bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Sex-Based Differences in Cardiac Phenotype on Atrial Fibrillation Recurrence in Patients Undergoing Pulmonary Vein Isolation
Authors: Yakimenka Alena , Labib Dina , Dykstra Steven , Mikami Yoko , Satriano Alessandro , Flewitt Jacqueline , Feuchter Patricia , Rivest Sandra , Howarth Andrew G. , Lydell Carmen P. , Quinn F. Russell , Wilton Stephen B. , White James A.
Published: July 2022

Background

Pulmonary vein isolation (PVI) is a commonly engaged therapy for symptomatic atrial fibrillation (AF). Prior studies have documented elevated AF recurrence rates among females vs. males. Sex-specific mechanisms underlying this phenomenon are poorly understood. This prospective cohort study aimed to evaluate the sex-based differences in cardiac phenotype and their influence on (AF) recurrence following first-time PVI.

Methods

A total of 204 consecutive patients referred for first-time PVI and 101 healthy subjects were prospectively studied by cardiovascular magnetic resonance (CMR) imaging. Multi-chamber volumetric and functional measures were assessed by sex-corrected Z-score analyses vs. healthy subjects. Patients were followed for a median of 2.6 years for the primary outcome of clinical AF recurrence. Multivariable analyses adjusting for age and comorbidities were performed to identify independent predictors of AF recurrence.

Results

AF recurrence following first PVI occurred in 41% of males and 59% of females (p = 0.03). Females were older with higher prevalence of hypertension and thyroid disorders. Z-score-based analyses revealed significantly reduced ventricular volumes, greater left atrial (LA) volumes, and reduced LA contractility in females vs. males. Multivariable analysis revealed each of LA minimum and pre-systolic volumes and booster EF Z-scores to be independently associated with AF recurrence, providing respective hazard ratios of 1.10, 1.19, and 0.89 (p = 0.001, 0.03, and 0.01).

Conclusion

Among patients referred for first time PVI, females were older and demonstrated significantly poorer LA contractile health vs. males, the latter independently associated with AF recurrence. Assessment of LA contractile health may therefore be of value to identify female patients at elevated risk of AF recurrence. Factors influencing female patient referral for PVI at more advanced stages of atrial disease warrant focused investigation.
The Etiology and Molecular Mechanism Underlying Smooth Muscle Phenotype Switching in Intimal Hyperplasia of Vein Graft and the Regulatory Role of microRNAs
Authors: Zhang Dengshen , Cao Yiran , Liu Daxing , Zhang Jian , Guo Yingqiang
Published: July 2022

Mounting evidence suggests that the phenotypic transformation of venous smooth muscle cells (SMCs) from differentiated (contractile) to dedifferentiated (proliferative and migratory) phenotypes causes excessive proliferation and further migration to the intima leading to intimal hyperplasia, which represents one of the key pathophysiological mechanisms of vein graft restenosis. In recent years, numerous miRNAs have been identified as specific phenotypic regulators of vascular SMCs (VSMCs), which play a vital role in intimal hyperplasia in vein grafts. The review sought to provide a comprehensive overview of the etiology of intimal hyperplasia, factors affecting the phenotypic transformation of VSMCs in vein graft, and molecular mechanisms of miRNAs involved in SMCs phenotypic modulation in intimal hyperplasia of vein graft reported in recent years.
Non-coding RNAs: Important participants in cardiac fibrosis
Authors: Dong Yiheng , Peng Naling , Dong Lini , Tan Shengyu , Zhang Xiangyu
Published: July 2022

Cardiac remodeling is a pathophysiological process activated by diverse cardiac stress, which impairs cardiac function and leads to adverse clinical outcome. This remodeling partly attributes to cardiac fibrosis, which is a result of differentiation of cardiac fibroblasts to myofibroblasts and the production of excessive extracellular matrix within the myocardium. Non-coding RNAs mainly include microRNAs and long non-coding RNAs. These non-coding RNAs have been proved to have a profound impact on biological behaviors of various cardiac cell types and play a pivotal role in the development of cardiac fibrosis. This review aims to summarize the role of microRNAs and long non-coding RNAs in cardiac fibrosis associated with pressure overload, ischemia, diabetes mellitus, aging, atrial fibrillation and heart transplantation, meanwhile shed light on the diagnostic and therapeutic potential of non-coding RNAs for cardiac fibrosis.
Accelerated vascular aging: Ethnic differences in basilar artery length and diameter, and its association with cardiovascular risk factors and cerebral small vessel disease
Authors: Sudre Carole H. , Moriconi Stefano , Rehwald Rafael , Smith Lorna , Tillin Therese , Barnes Josephine , Atkinson David , Ourselin Sébastien , Chaturvedi Nish , Hughes Alun D. , Jäger H. Rolf , Cardoso M. Jorge
Published: July 2022

Background and aims

Risk of stroke and dementia is markedly higher in people of South Asian and African Caribbean descent than white Europeans in the UK. This is unexplained by cardiovascular risk factors (CVRF). We hypothesized this might indicate accelerated early vascular aging (EVA) and that EVA might account for stronger associations between cerebral large artery characteristics and markers of small vessel disease.

