bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Tolerability of Nilotinib in Patients with Chronic Myeloid Leukemia during Routine Clinical Practice: Results from the ERASER Study from Greece
Authors: Symeonidis Argiris , Anagnostopoulos Achilles , Ximeri Maria , Kaiafa Georgia , Kapsali Eleni , Viniou Nora Athina , Marinakis Theodoros , Karakasis Dimitrios , Pappa Vasiliki , Vassilopoulos George , Margaritis Dimitrios , Tabitsika Maria , Dimou Maria
Published: March 2023

Regional real-world evidence on the safety and efficacy of tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) is limited. This multicenter, observational, prospective study, ERASER, evaluated the safety and tolerability of nilotinib in routine clinical practice in Greece.

Adult patients with newly diagnosed BCR/ABL+ chronic phase (CP) CML and those with CP CML, resistant/intolerant to prior therapy were included in this study and followed up for 36 months. Nilotinib 300 mg/400 mg twice daily was prescribed, with appropriate dose adjustment by the investigator.

The analysis population (57 patients; median age, 55 years) remained in the study for a median of 34 months. Overall, 44 (77.2%) and 13 (22.8%) patients received nilotinib as first-line treatment and owing to resistance/intolerance to prior therapy, respectively. The most common adverse events (AEs) were thrombocytopenia in 8 (14%), neutropenia in 6 (10.5%), and blood bilirubin increased/hyperbilirubinemia in 10 (17.5%) patients. Permanent treatment discontinuation, including deaths and progression, occurred in 13 (22.8%) patients. Of 52 patients with available molecular response (MR), 30 achieved MR4.5 by end of the study.

The study affirms the long-term safety of nilotinib in real-world setting in Greece, in patients with newly diagnosed CML, and in those with resistance/intolerance to prior therapy.
GPMatch: A Bayesian causal inference approach using Gaussian process covariance function as a matching tool
Authors: Huang Bin , Chen Chen , Liu Jinzhong , Sivaganisan Siva
Published: March 2023

A Gaussian process (GP) covariance function is proposed as a matching tool for causal inference within a full Bayesian framework under relatively weaker causal assumptions. We demonstrate that matching can be accomplished by utilizing GP prior covariance function to define matching distance. The matching properties of GPMatch is presented analytically under the setting of categorical covariates. Under the conditions of either (1) GP mean function is correctly specified; or (2) the GP covariance function is correctly specified, we suggest GPMatch possesses doubly robust properties asymptotically. Simulation studies were carried out without assuming any a priori knowledge of the functional forms of neither the outcome nor the treatment assignment. The results demonstrate that GPMatch enjoys well-calibrated frequentist properties and outperforms many widely used methods including Bayesian Additive Regression Trees. The case study compares the effectiveness of early aggressive use of biological medication in treating children with newly diagnosed Juvenile Idiopathic Arthritis, using data extracted from electronic medical records. Discussions and future directions are presented.
Novel role of HIV-1 Nef in regulating the ubiquitination of cellular proteins
Authors: Ghaly Maria , Proulx Jessica , Borgmann Kathleen , Park In-Woo
Published: March 2023

Our recent data established that HIV-1 Nef is pivotal in determining the fate of cellular proteins by modulating ubiquitination. However, it is unknown which proteins are ubiquitinated in the presence of Nef, a question critical for understanding the proliferation/restriction strategies of HIV-1 in infected cells. To identify cellular proteins ubiquitinated by Nef, we conducted a proteomic analysis of cellular proteins in the presence and absence of Nef. Proteomic analysis in HEK293T cells indicated that 93 proteins were upregulated and 232 were downregulated in their ubiquitination status by Nef. Computational analysis classified these proteins based on molecular function, biological process, subcellular localization, and biological pathway. Of those proteins, we found a majority of molecular functions to be involved in binding and catalytic activity. With respect to biological processes, a significant portion of the proteins identified were related to cellular and metabolic processes. Subcellular localization analysis showed the bulk of proteins to be localized to the cytosol and cytosolic compartments, which is consistent with the known function and location of Nef during HIV-1 infection. As for biological pathways, the wide range of affected proteins was denoted by the multiple modes to fulfill function, as distinguished from a strictly singular means, which was not detected. Among these ubiquitinated proteins, six were found to directly interact with Nef, wherein two were upregulated and four downregulated. We also identified 14 proteins involved in protein stability through directly participating in the Ubiquitin Proteasome System (UPS)-mediated proteasomal degradation pathway. Of those proteins, we found six upregulated and eight downregulated. Taken together, these analyses indicate that HIV-1 Nef is integral to regulating the stability of various cellular proteins via modulating ubiquitination. The molecular mechanisms directing Nef-triggered regulation of cellular protein ubiquitination are currently under investigation.
A web-based application for eliciting narrative discourse from Greek-speaking people with and without language impairments
Authors: Stamouli Spyridoula , Nerantzini Michaela , Papakyritsis Ioannis , Katsamanis Athanasios , Chatzoudis Gerasimos , Dimou Athanasia-Lida , Plitsis Manos , Katsouros Vassilis , Varlokosta Spyridoula , Terzi Arhonto
Published: March 2023

