bluuebunny/crossref_metadata_2025 huggingface dataset:
Feminism, Intersectionality, and Gender Category: Essential Contributions for Historical Thinking Development
Authors: Díez-Bedmar María del Consuelo
Published: March 2022

The following article inquires how introducing the gender category, feminism theories, and intersectionality into social sciences education, especially regarding historical thinking development, could be key for the construction of a more critical and egalitarian future. The main research problem is knowing how the use of the gender category is included, or not, in the development of historical thinking in pre-service teacher beliefs and how it could condition them when they work on historical and social problems in the classroom. The main objective is to analyze the historical thinking development in pre-service Spanish teacher students and their capacity for constructing critical discourses with a gender perspective. Pre-service teachers of five Spanish universities (of the Primary and Secondary Education Degree) were asked about a report from a digital newspaper version that forces them to use historical thinking and to consider gender stereotypes and prejudices. Their responses were analyzed both qualitatively and quantitatively. The results indicate that pre-service teachers are not able to identify their own gender roles and prejudiced attitudes when they attempt to explain a social problem and they propose solutions, even when they could verify that there was another manner to understand this report. Hence, this research highlights the relevance of implementing feminism, intersectionality, and gender category for historical thinking development since these future teachers need to work around democratic culture competences. By contrast, not including this perspective will lead to them still maintaining historical thinking and democracy configured on hegemonic, heteropatriarchal, sexist, and Eurocentric cultural models.
Pre-service Teachers’ Attitudes Toward Students With Behavioral Difficulties: Associations With Individual and Education Program Characteristics
Authors: Massé Line , Nadeau Marie-France , Gaudreau Nancy , Nadeau Sandy , Gauthier Catherine , Lessard Anne
Published: March 2022

Teachers’ belief toward students with special educational needs (SEN) in the regular classroom is a condition that may influence the implementation of inclusive education. Nevertheless, some studies suggest that teachers’ attitudes or self-efficacy beliefs toward students with behavioral difficulties (BD) are quite negative, but much less emphasis has been placed on the factors and mechanisms contributing to these attitudes. This study investigates associations between pre-service teachers’ (PT) attitudes toward students with BD, PT’s individual characteristics including self-efficacy beliefs, and PT’s education program characteristics. Participants surveyed were 1,499 PT enrolled in a 4-year teacher education program (bachelor’s degree) in Quebec Province, Canada. Descriptive analysis showed that PT’s report generally positive attitudes toward students with BD on the three components of attitudes, while behavioral components were significantly more positive than the affective and cognitive components. Among the individual characteristics of PTs, the more advanced their academic level, the more negative their attitudes were on all three components. The characteristics related to the teacher education program (general vs. special) and the number of hours of courses on the BD revealed significant differences only on the cognitive component. Results of the mediation analysis further revealed that the association between the PT’s characteristics and the three components of attitudes was mediated by PT’s self-efficacy beliefs. Results are discussed considering their implications for the field of teacher education.
Male Sex Is an Independent Predictor of Recurrence-Free Survival in Middle Eastern Papillary Thyroid Carcinoma
Authors: Siraj Abdul K. , Parvathareddy Sandeep Kumar , Annaiyappanaidu Padmanaban , Siraj Nabil , Al-Sobhi Saif S. , Al-Dayel Fouad , Al-Kuraya Khawla S.
Published: March 2022

Background

Disparity between sexes with regard to incidence, disease aggressiveness, and prognosis has been documented in several cancers. Although various reports have documented the association between male sex and aggressive papillary thyroid carcinoma (PTC), the prognostic impact of sex on PTC has been inconsistent. The role of sex in PTC aggressiveness and outcome in Middle Eastern PTC remains unknown. Therefore, our study retrospectively analyzed the data of a large cohort of Middle Eastern PTC patients to address this issue.

Methods

We compared men and women with respect to clinico-pathological characteristics, disease persistence, structural recurrence, risk stratification, and prognosis. We included 1,430 patients—1,085 (75.9%) women and 345 (24.1%) men.

Results

The median follow-up was 9.3 years. At diagnosis, 27% (93/345) of men were ≥55 years, compared with 17.8% (193/1085) of women (p = 0.0003). Men had significantly more advanced disease at presentation: higher stage (p = 0.0074), larger tumor size (p = 0.0069), higher rates of lymphovascular invasion (p = 0.0129), extrathyroidal extension (p = 0.0086), regional lymph node metastasis (p = 0.0279), and distant metastasis (p = 0.0101). There was a higher rate of recurrence (p < 0.0001) and TERT mutations (p = 0.0003) in male PTC patients than in female patients. Additionally, radioiodine refractoriness was higher in male PTC patients (p = 0.0014). In multivariate analysis, male sex was an independent prognostic factor for poor recurrence-free survival (RFS) (hazard ratio = 1.58; 95% confidence interval = 1.20–2.06; p = 0.0011).