Methods

360 participants in a tri-ethnic population-based study (120 per ethnic group) underwent cerebral and vertebral MRI. Length and median diameter of the basilar artery (BA) were derived from Time of Flight images, while white matter hyperintensities (WMH) volumes were obtained from T1 and FLAIR images. Associations between BA characteristics and CVRF were assessed using multivariable linear regression. Partial correlation coefficients between WMH load and BA characteristics were calculated after adjustment for CVRF and other potential confounders.

Results

BA diameter was strongly associated with age in South Asians (+11.3 μm/year 95% CI = [3.05; 19.62];p= 0.008), with unconvincing relationships in African Caribbeans (3.4 μm/year [−5.26, 12.12];p= 0.436) or Europeans (2.6 μm/year [−5.75, 10.87];p= 0.543). BA length was associated with age in South Asians (+0.34 mm/year [0.02; 0.65];p= 0.037) and African Caribbeans (+0.39 mm/year [0.12; 0.65];p= 0.005) but not Europeans (+0.08 mm/year [−0.26; 0.41];p= 0.653). BA diameter (rho = 0.210;p= 0.022) and length (rho = 0.261;p= 0.004) were associated with frontal WMH load in South Asians (persisting after multivariable adjustment for CVRF).

Conclusions

Compared with Europeans, the basilar artery undergoes more accelerated EVA in South Asians and in African Caribbeans, albeit to a lesser extent. Such EVA may contribute to the higher burden of CSVD observed in South Asians and excess risk of stroke, vascular cognitive impairment and dementia observed in these ethnic groups.
A head-to-head comparison of myocardial strain by fast-strain encoding and feature tracking imaging in acute myocardial infarction
Authors: El-Saadi Walid , Engvall Jan Edvin , Alfredsson Joakim , Karlsson Jan-Erik , Martins Marcelo , Sederholm Sofia , Faisal Zaman Shaikh , Ebbers Tino , Kihlberg Johan
Published: July 2022

Background

Myocardial infarction (MI) is a major cause of heart failure. Left ventricular adverse remodeling is common post-MI. Several studies have demonstrated a correlation between reduced myocardial strain and the development of adverse remodeling. Cardiac magnetic resonance (CMR) with fast-strain encoding (fast-SENC) or feature tracking (FT) enables rapid assessment of myocardial deformation. The aim of this study was to establish a head-to-head comparison of fast-SENC and FT in post-ST-elevated myocardial infarction (STEMI) patients, with clinical 2D speckle tracking echocardiography (2DEcho) as a reference.

Methods

Thirty patients treated with primary percutaneous coronary intervention for STEMI were investigated. All participants underwent CMR examination with late gadolinium enhancement, cine-loop steady-state free precession, and fast-SENC imaging using a 1.5T scanner as well as a 2DEcho. Global longitudinal strain (GLS), segmental longitudinal strain (SLS), global circumferential strain (GCS), and segmental circumferential strain (SCS) were assessed along with the MI scar extent.

Results

The GCS measurements from fast-SENC and FT were nearly identical: the mean difference was 0.01 (2.5)% (95% CI – 0.92 to 0.95). For GLS, fast-SENC values were higher than FT, with a mean difference of 1.8 (1.4)% (95% CI 1.31–2.35). Tests of significance for GLS did not show any differences between the MR methods and 2DEcho. Average strain in the infarct-related artery (IRA) segments compared to the remote myocardium was significantly lower for the left anterior descending artery and right coronary artery culprits but not for the left circumflex artery culprits. Fast-SENC displayed a higher area under the curve for detecting infarcted segments than FT for both SCS and SLS.