In this paper we present a web-based data collection method designed to elicit narrative discourse from adults with and without language impairments, both in an in-person set up and remotely. We describe the design, methodological considerations and technical requirements regarding the application development, the elicitation tasks, materials and guidelines, as well as the implementation of the assessment procedure. To investigate the efficacy of remote elicitation of narrative discourse with the use of the technology-enhanced method presented here, a pilot study was conducted, aiming to compare narratives elicited remotely to narratives collected in an in-person elicitation mode from ten unimpaired adults, using a within-participants research design. In the remote elicitation setting, each participant performed the tasks of a narrative elicitation protocol via the web application in their own environment, with the assistance of an investigator in the context of a virtual meeting (video conferencing). In the in-person elicitation setting, the participant was in the same environment with the investigator, who administered the tasks using the web application. Data were manually transcribed, and transcripts were processed with Natural Language Processing (NLP) tools. Linguistic features representing key measures of spoken narrative discourse were automatically calculated: linguistic productivity, content richness, fluency, syntactic complexity at clausal and inter-clausal level, lexical diversity, and verbal output. The results show that spoken narratives produced by the same individuals in the two different experimental settings do not present significant differences regarding the linguistic variables analyzed, in sixty six out of seventy statistical tests. These results indicate that the presented web-based application is a feasible method for the remote collection of spoken narrative discourse from adults without language impairments in the context of online assessment.
Pathways to coexistence with dingoes across Australian farming landscapes
Authors: Boronyak Louise , Jacobs Brent
Published: March 2023

Introduction

Agriculture and biodiversity conservation are both vitally important human activities that overlap geographically and are often in conflict. Animal agriculture has been implicated in species loss and the degradation of ecosystems due to land clearing, overgrazing, and conflicts with large carnivores such as dingoes (Canis dingo). This paper explores the potential for transformation in Australian commercial livestock production from human-dingo conflict towards social-ecological coexistence.

Method

A qualitative model that depicts transformative change was developed from field observations and twenty-one in-depth interviews with livestock producers, conservation researchers, grazing industry representatives and policy makers across Australia. The model articulates the current state of dingo management and the drivers of system change.

Results

Seven pathways are described to catalyse transformation from routine lethal management of dingoes towards a future vision that embeds mutually beneficial coexistence. Central to transformation is the adoption by livestock producers of preventive non-lethal innovations supported by a new farming movement, Predator Smart Farming, that balances livestock grazing and wildlife conservation values to unlock the resilience of landscapes, animals (domesticated and wild) and livelihoods. Other key pathways include targeted research, capacity building, outreach and knowledge sharing networks; institutional (policy, legislation, and economic incentives) and cultural change; public awareness raising and advocacy to reduce lethal control; and greater involvement of Indigenous Australians in decisions relating to wildlife management.

Discussion

The seven transition pathways are discussed in relation to how they can collectively foster coexistence with dingoes in extensive rangelands grazing systems. International examples of interventions are used to illustrate the types of successful actions associated with each pathway that could inform action in Australia. The findings have implications for coexistence with large carnivores in rangeland ecosystems globally.
Preparation of (3R)-quinuclidinol using heterogeneous biocatalytic hydrogenation in a dynamically-mixed continuous flow reactor
Authors: Cleary Sarah E. , Kazantzi Sofia , Trenchard Joshua A. , Monedero Martin , Allman Jack W. , Lurshay Tara C. , Zhao Xu , Kenny Michael B. C. , Reeve Holly A.
Published: March 2023

Introduction: This work was carried out to understand if a heterogeneous biocatalytic hydrogenation system could be implemented in a slurry mode continuous flow reactor, as a “slot-in” alternative to a metal/carbon catalyst with minimal process or chemical engineering development.

Method: Biocatalytic hydrogenation was compared to metal (Pd/C) catalysed hydrogenation for ketone to chiral alcohol conversion in both a continuous flow reactor (Coflore ACR, AM Technology) and analogous scaled down batch reactions.

Results and discussion: Initial results demonstrated that batch reactions can achieve high conversions in 30 min, with relatively low biocatalyst loadings, meeting critical criteria for operation as continuous slurry mode process. Further results demonstrated full conversion of quinuclidinone to (3R)-quinuclidinol in continuous flow under mild conditions (35°C, 2 bar H2). On intensification of the process to higher substrate loading (50 mM), conversion was similar to with Pd/C, however the biocatalytic system achieved far higher turnover frequency and total turnover number (65 min−1 and 20,000, respectively) than the metal system (0.16 min−1, 37). Comparison to an analogous batch reaction highlights that the biocatalytic system has promise for further optimisation and intensification in the scalable Coflore ACR. Overall, biocatalytic hydrogenation is shown to offer a decarbonised biocatalytic route and a “slot-in” replacement to metal catalysts for hydrogenation reactions in continuous flow reactors.
Graft thrombosis after coronary artery bypass surgery and current practice for prevention
Authors: Harik Lamia , Perezgrovas-Olaria Roberto , Soletti Giovanni , Dimagli Arnaldo , Alzghari Talal , An Kevin R. , Cancelli Gianmarco , Gaudino Mario , Sandner Sigrid
Published: March 2023