Conclusions

Men with PTC are more likely to present with more advanced and aggressive disease. Importantly, male sex was an independent prognostic factor for RFS. Thus, men may benefit from more aggressive management and therapeutic interventions.
Derivation and Validation of a Prediction Model of End-Stage Renal Disease in Patients With Type 2 Diabetes Based on a Systematic Review and Meta-analysis
Authors: Ren Qiuyue , Chen Dong , Liu Xinbang , Yang Ronglu , Yuan Lisha , Ding Min , Zhang Ning
Published: March 2022

Objectives

To develop and validate a model for predicting the risk of end-stage renal disease (ESRD) in patients with type 2 diabetes.

Methods

The derivation cohort was from a meta-analysis. Statistically significant risk factors were extracted and combined to the corresponding risk ratio (RR) to establish a risk assessment model for ESRD in type 2 diabetes. All risk factors were scored according to their weightings to establish the prediction model. Model performance is evaluated using external validation cohorts. The outcome was the occurrence of ESRD defined as eGFR<15 ml min-1 1.73 m-2 or received kidney replacement therapy (dialysis or transplantation).

Results

A total of 1,167,317 patients with type 2 diabetes were included in our meta-analysis, with a cumulative incidence of approximately 1.1%. The final risk factors of the prediction model included age, sex, smoking, diabetes mellitus (DM) duration, systolic blood pressure (SBP), hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and triglyceride (TG). All risk factors were scored according to their weightings, with the highest score being 36.5. External verification showed that the model has good discrimination, AUC=0.807(95%CI 0.753–0.861). The best cutoff value is 16 points, with the sensitivity and specificity given by 85.33% and 60.45%, respectively.

Conclusion

The study established a simple risk assessment model including 8 routinely available clinical parameters for predicting the risk of ESRD in type 2 diabetes.
Characterization and Survival of Human Infant Testicular Cells After Direct Xenotransplantation
Authors: Wang Danyang , Hildorf Simone , Ntemou Elissavet , Dong Lihua , Pors Susanne Elisabeth , Mamsen Linn Salto , Fedder Jens , Hoffmann Eva R. , Clasen-Linde Erik , Cortes Dina , Thorup Jørgen , Andersen Claus Yding
Published: March 2022

Background

Cryopreservation of prepubertal testicular tissue preserves spermatogonial stem cells (SSCs) that may be used to restore fertility in men at risk of infertility due to gonadotoxic treatments for either a malignant or non-malignant disease. Spermatogonial stem cell-based transplantation is a promising fertility restoration technique. Previously, we performed xenotransplantation of propagated SSCs from prepubertal testis and found human SSCs colonies within the recipient testes six weeks post-transplantation. In order to avoid the propagation step of SSCs in vitro that may cause genetic and epigenetic changes, we performed direct injection of single cell suspension in this study, which potentially may be safer and easier to be applied in future clinical applications.

Methods

Testis biopsies were obtained from 11 infant boys (median age 1.3 years, range 0.5-3.5) with cryptorchidism. Following enzymatic digestion, dissociated single-cell suspensions were prelabeled with green fluorescent dye and directly transplanted into seminiferous tubules of busulfan-treated mice. Six to nine weeks post-transplantation, the presence of gonocytes and SSCs was determined by whole-mount immunofluorescence for a number of germ cell markers (MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28), somatic cell markers (SOX9, CYP17A1).

Results

Following xenotransplantation human infant germ cells, consisting of gonocytes and SSCs, were shown to settle on the basal membrane of the recipient seminiferous tubules and form SSC colonies with expression of MAGEA, GAGE, UCHL1, SALL4, UTF1, and LIN28. The colonization efficiency was approximately 6%. No human Sertoli cells were detected in the recipient mouse testes.

Conclusion

Xenotransplantation, without in vitro propagation, of testicular cell suspensions from infant boys with cryptorchidism resulted in colonization of mouse seminiferous tubules six to nine weeks post-transplantation. Spermatogonial stem cell-based transplantation could be a therapeutic treatment for infertility of prepubertal boys with cryptorchidism and boys diagnosed with cancer. However, more studies are required to investigate whether the low number of the transplanted SSC is sufficient to secure the presence of sperm in the ejaculate of those patients over time.
Lipidomic Analysis of TRPC1 Ca2+-Permeable Channel-Knock Out Mouse Demonstrates a Vital Role in Placental Tissue Sphingolipid and Triacylglycerol Homeostasis Under Maternal High-Fat Diet
Authors: Bukowski Michael R. , Singh Brij B. , Roemmich James N. , Claycombe-Larson Kate J.
Published: March 2022