Conclusion

GLS and GCS did not significantly differ between fast-SENC and FT. Both showed acceptable agreement with 2DEcho for longitudinal strain. Segments perfused by the IRA showed significantly reduced strain values compared to the remote myocardium. Fast-SENC presented a higher sensitivity and specificity for detecting infarcted segments than FT.
Exercise and physical performance in older adults with sarcopenic obesity: A systematic review
Authors: Ghiotto Laura , Muollo Valentina , Tatangelo Toni , Schena Federico , Rossi Andrea P.
Published: July 2022

Background

Sarcopenic obesity is characterized by low muscle mass and high body fat; prevalence increases with age, particularly after age 65 years. For this systematic literature review we searched scientific databases for studies on exercise interventions for improving physical performance in adults with sarcopenic obesity; also, we identified potential gaps in clinical practice guidelines that need to be addressed.

Methods

We followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The databases were searched for studies published through November 2021 that measured physical performance in adults with sarcopenic obesity.

Results

Most of the studies applied a strength training protocol in which improvement was noted post-treatment on the Time Chair Rise (TCR), 30-s Chair Stand, and Single Leg Stance (SLS) tests. Discrepancies between the studies were observed when resistance training was combined with or without elastic bands or electromyostimulation, as measured with the Short Physical Performance Battery (SPPB), Physical Performance Test (PPT), Gait Speed, and Timed Up & Go (TUG) test. Post-intervention SPPB, PPT, and gait speed scores showed an increase or maintenance of performance, while TUG test scores were higher according to one study but lower according to another.

Conclusions

Engagement in physical exercise, and resistance training in particular, can improve or maintain physical performance in adults with sarcopenic obesity. Study samples should include more men. A future area of focus should be the impact of different types of training (aerobic, power training, combined modalities). Finally, studies with longer intervention periods and follow-up periods are needed to gain a better understanding of the effectiveness of exercise on physical function in adults with sarcopenic obesity.
Small molecules to regulate the GH/IGF1 axis by inhibiting the growth hormone receptor synthesis
Authors: van der Velden Lieke M. , Maas Peter , van Amersfoort Miranda , Timmermans-Sprang Elpetra P M. , Mensinga Anneloes , van der Vaart Elisabeth , Malergue Fabrice , Viëtor Henk , Derksen Patrick W B. , Klumperman Judith , van Agthoven Andreas , Egan David A. , Mol Jan A. , Strous Ger J.
Published: July 2022

Growth hormone (GH) and insulin‐like growth factor‐1 (IGF1) play an important role in mammalian development, cell proliferation and lifespan. Especially in cases of tumor growth there is an urgent need to control the GH/IGF1 axis. In this study we screened a 38,480-compound library, and in two consecutive rounds of analogues selection, we identified active lead compounds based on the following criteria: inhibition the GH receptor (GHR) activity and its downstream effectors Jak2 and STAT5, and inhibition of growth of breast and colon cancer cells. The most active small molecule (BM001) inhibited both the GH/IGF1 axis and cell proliferation with an IC50 of 10‐30 nM of human cancer cells. BM001 depleted GHR in human lymphoblasts. In preclinical xenografted experiments, BM001 showed a strong decrease in tumor volume in mice transplanted with MDA‐MB‐231 breast cancer cells. Mechanistically, the drug acts on the synthesis of the GHR. Our findings open the possibility to inhibit the GH/IGF1 axis with a small molecule.
The molecular signaling of exercise and obesity in the microbiota-gut-brain axis
Authors: Ribeiro Filipe M. , Silva Maycon A. , Lyssa Victória , Marques Gabriel , Lima Henny K. , Franco Octavio L. , Petriz Bernardo
Published: July 2022

Obesity is one of the major pandemics of the 21st century. Due to its multifactorial etiology, its treatment requires several actions, including dietary intervention and physical exercise. Excessive fat accumulation leads to several health problems involving alteration in the gut-microbiota-brain axis. This axis is characterized by multiple biological systems generating a network that allows bidirectional communication between intestinal bacteria and brain. This mutual communication maintains the homeostasis of the gastrointestinal, central nervous and microbial systems of animals. Moreover, this axis involves inflammatory, neural, and endocrine mechanisms, contributes to obesity pathogenesis. The axis also acts in appetite and satiety control and synthesizing hormones that participate in gastrointestinal functions. Exercise is a nonpharmacologic agent commonly used to prevent and treat obesity and other chronic degenerative diseases. Besides increasing energy expenditure, exercise induces the synthesis and liberation of several muscle-derived myokines and neuroendocrine peptides such as neuropeptide Y, peptide YY, ghrelin, and leptin, which act directly on the gut-microbiota-brain axis. Thus, exercise may serve as a rebalancing agent of the gut-microbiota-brain axis under the stimulus of chronic low-grade inflammation induced by obesity. So far, there is little evidence of modification of the gut-brain axis as a whole, and this narrative review aims to address the molecular pathways through which exercise may act in the context of disorders of the gut-brain axis due to obesity.
The progress of pluripotent stem cell-derived pancreatic β-cells regeneration for diabetic therapy
Authors: Wang Xin , Gao Mengxi , Wang Yali , Zhang Yucheng
Published: July 2022