Coronary artery bypass grafting (CABG) is the most frequently performed cardiac surgery worldwide. The reported incidence of graft failure ranges between 10% and 50%, depending upon the type of conduit used. Thrombosis is the predominant mechanism of early graft failure, occurring in both arterial and vein grafts. Significant advances have been made in the field of antithrombotic therapy since the introduction of aspirin, which is regarded as the cornerstone of antithrombotic therapy for prevention of graft thrombosis. Convincing evidence now exists that dual antiplatelet therapy (DAPT), consisting of aspirin and a potent oral P2Y12 inhibitor, effectively reduces the incidence of graft failure. However, this is achieved at the expense of an increase in clinically important bleeding, underscoring the importance of balancing thrombotic risk and bleeding risk when considering antithrombotic therapy after CABG. In contrast, anticoagulant therapy has proved ineffective at reducing the occurrence of graft thrombosis, pointing to platelet aggregation as the key driver of graft thrombosis. We provide a comprehensive review of current practice for prevention of graft thrombosis and discuss potential future concepts for antithrombotic therapy including P2Y12 inhibitor monotherapy and short-term DAPT.
Markers for predicting the efficacy of beta-blockers in vasovagal syncope management in children: A mini-review
Authors: Wang Jing , Liu Xueqin , Jin Hongfang , Du Junbao
Published: March 2023

Vasovagal syncope (VVS) is a common subtype of neurally mediated syncope. It is prevalent in children and adolescents, and critically affects the quality of life of patients. In recent years, the management of pediatric patients with VVS has received extensive attention, and β-blocker serves as an important choice of the drug therapy for children with VVS. However, the empirical use of β-blocker treatment has limited therapeutic efficacy in patients with VVS. Therefore, predicting the efficacy of β-blocker therapy based on biomarkers related to the pathophysiological mechanism is essential, and great progress has been made by applying these biomarkers in formulating individualized treatment plans for children with VVS. This review summarizes recent advances in predicting the effect of β-blockers in the management of VVS in children.
Will they or won't they? Understanding New Zealand adults' attitudes towards using digital interventions
Authors: Wilson Holly , Hayward Penelope , Donkin Liesje
Published: March 2023

Background

Digital interventions deliver healthcare via the internet or smartphone application to support people's well-being and health. Yet uptake is relatively poor. Furthermore, several studies exploring attitudes towards digital interventions have found inconsistent attitudes. In addition to this, regional and cultural nuances may further influence attitudes to digital interventions.

Objective

This study aimed to understand New Zealand adults' attitudes towards digital interventions and their influences.

Results

A mixed-method design consisting of a cross-sectional survey and semi-structured interviews found that New Zealand adults hold varied and complex attitudes towards digital interventions. Attitudes were found to be influenced by group membership and the scenarios in which digital interventions are made available. In addition, beliefs about the benefits and concerns surrounding digital interventions, knowledge, perceived views of others, and previous experience and confidence influenced these attitudes.

Conclusions

Findings indicated that digital interventions would be acceptable if offered as part of the healthcare service rather than a standalone intervention. Key modifiable factors that could positively influence attitudes were identified and could be leveraged to increase the perceived acceptability of digital interventions.
Analysis of cumulative outcomes and influencing factors of patients with discrepancies between age and AMH levels in the early follicular phase prolonged protocol
Authors: Wang Kexin , Guan Yichun , Zhang Yuchao , Jia Ruolin , Wu Shanshan , Yao Zhuolin , Zhang Mingmei , Li Zhen
Published: March 2023

Objective

To explore the cumulative outcomes and influencing factors of patients with discrepancies between age and Anti-Müllerian hormone (AMH) levels in the early follicular phase prolonged protocol.

Methods

A total of 1282 cycles of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) assisted pregnancy with the early follicular phase prolonged protocol in the Reproductive Medicine Center of the Third Affiliated Hospital of Zhengzhou University from September 2015 to December 2020 were retrospectively analyzed. They were divided into the young low-AMH group (n=1076) and the older high-AMH group (n=206). The primary outcomes included cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLBR). Secondary outcomes included the number of oocytes retrieved, number of available embryos, clinical pregnancy rate (CPR), live birth rate (LBR), miscarriage rate (MR), pregnancy complications, and neonatal outcomes.

Results

The CPR (68.7% vs. 59.4%) and the LBR (60.7% vs. 43.1%) in the young low-AMH group were higher than those in the older high-AMH group. In contrast, the number of oocytes retrieved (11 vs. 17), number of available embryos (5 vs. 8), and MR (10.6% vs. 18.3%) in the young low-AMH group were lower. There was no significant difference between the two groups in the CCPR, CLBR, pregnancy complications, and neonatal outcomes. Logistic regression analysis showed that infertility duration, basal follicle-stimulating hormone (FSH), and antral follicle count (AFC) correlated with CCPR, while maternal age, type of infertility, basal FSH, AFC, and infertility duration correlated with CLBR. The area under the receiver operating characteristic curves (ROC) curve for the combined model of infertility duration, AFC, and basal FSH to predict cumulative pregnancy was 0.629 (95%CI:0.592-0.666), while the combined model of maternal age, AFC, basal FSH, infertility duration, and type of infertility to predict cumulative live birth was 0.649 (95%CI:0.615-0.682).