The transient receptor potential canonical channel 1 (TRPC1) is a ubiquitous Ca2+-permeable integral membrane protein present in most tissues, including adipose and placenta, and functionally regulates energetic homeostasis. We demonstrated that elimination of TRPC1 in a mouse model increased body adiposity and limited adipose accumulation under a high fat diet (HFD) even under conditions of exercise. Additionally, intracellular Ca2+ regulates membrane lipid content via the activation of the protein kinase C pathway, which may impact placental membrane lipid content and structure. Based upon this we investigated the effect of HFD and TRPC1 elimination on neutral lipids (triacylglycerol and cholesteryl ester), membrane lipids (phosphatidylcholine and phosphatidylethanolamine), and other multifunctional lipid species (unesterified cholesterol, sphingomyelins, ceramides). The concentration of unesterified cholesterol and sphingomyelin increased with gestational age (E12.5 to E 18.5.) indicating possible increases in plasma membrane fluidity. Diet-dependent increases ceramide concentration at E12.5 suggest a pro-inflammatory role for HFD in early gestation. TRPC1-dependent decreases in cholesterol ester concentration with concomitant increases in long-chain polyunsaturated fatty acid -containing triacylglycerols indicate a disruption of neutral lipid homeostasis that may be tied to Ca2+ regulation. These results align with changes in lipid content observed in studies of preeclamptic human placenta.
In-Situ Test Method for Hydrodynamic Characteristics of Water Flowing Around Piles
Authors: Liu Mingwei , Zeng Liqin , Wu Linjian , Chen Gang , Shen Lilong , Abi Erdi
Published: March 2022

The dynamic characteristics of the flow around the pile directly determine the distribution law of the force of the flow on the pile, which is the basis of the calculation of the flow load of the hydraulic structure. At present, the model test and numerical simulation methods are mainly used to study the flow characteristics around the pile. There are problems of model scale effect and test accuracy in the laboratory model test, and inherent problems in the numerical simulation method, such as the determination of medium parameters, mesh division, and boundary conditions. Therefore, the research results cannot reflect the actual situation of the interaction between water flow and pile. This paper developed a field test system for measuring the hydrodynamic pressures on surface of piles which are the vital foundations of wharves under superhigh Reynolds number. And the analysis methods of in-situ data, which can realize the multifunction including calibration and transformation for test data, frequency and time-domain statistical analysis process, were put forward according to the theory of stationary random process and mathematical statistics method. A representative frame wharf located in the upper reaches of the Yangtze River was performed as a case study, and the developed system was utilized to operate the in-situ test on this practice. Application showed that the field test system and the analysis methods can be applied to obtain the more accurate distribution of the pile surface hydrodynamic pressure. And the drag coefficient in wharf field ranged from 0.30 to 0.40. These findings in this paper may provide significant technical support for the in-situ test in similar structures and some reference for drag force calculation of flow around pile in the engineering design.
RNA-Seq and Gene Regulatory Network Analyses Uncover Candidate Genes in the Early Defense to Two Hemibiotrophic Colletorichum spp. in Strawberry
Authors: Adhikari Tika B. , Aryal Rishi , Redpath Lauren E. , Van den Broeck Lisa , Ashrafi Hamid , Philbrick Ashley N. , Jacobs Raymond L. , Sozzani Rosangela , Louws Frank J.
Published: March 2022

Two hemibiotrophic pathogens, Colletotrichum acutatum (Ca) and C. gloeosporioides (Cg), cause anthracnose fruit rot and anthracnose crown rot in strawberry (Fragaria × ananassa Duchesne), respectively. Both Ca and Cg can initially infect through a brief biotrophic phase, which is associated with the production of intracellular primary hyphae that can infect host cells without causing cell death and establishing hemibiotrophic infection (HBI) or quiescent (latent infections) in leaf tissues. The Ca and Cg HBI in nurseries and subsequent distribution of asymptomatic infected transplants to fruit production fields is the major source of anthracnose epidemics in North Carolina. In the absence of complete resistance, strawberry varieties with good fruit quality showing rate-reducing resistance have frequently been used as a source of resistance to Ca and Cg. However, the molecular mechanisms underlying the rate-reducing resistance or susceptibility to Ca and Cg are still unknown. We performed comparative transcriptome analyses to examine how rate-reducing resistant genotype NCS 10-147 and susceptible genotype ‘Chandler’ respond to Ca and Cg and identify molecular events between 0 and 48 h after the pathogen-inoculated and mock-inoculated leaf tissues. Although plant response to both Ca and Cg at the same timepoint was not similar, more genes in the resistant interaction were upregulated at 24 hpi with Ca compared with those at 48 hpi. In contrast, a few genes were upregulated in the resistant interaction at 48 hpi with Cg. Resistance response to both Ca and Cg was associated with upregulation of MLP-like protein 44, LRR receptor-like serine/threonine-protein kinase, and auxin signaling pathway, whereas susceptibility was linked to modulation of the phenylpropanoid pathway. Gene regulatory network inference analysis revealed candidate transcription factors (TFs) such as GATA5 and MYB-10, and their downstream targets were upregulated in resistant interactions. Our results provide valuable insights into transcriptional changes during resistant and susceptible interactions, which can further facilitate assessing candidate genes necessary for resistance to two hemibiotrophic Colletotrichum spp. in strawberry.
Overexpression of the Hsa21 Transcription Factor RUNX1 Modulates the Extracellular Matrix in Trisomy 21 Cells
Authors: Mollo Nunzia , Aurilia Miriam , Scognamiglio Roberta , Zerillo Lucrezia , Cicatiello Rita , Bonfiglio Ferdinando , Pagano Pasqualina , Paladino Simona , Conti Anna , Nitsch Lucio , Izzo Antonella
Published: March 2022

