance or detract a state’s sovereignty claim. However, not all disputes involving territorial sovereignty are out of their jurisdiction. Provided that the court judgment or arbitral award will not affect the settlement of the sovereignty dispute between the disputed states or the claim to sovereignty of any state, they may, to a certain extent, have jurisdiction over a dispute of the interpretation and application of UNCLOS with sovereignty dispute ancillary to it.
Integrating fishers’ knowledge contributions in Marine Science to tackle bycatch in the Bay of Biscay
Authors: Cazé Cosma , Réveillas Justine , Danto Anatole , Mazé Camille
Published: December 2022

The issue of bycatch is raising considerable political, mediatic and scientific attention. Bycatch is one of the main causes of at-sea mortality for small cetacean species and for seabirds. Scientists are raising alerts regarding the potential effects on the structure of the ecosystem, increasingly aiming for research-action. Decision-makers are facing a political trade-off, with increasing pressure from the European Commission and international nongovernmental organizations to implement mitigation measures such as space-time closure of the fisheries, which could present a risk of altering the well-being of the fishing industry in the short-term. The process of co-creation of knowledge on bycatch is key to understand better the fishers-species interactions and to develop regulations that are adapted to local specificities, towards an adaptive and inclusive socio-ecosystem-based management of the fisheries. But the knowledge co-creation process is hindered by tensions between the interests of stakeholders, the climate of mistrust, dense media coverage and power asymmetries between actors. In parallel, the fast rate of biodiversity degradation is calling for the rapid development of regulations. Understanding the complex system dynamics highlighted by these conflicts requires an analysis of the socio-political dimension of the interactions between fisheries and marine biodiversity. Based on a series of ethnographic interviews with the different stakeholders involved in the bycatch mitigation projects in the Bay of Biscay, this paper explores how co-creating knowledge through conflict and collaboration between researchers and fishers can generate collective learning for bycatch mitigation policies. We adopt an epistemological approach, with the objective to promote transparency in the exchange between researchers and fishers and to inform decision-making at various scales of governance. We argue that co-creation of knowledge on bycatch should not aim for consensus. We conclude that acknowledging the presence of conflicts between the stakeholders, and understanding their roots and their impact on the co-design process can allow identifying factors of path-dependency hindering the adaptive capacity of institutions. Moreover, we highlight the key role of the fishers’ representative bodies in knowledge co-creation, and the importance to improve our understanding of fishers’ perception of their political representation.
Real-world use of ustekinumab therapeutic drug monitoring in moderate to severe psoriasis
Authors: Elberdín Laida , Fernández-Torres Rosa M. , Mateos María , Outeda María , Blanco Eva , Gómez-Besteiro María I. , Martín-Herranz Isabel , Fonseca Eduardo
Published: December 2022

Introduction

There is growing evidence that therapeutic drug monitoring of biologic therapy is beneficial in psoriatic patients. With respect to ustekinumab, the available evidence has not shown any relationship yet. The objective of this study is to identify correlations among ustekinumab trough concentrations, anti-ustekinumab antibodies and clinical response in moderate-to-severe plaque psoriasis patients, in a real-world setting.

Methods

Observational prospective follow-up study in psoriatic patients treated with ustekinumab. Patients were classified in optimal (PASI ≤ 3) and suboptimal responders (PASI > 3). Mann–Whitney U test and Spearman’s rank correlation coefficient were used. Receiver-operator characteristic curve analysis was performed to identify ustekinumab concentration cut-off to achieve optimal response. A p-value < 0.05 was considered statistically significant.

Results

A total of 59 patients were included. Forty-eight patients (81.4%) corresponded to optimal responders and 11 (18.6%) to suboptimal responders. There was significant difference to ustekinumab concentrations: 0.7 μg/mL (range <0.1–1.8) vs. 0.4 μg/mL (range <0.1–0.8) respectively (p = 0.007). Positive correlation between ustekinumab concentration and psoriasis area and severity index (PASI) value was detected (p = 0.009). A cut-off value of 0.6 μg/mL ustekinumab concentration was found to achieve clinical response. Anti-ustekinumab antibodies were detected in 2 (3.4%) samples, both suboptimal responders.