Conclusion

Although AMH levels are low by contrast, young patients have a favorable outcome after IVF/ICSI. In patients with discrepancies between age and AMH levels in the early follicular phase prolonged protocol, maternal age correlates better with cumulative live birth. The model that combines maternal age and other factors can help predict cumulative live birth, but its value is limited.
Isolated anterior pituitary dysfunction in adulthood
Authors: Prencipe Nunzia , Marinelli Lorenzo , Varaldo Emanuele , Cuboni Daniela , Berton Alessandro Maria , Bioletto Fabio , Bona Chiara , Gasco Valentina , Grottoli Silvia
Published: March 2023

Hypopituitarism is defined as a complete or partial deficiency in one or more pituitary hormones. Anterior hypopituitarism includes secondary adrenal insufficiency, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency and prolactin deficiency. Patients with hypopituitarism suffer from an increased disability and sick days, resulting in lower health status, higher cost of care and an increased mortality. In particular during adulthood, isolated pituitary deficits are not an uncommon finding; their clinical picture is represented by vague symptoms and unclear signs, which can be difficult to properly diagnose. This often becomes a challenge for the physician. Aim of this narrative review is to analyse, for each anterior pituitary deficit, the main related etiologies, the characteristic signs and symptoms, how to properly diagnose them (suggesting an easy and reproducible step-based approach), and eventually the treatment. In adulthood, the vast majority of isolated pituitary deficits are due to pituitary tumours, head trauma, pituitary surgery and brain radiotherapy. Immune-related dysfunctions represent a growing cause of isolated pituitary deficiencies, above all secondary to use of oncological drugs such as immune checkpoint inhibitors. The diagnosis of isolated pituitary deficiencies should be based on baseline hormonal assessments and/or dynamic tests. Establishing a proper diagnosis can be quite challenging: in fact, even if the diagnostic methods are becoming increasingly refined, a considerable proportion of isolated pituitary deficits still remains without a certain cause. While isolated ACTH and TSH deficiencies always require a prompt replacement treatment, gonadal replacement therapy requires a benefit-risk evaluation based on the presence of comorbidities, age and gender of the patient; finally, the need of growth hormone replacement therapies is still a matter of debate. On the other side, prolactin replacement therapy is still not available. In conclusion, our purpose is to offer a broad evaluation from causes to therapies of isolated anterior pituitary deficits in adulthood. This review will also include the evaluation of uncommon symptoms and main etiologies, the elements of suspicion of a genetic cause and protocols for diagnosis, follow-up and treatment.
Increased prevalence of autoimmune thyroid disease after COVID-19: A single-center, prospective study
Authors: Rossini Alessandro , Cassibba Sara , Perticone Francesca , Benatti Simone Vasilij , Venturelli Serena , Carioli Greta , Ghirardi Arianna , Rizzi Marco , Barbui Tiziano , Trevisan Roberto , Ippolito Silvia
Published: March 2023

Introduction

Thyroid dysfunctions associated with SARS-CoV-2 acute infection have been extensively described since the beginning of COVID-19 pandemics. Conversely, few data are available on the occurrence of thyroid autoimmunity after COVID-19 resolution. We assessed the prevalence of autoimmune thyroid disease (ATD) and thyroid dysfunctions in COVID-19 survivors three months after hospital admission.

Design and methods

Single-center, prospective, observational, cohort study performed at ASST Papa Giovanni XXIII Hospital, Bergamo, Italy. 599 COVID-19 survivors were prospectively evaluated for thyroid function and autoimmunity thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb). When a positive antibody concentration was detected, thyroid ultrasound was performed. Multiple logistic regression model was used to estimate the association between autoimmunity and demographic characteristics, respiratory support, and comorbidities. Autoimmunity results were compared to a cohort of 498 controls referred to our Institution for non-thyroid diseases before the pandemic onset. A sensitivity analysis comparing 330 COVID-19 patients with 330 age and sex-matched controls was performed.

Results

Univariate and multivariate analysis found that female sex was positively associated (OR 2.01, SE 0.48, p = 0.003), and type 2 diabetes (T2DM) was negatively associated (OR 0.36, SE 0.16, p = 0.025) with thyroid autoimmunity; hospitalization, ICU admission, respiratory support, or COVID-19 treatment were not associated with thyroid autoimmunity (p > 0.05). TPOAb prevalence was greater in COVID-19 survivors than in controls: 15.7% vs 7.7%, p = 0.002. Ultrasonographic features of thyroiditis were present in 94.9% of the evaluated patients with positive antibodies. TSH was within the normal range in 95% of patients.

Conclusions

Autoimmune thyroid disease prevalence in COVID-19 survivors was doubled as compared to age and sex-matched controls, suggesting a role of SARS-CoV-2 in eliciting thyroid autoimmunity.
Value of machine learning-based transrectal multimodal ultrasound combined with PSA-related indicators in the diagnosis of clinically significant prostate cancer
Authors: Zhang Maoliang , Liu Yuanzhen , Yao Jincao , Wang Kai , Tu Jing , Hu Zhengbiao , Jin Yun , Du Yue , Sun Xingbo , Chen Liyu , Wang Zhengping
Published: March 2023

Objective

To investigate the effect of transrectal multimodal ultrasound combined with serum prostate-specific antigen (PSA)-related indicators and machine learning for the diagnosis of clinically significant prostate cancer.