Down syndrome is a neurodevelopmental disorder frequently characterized by other developmental defects, such as congenital heart disease. Analysis of gene expression profiles of hearts from trisomic fetuses have shown upregulation of extracellular matrix (ECM) genes. The aim of this work was to identify genes on chromosome 21 potentially responsible for the upregulation of ECM genes and to pinpoint any functional consequences of this upregulation. By gene set enrichment analysis of public data sets, we identified the transcription factor RUNX1, which maps to chromosome 21, as a possible candidate for regulation of ECM genes. We assessed that approximately 80% of ECM genes overexpressed in trisomic hearts have consensus sequences for RUNX1 in their promoters. We found that in human fetal fibroblasts with chromosome 21 trisomy there is increased expression of both RUNX1 and several ECM genes, whether located on chromosome 21 or not. SiRNA silencing of RUNX1 reduced the expression of 11 of the 14 ECM genes analyzed. In addition, collagen IV, an ECM protein secreted in high concentrations in the culture media of trisomic fibroblasts, was modulated by RUNX1 silencing. Attenuated expression of RUNX1 increased the migratory capacity of trisomic fibroblasts, which are characterized by a reduced migratory capacity compared to euploid controls.
Control of Dendritic Cell Function Within the Tumour Microenvironment
Authors: Gupta Yukti Hari , Khanom Abida , Acton Sophie E.
Published: March 2022

The tumour microenvironment (TME) presents a major block to anti-tumour immune responses and to effective cancer immunotherapy. The inflammatory mediators such as cytokines, chemokines, growth factors and prostaglandins generated in the TME alter the phenotype and function of dendritic cells (DCs) that are critical for a successful adaptive immune response against the growing tumour. In this mini review we discuss how tumour cells and the surrounding stroma modulate DC maturation and trafficking to impact T cell function. Fibroblastic stroma and the associated extracellular matrix around tumours can also provide physical restrictions to infiltrating DCs and other leukocytes. We discuss interactions between the inflammatory TME and infiltrating immune cell function, exploring how the inflammatory TME affects generation of T cell-driven anti-tumour immunity. We discuss the open question of the relative importance of antigen-presentation site; locally within the TME versus tumour-draining lymph nodes. Addressing these questions will potentially increase immune surveillance and enhance anti-tumour immunity.
Long Lasting Cellular Immune Response Induced by mRNA Vaccination: Implication for Prevention Strategies
Authors: Vitiello Laura , Gatta Lucia , Ilari Sara , Bonassi Stefano , Cristina Mario , Ciatti Filippo , Fini Massimo , Proietti Stefania , Russo Patrizia , Tomino Carlo , Limongi Dolores
Published: March 2022

As the COVID19 pandemic continues to spread and vaccinations are administered throughout the world at different rates and with different strategies, understanding the multiple aspects of the immune response to vaccinations is required to define more efficient vaccination strategies. To date, the duration of protection induced by COVID19 vaccines is still matter of debate. To assess whether 2-doses vaccination with BNT162b2 mRNA COVID-19 vaccine was sufficient to induce a persistent specific cellular immune response, we evaluated the presence of SARS-COV2 Spike-specific B and T lymphocytes in 28 healthcare workers 1 and 7 months after completing the vaccination cycle. The results showed that at 7 months after second dose a population of Spike-specific B lymphocytes was still present in 86% of the immunized subjects, with a higher frequency when compared to not-immunized controls (0.38% ± 0.07 vs 0.13% ± 0.03, p<0.001). Similarly, specific CD4+ and CD8+ T lymphocytes, able to respond in vitro to stimulation with Spike derived peptides, were found at 7 months. These results confirm that vaccination with BNT162b2 is able to induce a specific immune response, potentially long lasting, and could be helpful in defining future vaccination strategies.
SARS-CoV-2 T Cell Response in Severe and Fatal COVID-19 in Primary Antibody Deficiency Patients Without Specific Humoral Immunity
Authors: Steiner Sophie , Schwarz Tatjana , Corman Victor M. , Gebert Laura , Kleinschmidt Malte C. , Wald Alexandra , Gläser Sven , Kruse Jan M. , Zickler Daniel , Peric Alexander , Meisel Christian , Meyer Tim , Staudacher Olga L. , Wittke Kirsten , Kedor Claudia , Bauer Sandra , Besher Nabeel Al , Kalus Ulrich , Pruß Axel , Drosten Christian , Volk Hans-Dieter , Scheibenbogen Carmen , Hanitsch Leif G.
Published: March 2022

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.
Domain-Dependent Evolution Explains Functional Homology of Protostome and Deuterostome Complement C3-Like Proteins
Authors: Peng Maoxiao , Li Zhi , Cardoso João C. R. , Niu Donghong , Liu Xiaojun , Dong Zhiguo , Li Jiale , Power Deborah M.
Published: March 2022