Diabetes is a complex metabolic disorder of carbohydrate metabolism, characterized by high blood glucose levels either due to an absolute deficiency of insulin secretion or an ineffective response of cells to insulin, a hormone synthetized by β-cells in the pancreas. Despite the current substantial progress of new drugs and strategies to prevent and treat diabetes, we do not understand precisely the exact cause of the failure and impairment of β-cells. Therefore, there is an urgent need to find new methods to restore β-cells. In recent years, pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) can serve as an ideal alternative source for the pancreatic β-cells. In this review, we systematically summarize the current progress and protocols of generating pancreatic β-cells from human PSCs. Meanwhile, we also discuss some challenges and future perspectives of human PSCs treatments for diabetes.
Integrated analysis of proteomics and metabolomics in girls with central precocious puberty
Authors: Li Mei , Lan Dan , Chen Yanfei
Published: July 2022

Background

Central precocious puberty (CPP) is a multifactorial and complex condition. Traditional studies focusing on a single indicator cannot always elucidate this panoramic condition but these may be revealed by using omics techniques.

Objective

Proteomics and metabolomics analysis of girls with CPP were compared to normal controls and the potential biomarkers and pathways involved were explored.

Methods

Serum proteins and metabolites from normal girls and those with CPP were compared by LC-MS/MS. Multivariate and univariate statistical analysis were used to identify the differentially expressed proteins (DEPs) and differentially expressed metabolites (DEMs). Functional annotation and pathway enrichment analysis were performed by using GO and KEGG databases, and candidate markers were screened. Finally, bioinformatic analysis was used to integrate the results of proteomics and metabolomics to find the key differential proteins, metabolites and potential biomarkers of CPP.

Results

134 DEPs were identified in girls with CPP with 71 up- and 63 down-regulated, respectively. Up-regulated proteins were enriched mainly in the extracellular matrix, cell adhesion and cellular protein metabolic processes, platelet degranulation and skeletal system development. The down-regulated proteins were mainly enriched in the immune response. Candidate proteins including MMP9, TIMP1, SPP1, CDC42, POSTN, COL1A1, COL6A1, COL2A1 and BMP1, were found that may be related to pubertal development. 103 DEMs were identified, including 42 up-regulated and 61 down-regulated metabolites which were mainly enriched in lipid and taurine metabolic pathways. KGML network analysis showed that phosphocholine (16:1(9Z)/16:1(9Z)) was involved in arachidonic acid, glycerophospholipid, linoleic acid and α-linolenic acid metabolism and it may be used as a biomarker of CPP.

Conclusions

Our study is the first to integrate proteomics and metabolomics to analyze the serum of girls with CPP and we found some key differential proteins and metabolites as well as a potential biomarker for this condition. Lipid metabolism pathways are involved and these may provide a key direction to further explore the molecular mechanisms and pathogenesis of CPP.
Research on Information Extraction of the Dongting Lake Ecological Wetland Based on Genetic Algorithm Optimized Convolutional Neural Network
Authors: Wan Diandi , Yin Shaohua
Published: July 2022

Dongting Lake is an important lake wetland in China. How to quickly and accurately obtain the basic information of the Dongting Lake ecological wetland is of great + significance for the dynamic monitoring, protection, and sustainable utilization of the wetland. Therefore, this article proposes the information extraction of the Dongting Lake ecological wetland based on genetic algorithm optimized convolutional neural network (GA-CNN), an analysis model combining genetic algorithm (GA) and convolutional neural network (CNN). Firstly, we know the environmental information of Dongting Lake, take Gaofen-1 image as the data source, and use normalized vegetation index and normalized water body index as auxiliary data to preprocess the change detection of remote sensing images to obtain high-precision fitting images. GA-CNN is constructed to efficiently extract the information of the Dongting Lake ecological wetland, and the Relu excitation function is used to improve the phenomenon of gradient disappearance and convergence fluctuation so as to reduce the operation time. Logistic regression is used for feature extraction, and finally the automatic identification and information extraction of the Dongting Lake ecological wetland are realized. The research results show that the method proposed in this article can more deeply dig the information of ground objects, express depth features, and has high accuracy and credibility.
Research on the internal mechanism and path of the new growth point of marine biological economy
Authors: Zhou Jianlong , Li Bin
Published: July 2022