Methods

Based on Gleason score of postoperative pathological results, the subjects were divided into clinically significant prostate cancer groups(GS>6)and non-clinically significant prostate cancer groups(GS ≤ 6). The independent risk factors were obtained by univariate logistic analysis. Artificial neural network (ANN), logistic regression (LR), support vector machine (SVM), decision tree (DT), random forest (RF), and K-nearest neighbor (KNN) machine learning models were combined with clinically significant prostate cancer risk factors to establish the machine learning model, calculate the model evaluation indicators, construct the receiver operating characteristic curve (ROC), and calculate the area under the curve (AUC).

Results

Independent risk factor items (P< 0.05) were entered into the machine learning model. A comparison of the evaluation indicators of the model and the area under the ROC curve showed the ANN model to be best at predicting clinically significant prostate cancer, with a sensitivity of 80%, specificity of 88.6%, F1 score of 0.897, and the AUC was 0.855.

Conclusion

Establishing a machine learning model by rectal multimodal ultrasound and combining it with PSA-related indicators has definite application value in predicting clinically significant prostate cancer.
Bioinformatics identification and experimental validation of m6A-related diagnostic biomarkers in the subtype classification of blood monocytes from postmenopausal osteoporosis patients
Authors: Zhang Peng , Chen Honglin , Xie Bin , Zhao Wenhua , Shang Qi , He Jiahui , Shen Gengyang , Yu Xiang , Zhang Zhida , Zhu Guangye , Chen Guifeng , Yu Fuyong , Liang De , Tang Jingjing , Cui Jianchao , Liu Zhixiang , Ren Hui , Jiang Xiaobing
Published: March 2023

Background

Postmenopausal osteoporosis (PMOP) is a common bone disorder. Existing study has confirmed the role of exosome in regulating RNA N6-methyladenosine (m6A) methylation as therapies in osteoporosis. However, it still stays unclear on the roles of m6A modulators derived from serum exosome in PMOP. A comprehensive evaluation on the roles of m6A modulators in the diagnostic biomarkers and subtype identification of PMOP on the basis of GSE56815 and GSE2208 datasets was carried out to investigate the molecular mechanisms of m6A modulators in PMOP.

Methods

We carried out a series of bioinformatics analyses including difference analysis to identify significant m6A modulators, m6A model construction of random forest, support vector machine and nomogram, m6A subtype consensus clustering, GO and KEGG enrichment analysis of differentially expressed genes (DEGs) between different m6A patterns, principal component analysis, and single sample gene set enrichment analysis (ssGSEA) for evaluation of immune cell infiltration, experimental validation of significant m6A modulators by real-time quantitative polymerase chain reaction (RT-qPCR), etc.

Results

In the current study, we authenticated 7 significant m6A modulators via difference analysis between normal and PMOP patients from GSE56815 and GSE2208 datasets. In order to predict the risk of PMOP, we adopted random forest model to identify 7 diagnostic m6A modulators, including FTO, FMR1, YTHDC2, HNRNPC, RBM15, RBM15B and WTAP. Then we selected the 7 diagnostic m6A modulators to construct a nomogram model, which could provide benefit with patients according to our subsequent decision curve analysis. We classified PMOP patients into 2 m6A subtypes (clusterA and clusterB) on the basis of the significant m6A modulators via a consensus clustering approach. In addition, principal component analysis was utilized to evaluate the m6A score of each sample for quantification of the m6A subgroups. The m6A scores of patients in clusterB were higher than those of patients in clusterA. Moreover, we observed that the patients in clusterA had close correlation with immature B cell and gamma delta T cell immunity while clusterB was linked to monocyte, neutrophil, CD56dim natural killer cell, and regulatory T cell immunity, which has close connection with osteoclast differentiation. Notably, m6A modulators detected by RT-qPCR showed generally consistent expression levels with the bioinformatics results.

Conclusion

In general, m6A modulators exert integral function in the pathological process of PMOP. Our study of m6A patterns may provide diagnostic biomarkers and immunotherapeutic strategies for future PMOP treatment.
RobustTree: An adaptive, robust PCA algorithm for embedded tree structure recovery from single-cell sequencing data
Authors: Chen Ziwei , Zhang Bingwei , Gong Fuzhou , Wan Lin , Ma Liang
Published: March 2023

Robust Principal Component Analysis (RPCA) offers a powerful tool for recovering a low-rank matrix from highly corrupted data, with growing applications in computational biology. Biological processes commonly form intrinsic hierarchical structures, such as tree structures of cell development trajectories and tumor evolutionary history. The rapid development of single-cell sequencing (SCS) technology calls for the recovery of embedded tree structures from noisy and heterogeneous SCS data. In this study, we propose RobustTree, a unified framework to reconstruct the inherent topological structure underlying high-dimensional data with noise. By extending RPCA to handle tree structure optimization, RobustTree leverages data denoising, clustering, and tree structure reconstruction. It solves the tree optimization problem with an adaptive parameter selection scheme that we proposed. In addition to recovering real datasets, RobustTree can reconstruct continuous topological structure and discrete-state topological structure of underlying SCS data. We apply RobustTree on multiple synthetic and real datasets and demonstrate its high accuracy and robustness when analyzing high-noise SCS data with embedded complex structures. The code is available at https://github.com/ucasdp/RobustTree.
Bayesian feature selection for radiomics using reliability metrics
Authors: Shoemaker Katherine , Ger Rachel , Court Laurence E. , Aerts Hugo , Vannucci Marina , Peterson Christine B.
Published: March 2023