Complement proteins emerged early in evolution but outside the vertebrate clade they are poorly characterized. An evolutionary model of C3 family members revealed that in contrast to vertebrates the evolutionary trajectory ofC3-likegenes in cnidarian, protostomes and invertebrate deuterostomes was highly divergent due to independent lineage and species-specific duplications. The deducedC3-likeand vertebrate C3, C4 and C5 proteins had low sequence conservation, but extraordinarily high structural conservation and 2-chain and 3-chain protein isoforms repeatedly emerged. Functional characterization of threeC3-likeisoforms in a bivalve representative revealed that in common with vertebrates complement proteins they were cleaved into two subunits, b and a, and the latter regulated inflammation-related genes, chemotaxis and phagocytosis. Changes within the thioester bond cleavage sites and the a-subunit protein (ANATO domain) explained the functional differentiation of bivalveC3-like. The emergence of domain-related functions early during evolution explains the overlapping functions of bivalveC3-likeand vertebrate C3, C4 and C5, despite low sequence conservation and indicates that evolutionary pressure acted to conserve protein domain organization rather than the primary sequence.
Impact of Hypogammaglobulinemia on the Course of COVID-19 in a Non-Intensive Care Setting: A Single-Center Retrospective Cohort Study
Authors: Scarpa Riccardo , Dell’Edera Alessandro , Felice Carla , Buso Roberta , Muscianisi Francesco , Finco Gambier Renato , Toffolo Sara , Grossi Ugo , Giobbia Mario , Barberio Giuseppina , Landini Nicholas , Facchini Cesarina , Agostini Carlo , Rattazzi Marcello , Cinetto Francesco
Published: March 2022

Background

Severity and mortality of COVID-19 largely depends on the ability of the immune system to clear the virus. Among various comorbidities potentially impacting on this process, the weight and the consequences of an antibody deficiency have not yet been clarified.

Methods

We used serum protein electrophoresis to screen for hypogammaglobulinemia in a cohort of consecutive adult patients with COVID-19 pneumonia, hospitalized in non-intensive care setting between December 2020 and January 2021. The disease severity, measured by a validated score and by the need for semi intensive (sICU) or intensive care unit (ICU) admission, and the 30-day mortality was compared between patients presenting hypogammaglobulinemia (HYPO) and without hypogammaglobulinemia (no-HYPO). Demographics, comorbidities, COVID-19 specific treatment during the hospital stay, disease duration, complications and laboratory parameters were also evaluated in both groups.

Results

We enrolled 374 patients, of which 39 represented the HYPO cohort (10.4%). In 10/39 the condition was previously neglected, while in the other 29/39 hematologic malignancies were common (61.5%); 2/39 were on regular immunoglobulin replacement therapy (IgRT). Patients belonging to the HYPO group more frequently developed a severe COVID-19 and more often required sICU/ICU admission than no-HYPO patients. IgRT were administered in 8/39 during hospitalization; none of them died or needed sICU/ICU. Among HYPO cohort, we observed a significantly higher prevalence of neoplastic affections, of active oncologic treatment and bronchiectasis, together with higher prevalence of viral and bacterial superinfections, mechanical ventilation, convalescent plasma and SARS-CoV-2 monoclonal antibodies administration during hospital stay, and longer disease duration. Multivariate logistic regression analysis and Cox proportional hazard regression confirmed the impact of hypogammaglobulinemia on the COVID-19 severity and the probability of sICU/ICU admission. The analysis of the mortality rate in the whole cohort showed no significant difference between HYPO and no-HYPO.

Conclusions

Hypogammaglobulinemia, regardless of its cause, in COVID-19 patients hospitalized in a non-intensive care setting was associated to a more severe disease course and more frequent admission to s-ICU/ICU, particularly in absence of IgRT. Our findings emphasize the add-value of routine serum protein electrophoresis evaluation in patients admitted with COVID-19 to support clinicians in patient care and to consider IgRT initiation during hospitalization.
Immunomodulatory Activity of Mesenchymal Stem Cells in Lupus Nephritis: Advances and Applications
Authors: Li Jicui , Luo Manyu , Li Bing , Lou Yan , Zhu Yuexin , Bai Xue , Sun Baichao , Lu Xuehong , Luo Ping
Published: March 2022

Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.
The Heterogeneity of Immune Cell Infiltration Landscape and Its Immunotherapeutic Implications in Hepatocellular Carcinoma
Authors: Guo Yuanyuan , Yang Jing , Ren Kaidi , Tian Xueke , Gao Hua , Tian Xin , Zhang Xiaojian , Kan Quancheng
Published: March 2022