Conclusion

A positive correlation exits between ustekinumab concentration and clinical response (optimal response PASI values ≤ 3) in blood draws performed before drug administration. The measurement of anti-ustekinumab antibodies could be considered in treatment failure.
Global attitudes on and the status of enteral nutrition therapy for pediatric inflammatory bowel disease
Authors: Luo Juan , Xie Yong-Mei , Wu Mei , Zhao Jin-Gui , Hu Liang-Liang
Published: December 2022

Enteral nutrition (EN) is a diet-remission therapy for inflammatory bowel disease (IBD) that plays a more important role in children than adults. EN includes exclusive enteral nutrition (EEN), partial enteral nutrition (PEN), and maintenance enteral nutrition (MEN). However, EEN remains an unstandardized treatment for pediatric IBD. The types and methods of EN differ around the world. The current study reviewed the EN literature on children with IBD. A total of 12 survey studies were identified that analyzed the current state of EN use, including clinical opinions, implementation methods, treatment course, EEN formula, IBD classification, progress, dietary reintroduction, and patient feedback. The findings revealed that EEN has a strong effect on mild to moderate Crohn’s disease (CD). The usage rates of this treatment in different sites were ileum/colon (Paris classification L3) > ileum (L1) > upper digestive tract (L4) > colon (L2) > perianal disease (P) > ulcerative colitis (UC) > extraintestinal lesions. The polymeric formula was the most used EN formulation. New EN diets include a CD exclusion diet (CDED), a specific carbohydrate diet (SCD), and a CD treatment-with-eating (CD-TREAT) diet. Children with IBD responded similarly to EEN administered orally or using a feeding tube. Most guidelines recommended 6–8 weeks of EEN treatment to induce remission. Many clinicians preferred to combine drug medications during EEN and recommended that MEN accounts for at least 25–35% of daily caloric intake. EN remains an unstandardized therapy that requires teamwork across disciplines.
Pseudomonas aeruginosa prosthetic joint-infection outcomes: Prospective, observational study on 43 patients
Authors: Prié Héloïse , Meyssonnier Vanina , Kerroumi Younes , Heym Beate , Lidove Olivier , Marmor Simon , Zeller Valérie
Published: December 2022

Objectives

Analysis the outcomes of Pseudomonas aeruginosa prosthetic joint infection (PJI), and of their clinical and microbiological characteristics, surgical strategies and antibiotic treatments.

Methods

Monocenter cohort study in a Bone-and-Joint-Infection Referral Center (08/2004 to 10/2018) including all consecutive P. aeruginosa PJIs. Data were extracted from the prospective database, including the following events: relapses, new PJIs, related deaths.

Results

Median [IQR]: among the 43 patients included (28 females; 72 [63–80] years old; 27 hip, 15 knee, and 1 shoulder PJIs), 29 (67%) had underlying comorbidities, 12 (28%) had previously been treated for another PJI and 9 (21%) had undergone previous surgeries for their P. aeruginosa PJI. Eleven (26%) PJIs were polymicrobial, 16 (37%) strains were wild type, 8 (19%) ciprofloxacin-resistant. PJIs were classified as late chronic (n = 33), early postoperative (n = 9) or acute hematogenous infection (n = 1). Forty patients underwent surgery: 27 one-stage and 5 two-stage exchanges, 3 debridement and implant retention, and 5 other surgical strategies. Antibiotic treatments were: 29 received 41 [37–43] days of combination therapy (IV anti-pseudomonal β-lactam and 3–5 days of amikacin, then β-lactam and oral ciprofloxacin), followed by oral ciprofloxacin for a total of 12 weeks; 10 received only IV antibiotics for 83 [77–86] days, including 37 [32–46] days of combination therapy; 49 days of ceftazidime alone for 1. During follow-up lasting 33 [24–64.5] months, 2 relapses, 3 new PJIs, and 2 related deaths occurred. Thirty-three (82%) patients and 93% of those managed with one-stage exchange experienced no event.

Conclusion

Outcomes of our cohort’s P. aeruginosa PJIs—predominantly monomicrobial, chronic, ciprofloxacin-susceptible, treated with one-stage exchange and prolonged IV antibiotics—were 82% favorable.