Introduction: Imaging of tumors is a standard step in diagnosing cancer and making subsequent treatment decisions. The field of radiomics aims to develop imaging based biomarkers using methods rooted in artificial intelligence applied to medical imaging. However, a challenging aspect of developing predictive models for clinical use is that many quantitative features derived from image data exhibit instability or lack of reproducibility across different imaging systems or image-processing pipelines.

Methods: To address this challenge, we propose a Bayesian sparse modeling approach for image classification based on radiomic features, where the inclusion of more reliable features is favored via a probit prior formulation.

Results: We verify through simulation studies that this approach can improve feature selection and prediction given correct prior information. Finally, we illustrate the method with an application to the classification of head and neck cancer patients by human papillomavirus status, using as our prior information a reliability metric quantifying feature stability across different imaging systems.
Transcriptomic profiles of age-related genes in female trachea and bronchus
Authors: Liu Jia , Lu Haiyan , Hu Silu , Wang Faping , Tang Xiaoju , Wan Huajing , Luo Fengming
Published: March 2023

Background: Studies demonstrated that age-related cellular and functional changes of airway significantly contribute to the pathogenesis of many airway diseases. However, our understanding on the age-related molecular alterations of human airway remains inadequate.

Methods: Airway (trachea and bronchus) brushing specimens were collected from 14 healthy, female non-smokers with ages ranging from 20 to 60 years. Bulk RNA sequencing was performed on all the specimens (n = 28). Airway cell types and their relative proportions were estimated using CIBERSORTx. The cell type proportions were compared between the younger (age 20–40) and elder group (age 40–60) in the trachea and bronchus respectively. The linear association between cell type proportion and age was assessed using the Pearson correlation coefficient. Differentially expressed genes (DEGs) between the two age groups were identified using DESeq2. Three kinds of enrichment analysis of the age-related DEGs were performed, including Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and disease enrichment analysis.

Results: Sixteen and thirteen cell types were separately identified in tracheal and bronchial brushings, with the airway epithelial cells (including suprabasal, submucosal gland (SMG) goblet, serous, secretory, multiciliated, cycling.basal, basal cells) accounting for 85.1% in the trachea and 92.5% in the bronchus. The lymphatic cell and NK cells had a higher abundance ratio in the trachea, compared with the bronchus. The proportion of basal cells was negatively related to age both in the trachea and bronchus. Thirty-one and fifty-two age-related DEGs (p < 0.1) were identified in the trachea and bronchus, respectively. Among them, five common DEGs (CXCL2, CXCL8, TCIM, P4HA3, AQP10) were identified. Pathway enrichment analysis showed both tracheal and bronchial age-related DEGs were primarily involved in immune regulatory signaling pathways (TNF, NF-kappa B, IL-17 et al.). Disease enrichment analysis suggested that tracheal age-related DEGs significantly related to asthmatic pulmonary eosinophilia, and chronic airflow obstruction et al., and that bronchial age-related DEGs were enriched in airflow obstruction, bronchiectasis, pulmonary emphysema, and low respiratory tract infection et al.

Conclusion: We found the proportion of basal cells decreased with age in both the trachea and bronchus, suggesting a weakening of their self-renew ability with age. We identified transcriptomic signature genes associated with the early aging process of the human trachea and bronchus, and provided evidence to support that changes in their immune regulatory function may play critical roles in age-related airway diseases.
Relevance of TMPRSS2, CD163/CD206, and CD33 in clinical severity stratification of COVID-19
Authors: Martínez-Diz Silvia , Marín-Benesiu Fernando , López-Torres Ginesa , Santiago Olivia , Díaz-Cuéllar José F. , Martín-Esteban Sara , Cortés-Valverde Ana I. , Arenas-Rodríguez Verónica , Cuenca-López Sergio , Porras-Quesada Patricia , Ruiz-Ruiz Carmen , Abadía-Molina Ana C. , Entrala-Bernal Carmen , Martínez-González Luis J. , Álvarez-Cubero Maria Jesus
Published: March 2023

Background

Approximately 13.8% and 6.1% of coronavirus disease 2019 (COVID-19) patients require hospitalization and sometimes intensive care unit (ICU) admission, respectively. There is no biomarker to predict which of these patients will develop an aggressive stage that we could improve their quality of life and healthcare management. Our main goal is to include new markers for the classification of COVID-19 patients.

Methods

Two tubes of peripheral blood were collected from a total of 66 (n = 34 mild and n = 32 severe) samples (mean age 52 years). Cytometry analysis was performed using a 15-parameter panel included in the Maxpar® Human Monocyte/Macrophage Phenotyping Panel Kit. Cytometry by time-of-flight mass spectrometry (CyTOF) panel was performed in combination with genetic analysis using TaqMan® probes for ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants. GemStone™ and OMIQ software were used for cytometry analysis.