Immunotherapy, closely associated with immune infiltration and tumor mutation burden (TMB), is emerging as a promising strategy for treating tumors, but its low response rate in hepatocellular carcinoma (HCC) remains a major challenge. Herein, we applied two algorithms to uncover the immune infiltration landscape of the immune microenvironment in 491 HCC patients. Three immune infiltration patterns were defined using the CIBERSORT method, and the immune cell infiltration (ICI) scores were established using principal component analysis. In the high ICI score group, the activation of the Wnt/β-catenin pathway was significantly enriched and expressions of immune checkpoint genes increased, which showed a pessimistic outcome. The low ICI score group was characterized by increased TMB and enrichment of metabolism-related pathways. Further analysis found that the ICI score exhibited a significant difference in age ≥65/age <65, grade I/grade II–IV, and response to immunotherapy. Moreover, the CTNNB1 mutation status was found to be closely associated with prognosis and immunotherapeutic efficiency, significantly affecting the ICI score and TMB, which might be regarded as a potential marker for the treatment of HCC. The evaluation of immune infiltration patterns can improve the understanding of the tumor immune microenvironment and provide new directions for the study of individualized immunotherapy strategies for HCC.
New Aspects of Kidney Fibrosis–From Mechanisms of Injury to Modulation of Disease
Authors: Moeller Marcus J. , Kramann Rafael , Lammers Twan , Hoppe Bernd , Latz Eicke , Ludwig-Portugall Isis , Boor Peter , Floege Jürgen , Kurts Christian , Weiskirchen Ralf , Ostendorf Tammo
Published: March 2022

Organ fibrogenesis is characterized by a common pathophysiological final pathway independent of the underlying progressive disease of the respective organ. This makes it particularly suitable as a therapeutic target. The Transregional Collaborative Research Center “Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease” (referred to as SFB/TRR57) was hosted from 2009 to 2021 by the Medical Faculties of RWTH Aachen University and the University of Bonn. This consortium had the ultimate goal of discovering new common but also different fibrosis pathways in the liver and kidneys. It finally successfully identified new mechanisms and established novel therapeutic approaches to interfere with hepatic and renal fibrosis. This review covers the consortium's key kidney-related findings, where three overarching questions were addressed: (i) What are new relevant mechanisms and signaling pathways triggering renal fibrosis? (ii) What are new immunological mechanisms, cells and molecules that contribute to renal fibrosis?, and finally (iii) How can renal fibrosis be modulated?
Postoperative Adjuvant Imatinib Therapy-Associated Nomogram to Predict Overall Survival of Gastrointestinal Stromal Tumor
Authors: Liu Xuechao , Lin Enyu , Sun Yuqi , Liu Xiaodong , Li Zequn , Jiao Xuelong , Li Yi , Guo Dong , Zhang Peng , Feng Xingyu , Chen Tao , Niu Zhaojian , Zhou Zhiwei , Qiu Haibo , Zhou Yanbing
Published: March 2022

Background

Adjuvant imatinib therapy has been shown to improve overall survival (OS) of gastrointestinal stromal tumor (GIST) significantly. Few nomograms combining the use of adjuvant imatinib and clinicopathological characteristics estimate the outcome of patients. We aimed to establish a more comprehensive nomogram for predicting OS in patients with GIST.

Methods

In total, 1310 GIST patients undergoing curative resection at four high-volume medical centers between 2001 and 2015 were enrolled. Independent prognostic factors were identified by multivariate Cox analysis. Eligible patients were randomly assigned in a ratio of 7:3 into a training set (916 cases) and a validation set (394 cases). A nomogram was established by R software and its predictive power compared with that of the modified National Institutes of Health (NIH) classification using time-dependent receiver operating characteristic (ROC) curves and calibration plot.

Results

Age, tumor site, tumor size, mitotic index, postoperative imatinib and diagnostic delay were identified as independent prognostic parameters and used to construct a nomogram. Of note, diagnostic delay was for the first time included in a prognostic model for GIST. The calibrated nomogram resulted in predicted survival rates consistent with observed ones. And the decision curve analysis suggested that the nomogram prognostic model was clinically useful. Furthermore, time-dependent ROC curves showed the nomogram exhibited greater discrimination power than the modified NIH classification in 3- and 5-year survival predictions for both training and validation sets (all P < 0.05).

Conclusions

Postoperative adjuvant imatinib therapy improved the survival of GIST patients. We developed and validated a more comprehensive prognostic nomogram for GIST patients, and it could have important clinical utility in improving individualized predictions of survival risks and treatment decision-making.
Accessory and Expiratory Muscles Activation During Spontaneous Breathing Trial: A Physiological Study by Surface Electromyography
Authors: Pozzi Matteo , Rezoagli Emanuele , Bronco Alfio , Rabboni Francesca , Grasselli Giacomo , Foti Giuseppe , Bellani Giacomo
Published: March 2022

Background

The physiological and prognostical significance of accessory and expiratory muscles activation is unknown during a spontaneous breathing trial (SBT). We hypothesized that, in patients experiencing weaning failure, accessory and expiratory muscles are activated to cope with an increased respiratory workload.

Purpose

To describe accessory and expiratory muscle activation non-invasively by surface electromyography (sEMG) during an SBT and to assess differences in electrical activity (EA) of the inspiratory and expiratory muscles in successful vs. failing weaning patients.

Methods

Intubated patients on mechanical ventilation for more than 48 h undergoing an SBT were enrolled in a medical and surgical third-level ICU of the University Teaching Hospital. Baseline characteristics and physiological variables were recorded in a crossover physiologic prospective clinical study.

Results

Of 37 critically ill mechanically ventilated patients, 29 (78%) patients successfully passed the SBT. Rapid shallow breathing index (RSBI) was higher in patients who failed SBT compared with the successfully weaned patients at baseline and over time (group-by-time interaction p < 0.001). EA of both the diaphragm (EAdisurf) and of accessory muscles (ACCsurf) was higher in failure patients compared with success (group-by-time interaction p = 0.0174 and p < 0.001, respectively). EA of expiratory muscles (ESPsurf) during SBT increased more in failure than in weaned patients (group-by-time interaction p < 0.0001).

Conclusion

Non-invasive respiratory muscle monitoring by sEMG was feasible during SBT. Respiratory muscles EA increased during SBT, regardless of SBT outcome, and patients who failed the SBT had a higher increase of all the inspiratory muscles EA compared with the patients who passed the SBT. Recruitment of expiratory muscles—as quantified by sEMG—is associated with SBT failure.
Comparison of Anterior Capsule Polishing on the Rate of Neodymium: YAG Laser Capsulotomy After Two Multifocal Intraocular Lens Implantation
Authors: Leng Lin , Bai Huiran , Li Honglei , Liu Dongle , Han Yanfeng , Wu Xiaoming
Published: March 2022

Purpose

To compare the impact of anterior capsule polishing (ACP) during cataract surgery on the rate of neodymium: YAG (Nd: YAG) laser capsulotomy in pseudophakic eyes with two multifocal intraocular lenses (MIOLs).

Methods

Data were collected on patients who underwent cataract surgery and implanted segmental refractive MIOLs (SBL-3, Lenstec) or diffracted MIOLs (AT LISA tri 839MP, Carl Zeiss Meditec). The participants were divided into ACP and non-ACP groups based on whether the anterior capsule was polished. The primary outcome measure was whether Nd: YAG capsulotomy was performed during the 3 years follow-up. We used Kaplan–Meier survival curves to determine the time from IOL implantation to Nd: YAG laser capsulotomy.

Results

ACP and non-ACP groups comprised 70 and 60 eyes, respectively. One year postoperatively, 7.14% of ACP group eyes and 8.33% of non-ACP group required Nd: YAG laser capsulotomy (P > 0.99). After 2 years, it was 24.29 and 18.33%, respectively (P = 0.52), while after 3 years, it reached 30.0 and 28.33% (P = 0.85). No distinct difference existed in the probability of using Nd: YAG laser in both groups evaluated using Kaplan-Meier survival curves (P = 0.81). Patients with diffractive MIOLs (AT LISA tri 839MP) implantation were more likely to require Nd: YAG laser capsulotomy (P < 0.01).

Conclusion

Polishing the anterior capsule had no remarkable effect on reducing the rate of Nd: YAG laser capsulotomy following phacoemulsification in MIOLs. Patients with diffractive MIOLs implantation had a high probability of requiring Nd: YAG laser capsulotomy.
Cell-Matrix Interactions Contribute to Barrier Function in Human Colon Organoids
Authors: Varani James , McClintock Shannon D. , Aslam Muhammad N.
Published: March 2022

The importance of cell-matrix adhesion to barrier control in the colon is unclear. The goals of the present study were to: (i) determine if disruption of colon epithelial cell interactions with the extracellular matrix alters permeability control measurement and (ii) determine if increasing the elaboration of protein components of cell-matrix adhesion complexes can mitigate the effects of cell-matrix disruption. Human colon organoids were interrogated for transepithelial electrical resistance (TEER) under control conditions and in the presence of Aquamin®, a multi-mineral product. A function-blocking antibody directed at the C-terminal region of the laminin α chain was used in parallel. The effects of Aquamin® on cell-matrix adhesion protein expression were determined in a proteomic screen and by Western blotting. Aquamin® increased the expression of multiple basement membrane, hemidesmosomal and focal adhesion proteins as well as keratin 8 and 18. TEER values were higher in the presence of Aquamin® than they were under control conditions. The blocking antibody reduced TEER values under both conditions but was most effective in the absence of Aquamin®, where expression of cell-matrix adhesion proteins was lower to begin with. These findings provide evidence that cell-matrix interactions contribute to barrier control in the colon.
Global Distribution of Fluoroquinolone and Colistin Resistance and Associated Resistance Markers in Escherichia coli of Swine Origin – A Systematic Review and Meta-Analysis
Authors: Hayer Shivdeep Singh , Casanova-Higes Alejandro , Paladino Eliana , Elnekave Ehud , Nault Andre , Johnson Timothy , Bender Jeff , Perez Andres , Alvarez Julio
Published: March 2022

Background

Fluoroquinolones and polymyxins (colistin) are considered as critical drugs for human medicine. Antimicrobials of these classes are also used in swine production worldwide and this usage can contribute to selection of antimicrobial resistance (AMR), which is a threat to both human and animal health. Given the dynamic epidemiology of AMR, updating our knowledge regarding distribution and trends in the proportion of resistant bacteria is of critical importance.