Results

The frequency of CD163+/CD206- population of transitional monocytes (T-Mo) was decreased in the mild group compared to that of the severe one, while T-Mo CD163-/CD206- were increased in the mild group compared to that of the severe one. In addition, we also found differences in CD11b expression in CD14dim monocytes in the severe group, with decreased levels in the female group (p = 0.0412). When comparing mild and severe disease, we also found that CD45- [p = 0.014; odds ratio (OR) = 0.286, 95% CI 0.104–0.787] and CD14dim/CD33+ (p = 0.014; OR = 0.286, 95% CI 0.104–0.787) monocytes were the best options as biomarkers to discriminate between these patient groups. CD33 was also indicated as a good biomarker for patient stratification by the analysis of GemStone™ software. Among genetic markers, we found that G carriers of TMPRSS2 (rs2070788) have an increased risk (p = 0.02; OR = 3.37, 95% CI 1.18–9.60) of severe COVID-19 compared to those with A/A genotype. This strength is further increased when combined with CD45-, T-Mo CD163+/CD206-, and C14dim/CD33+.

Conclusions

Here, we report the interesting role of TMPRSS2, CD45-, CD163/CD206, and CD33 in COVID-19 aggressiveness. This strength is reinforced for aggressiveness biomarkers when TMPRSS2 and CD45-, TMPRSS2 and CD163/CD206, and TMPRSS2 and CD14dim/CD33+ are combined.
Efficacy and safety of Iguratimod as an add-on therapy for refractory lupus nephritis: A preliminary investigational study
Authors: Yan Qingran , Zhang Mei , Du Fang , Kang Yuening , Ye Ping , Li Qianqian , Liu Bei , Dai Min , Bao Chunde
Published: March 2023

Objectives

IGU (IGU), a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective and safe as monotherapy in a small population with refractory lupus nephritis (LN). The aim of this prospective study was to evaluate the efficacy and safety of IGU as an add-on therapy in patients with refractory LN in the context of clinical practice.

Methods

This is a single-arm observational study. We have enrolled LN patients since 2019 at Renji Hospital. All participants should have recurrent or refractory LN with at least one immunosuppressant (IS) and have a baseline urine protein/creatinine ratio (UPCR) >1.0. After enrollment, we added IGU (25 mg twice daily) to one of their previous immunosuppressants (IS) without increasing the dose of steroids. The primary outcome was the complete renal response (CRR) in the 6th month. UPCR decrease of over 50% was defined as partial response (PR). Extended follow-up was performed after the initial 6 months.

Results

We enrolled 26 eligible participants. 11/26 patients had chronic kidney disease (CKD) stage 2/3 at the baseline. The IS combined with IGU included mycophenolate mofetil, tacrolimus, and cyclosporin A. No IS change was allowed. 80.7% of patients had baseline steroids less than 0.5mg/kg daily and there was no steroids escalation during the IGU treatment. The CRR rate was 42.3% (11/26) at month 6. With a median follow-up of 52 weeks (range: 23-116 weeks), the CRR rate at the last visit was 50% (13/26) and 73.1% (19/26) of patients had UPCR decrease of over 50%. Six patients withdrew, three for no response and three for renal flare after initial CRR. One patient had an estimated glomerular filtration rate worsening of over 20% and was classified as renal flare. Three mild to moderate adverse events were recorded.

Conclusions

Our investigation merits further investigation in IGU as a potentially tolerable component of combination therapy for refractory LN.
Effect of postoperative systemic prednisolone on short-term and long-term outcomes in chronic rhinosinusitis with nasal polyps: A multi-centered randomized clinical trial
Authors: Mueller Sarina K. , Wendler Olaf , Mayr Susanne , Traxdorf Maximilian , Hosemann Werner , Olze Heidi , Steinhart Helmut , Wiegand Susanne , Teymoortash Afshin , Kuehnel Thomas , Hackenberg Stephan , Hummel Thomas , Ambrosch Petra , Fazel Azita , Schick Bernhard , Baenkler Hanns-Wolf , Koch Michael , Buerner Harald , Mantsopoulos Konstantinos , Grundtner Philipp , Nocera Angela , Agaimy Abbas , Bleier Benjamin , Iro Heinrich
Published: March 2023

Introduction

The objective of this study was to determine whether postoperative additive systemic steroid administration in chronic rhinosinusitis with nasal polyps (CRSwNP) impacted selected endoscopic, subjective and objective outcome measures.

Methods

This was a prospective, randomized, double-blind, placebo-controlled, noninferiority multicenter trial of n=106 patients with CRSwNP. All patients underwent primary functional endoscopic sinus surgery (FESS) followed by topical nasal steroids. Patients were randomized to a systemic steroid or placebo for 1 month. Patients were followed up for 2 years over 9 time points. The primary outcome measures were the differences between groups with respect to the nasal polyp score (NPS) and sinonasal quality of life (SNQoL). Secondary outcome measures included interactions with respect to the Lund-Kennedy score (LKS), sinonasal symptoms, general quality of life (GQoL), 16-item odor identification test scores, recurrence rates, need for revision surgery and mucus biomarker levels.