Objectives

The aim of this systematic review and meta-analysis was to describe the global prevalence of phenotypic and genotypic resistance to fluoroquinolones and colistin in Escherichia coli collected from swine.

Results

Four databases (PubMed, PubAg, Web of Science, and CAB abstracts) and reports of national surveillance programs were scanned and 360 articles were included in the analysis. We identified higher prevalence levels of fluoroquinolone and colistin resistance in isolates from pig populations in Asia compared to Europe. The heterogeneity of pooled estimates was also higher in Asian countries suggesting that prevalence of AMR is still not fully characterized. There was a major knowledge gap about the situation of AMR in South American and African countries. We also identified key deficiencies in how AMR data was reported in the studies. A meta-analysis using 6,167 publicly available genomes of swine E. coli established the prevalence and global distribution of genetic determinants that can lead to fluoroquinolone and colistin resistance.

Conclusion

This study provides the most comprehensive information on prevalence of phenotypic and genotypic resistance to key antimicrobials in pig populations globally. There is a need to establish national surveillance programs and effective policies, particularly in certain world regions, to curtail the threat of evolution of resistant isolates in swine production that can potentially contribute to public health detrimentally.
Reactivation of Occult Hepatitis B Virus Infection During Long-Term Entecavir Antiviral Therapy
Authors: Yuan Chunyan , Peng Jing , Xia Renxiang , He Jian , Qiu Tianji , Yao Yunqing
Published: March 2022

Up to now, it has not been clear whether occult hepatitis B virus (HBV) infection (OBI) can be treated with antiviral therapy whether OBI can develop drug resistance gene mutation or not. We report a middle-aged female patient with OBI who showed HBV reactivation (HBVr) during more than 3 years of intermittent entecavir (ETV) antiviral therapy: seropositive HBV surface antigen (HBsAg), increased e antigen (HBeAg), and repeatedly elevated serum HBV DNA. Genotype analysis showed that the patient was infected with HBV type B. Genetic sequencing of HBV showed the mutants of S143T, D144G, and G145R in the S gene region, and the mutant of site 1896 in the pre-Core region coexisted with the wild type (G1896A/G). No mutation was found in other HBV gene segments. Drug resistance gene analysis found RtL229W mutant, resistant to lamivudine but sensitive to ETV and other nucleoside analogs. This case of OBI provides us with the following clinical experiences: Firstly, it is necessary to detect HBV genotype, mutation, and drug-resistant genes at the initial diagnosis, which can be helpful for reasonable treatment. Secondly, identifying the risk factors and mechanisms associated with HBVr could help quantify the risk of HBVr and manage the clinical consequences. Thirdly, the OBI patients with hepatitis B e antigen-positive, HBV DNA > 1 × 103 IU/ml should be recommended regular and continuous antiviral therapy as soon as possible to prevent the occurrence of hepatocirrhosis and hepatocellular carcinoma (HCC).
Ni2+-Assisted Hydrolysis May Affect the Human Proteome; Filaggrin Degradation Ex Vivo as an Example of Possible Consequences
Authors: Podobas Ewa Izabela , Gutowska-Owsiak Danuta , Moretti Sébastien , Poznański Jarosław , Kulińczak Mariusz , Grynberg Marcin , Gruca Aleksandra , Bonna Arkadiusz , Płonka Dawid , Frączyk Tomasz , Ogg Graham , Bal Wojciech
Published: March 2022

Deficiency in a principal epidermal barrier protein, filaggrin (FLG), is associated with multiple allergic manifestations, including atopic dermatitis and contact allergy to nickel. Toxicity caused by dermal and respiratory exposures of the general population to nickel-containing objects and particles is a deleterious side effect of modern technologies. Its molecular mechanism may include the peptide bond hydrolysis in X1-S/T-c/p-H-c-X2 motifs by released Ni2+ ions. The goal of the study was to analyse the distribution of such cleavable motifs in the human proteome and examine FLG vulnerability of nickel hydrolysis. We performed a general bioinformatic study followed by biochemical and biological analysis of a single case, the FLG protein. FLG model peptides, the recombinant monomer domain human keratinocytes in vitro and human epidermis ex vivo were used. We also investigated if the products of filaggrin Ni2+-hydrolysis affect the activation profile of Langerhans cells. We found X1-S/T-c/p-H-c-X2 motifs in 40% of human proteins, with the highest abundance in those involved in the epidermal barrier function, including FLG. We confirmed the hydrolytic vulnerability and pH-dependent Ni2+-assisted cleavage of FLG-derived peptides and FLG monomer, using in vitro cell culture and ex-vivo epidermal sheets; the hydrolysis contributed to the pronounced reduction in FLG in all of the models studied. We also postulated that Ni-hydrolysis might dysregulate important immune responses. Ni2+-assisted cleavage of barrier proteins, including FLG, may contribute to clinical disease associated with nickel exposure.