Results

106 patients were randomized to either the placebo or the systemic steroid group (n=53 per group). Postoperative systemic steroids were not superior to placebo with respect to all primary (p= 0.077) and secondary outcome measures (p>0.05 for all). Reported adverse events were similar between the two groups.

Conclusion

In conclusion, the addition of postoperative systemic steroids after primary FESS did not confer a benefit over topical steroid nasal spray alone with respect to NPS, SNQOL, LKS, GQOL, sinonasal symptoms, smell scores, recurrence rates, the need for revision surgery or biomarkers over a short-term follow-up of up to 9 months and a long-term follow-up of up to 24 months in CRSwNP patients. Functional endoscopic surgery did, however, show a strong effect on all outcome measures, which remained relatively stable up to the endpoint at 2 years.
Integrative bioinformatics analysis to identify novel biomarkers associated with non-obstructive azoospermia
Authors: Zhong Yucheng , Zhao Jun , Deng Hao , Wu Yaqin , Zhu Li , Yang Meiqiong , Liu Qianru , Luo Guoqun , Ma Wenmin , Li Huan
Published: March 2023

Aim

This study aimed to identify autophagy-related genes (ARGs) associated with non-obstructive azoospermia and explore the underlying molecular mechanisms.

Methods

Two datasets associated with azoospermia were downloaded from the Gene Expression Omnibus database, and ARGs were obtained from the Human Autophagy-dedicated Database. Autophagy-related differentially expressed genes were identified in the azoospermia and control groups. These genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction (PPI) network, and functional similarity analyses. After identifying the hub genes, immune infiltration and hub gene–RNA-binding protein (RBP)–transcription factor (TF)–miRNA–drug interactions were analyzed.

Results

A total 46 differentially expressed ARGs were identified between the azoospermia and control groups. These genes were enriched in autophagy-associated functions and pathways. Eight hub genes were selected from the PPI network. Functional similarity analysis revealed that HSPA5 may play a key role in azoospermia. Immune cell infiltration analysis revealed that activated dendritic cells were significantly decreased in the azoospermia group compared to those in the control groups. Hub genes, especially ATG3, KIAA0652, MAPK1, and EGFR were strongly correlated with immune cell infiltration. Finally, a hub gene–miRNA–TF–RBP–drug network was constructed.

Conclusion

The eight hub genes, including EGFR, HSPA5, ATG3, KIAA0652, and MAPK1, may serve as biomarkers for the diagnosis and treatment of azoospermia. The study findings suggest potential targets and mechanisms for the occurrence and development of this disease.
Integrated bioinformatics analysis identifies shared immune changes between ischemic stroke and COVID 19
Authors: Liu Wenhao , Han Fei , Wan Mengyao , Yang Xin-Zhuang
Published: March 2023

Although COVID-19 is primarily a respiratory disease, its neurological complications, such as ischemic stroke (IS), have aroused growing concerns and reports. However, the molecular mechanisms that underlie IS and COVID-19 are not well understood. Therefore, we implemented transcriptomic analysis from eight GEO datasets consist of 1191 samples to detect common pathways and molecular biomarkers in IS and COVID-19 that help understand the linkage between them. Differentially expressed genes (DEGs) were detected for IS and COVID-19 separately for finding shared mechanisms and we found that immune-related pathways were outlined with statistical significance. JAK2, which was identified as a hub gene, was supposed to be a potential therapeutic gene targets during the immunological process of COVID-19 and IS. Besides, we found a decrease in the proportion of CD8+ T and T helper 2 cells in the peripheral circulation of both COVID and IS patients, and NCR3 expression was significantly correlated with this change. In conclusion, we demonstrated that transcriptomic analyses reported in this study could make a deeper understanding of the common mechanism and might be promising for effective therapeutic for IS and COVID-19.
Macrophages in aseptic loosening: Characteristics, functions, and mechanisms
Authors: Cong Yehao , Wang Yi , Yuan Tao , Zhang Zheng , Ge Jianxun , Meng Qi , Li Ziqing , Sun Shui
Published: March 2023

Aseptic loosening (AL) is the most common complication of total joint arthroplasty (TJA). Both local inflammatory response and subsequent osteolysis around the prosthesis are the fundamental causes of disease pathology. As the earliest change of cell behavior, polarizations of macrophages play an essential role in the pathogenesis of AL, including regulating inflammatory responses and related pathological bone remodeling. The direction of macrophage polarization is closely dependent on the microenvironment of the periprosthetic tissue. When the classically activated macrophages (M1) are characterized by the augmented ability to produce proinflammatory cytokines, the primary functions of alternatively activated macrophages (M2) are related to inflammatory relief and tissue repair. Yet, both M1 macrophages and M2 macrophages are involved in the occurrence and development of AL, and a comprehensive understanding of polarized behaviors and inducing factors would help in identifying specific therapies. In recent years, studies have witnessed novel discoveries regarding the role of macrophages in AL pathology, the shifts between polarized phenotype during disease progression, as well as local mediators and signaling pathways responsible for regulations in macrophages and subsequent osteoclasts (OCs). In this review, we summarize recent progress on macrophage polarization and related mechanisms during the development of AL and discuss new findings and concepts in the context of existing work.