In order to explore how the marine economy can realize the new growth point of economic development, this study puts forward a research method based on the internal mechanism and path of the new growth point of marine economic development. This method recommends key technical problems and solutions based on the research method of the internal mechanism and path of developing new growth points, amphibious science that further integrates, ecological, and socialized theory and application and explores the internal mechanism and path of how the marine economy realizes the new growth points of economic development. The research shows that the research on the internal mechanism and path of developing new growth points has increased the marine economy by nearly 45%, deeply analyzes the internal relationship between coastal economic growth and marine pollution, the close relationship between marine resources development and marine economic growth, and briefly summarizes the marine economic growth path against the background of the adjustment and change of marine industrial structure.
Research on the Optimization of Cold Chain Logistics Distribution Path of Agricultural Products E-Commerce in Urban Ecosystem From the Perspective of Carbon Neutrality
Authors: Jia Xinzhong
Published: July 2022

In order to further cope with climate change, achieve green and low-carbon economic development and further improve the construction of ecological civilization, a research method for optimization of cold chain logistics distribution path of agricultural products e-commerce from the perspective of carbon neutrality was proposed. This method takes full account of the requirements of distribution path optimization, it is based on ecological theory and applies ecological methods to study the structure, function and dynamics of human-centered urban ecosystems, as well as the laws of interaction between system components and between the system and the surrounding ecosystems, which is in line with the optimization goal of minimizing distribution operating costs, and the ant colony algorithm is used to construct the cost optimization model of cold chain logistics distribution path based on the weight limit of distribution vehicles and the time window limit. By comparison of simulation experiments, the best parameter solution is 2,873.9931. The difference with other combinations is only 1–2%, and the optimal parameter matching of the algorithm isα = 1,β = 2,ρ = 0.5. Experiments show that the optimal parameter combination is determined on the basis of reflecting different distribution results.
Distribution and efficacy of ofatumumab and ocrelizumab in humanized CD20 mice following subcutaneous or intravenous administration
Authors: Torres Julia Baguña , Roodselaar Jay , Sealey Megan , Ziehn Marina , Bigaud Marc , Kneuer Rainer , Leppert David , Weckbecker Gisbert , Cornelissen Bart , Anthony Daniel C.
Published: July 2022

Approval of B-cell-depleting therapies signifies an important advance in the treatment of multiple sclerosis (MS). However, it is unclear whether the administration route of anti-CD20 monoclonal antibodies (mAbs) alters tissue distribution patterns and subsequent downstream effects. This study aimed to investigate the distribution and efficacy of radiolabeled ofatumumab and ocrelizumab in humanized-CD20 (huCD20) transgenic mice following subcutaneous (SC) and intravenous (IV) administration. For distribution analysis, huCD20 and wildtype mice (n = 5 per group) were imaged by single-photon emission computed tomography (SPECT)/CT 72 h after SC/IV administration of ofatumumab or SC/IV administration of ocrelizumab, radiolabeled with Indium-111 (111In-ofatumumab or 111In-ocrelizumab; 5 µg, 5 MBq). For efficacy analysis, huCD20 mice with focal delayed-type hypersensitivity lesions and associated tertiary lymphoid structures (DTH-TLS) were administered SC/IV ofatumumab or SC/IV ocrelizumab (7.5 mg/kg, n = 10 per group) on Days 63, 70 and 75 post lesion induction. Treatment impact on the number of CD19+ cells in select tissues and the evolution of DTH-TLS lesions in the brain were assessed. Uptake of an 111In-labelled anti-CD19 antibody in cervical and axillary lymph nodes was also assessed before and 18 days after treatment initiation as a measure of B-cell depletion. SPECT/CT image quantification revealed similar tissue distribution, albeit with large differences in blood signal, of 111In-ofatumumab and 111In-ocrelizumab following SC and IV administration; however, an increase in both mAbs was observed in the axillary and inguinal lymph nodes following SC versus IV administration. In the DTH-TLS model of MS, both treatments significantly reduced the 111In-anti-CD19 signal and number of CD19+ cells in select tissues, where no differences between the route of administration or mAb were observed. Both treatments significantly decreased the extent of glial activation, as well as the number of B- and T-cells in the lesion following SC and IV administration, although this was mostly achieved to a greater extent with ofatumumab versus ocrelizumab. These findings suggest that there may be more direct access to the lymph nodes through the lymphatic system with SC versus IV administration. Furthermore, preliminary findings suggest that ofatumumab may be more effective than ocrelizumab at controlling MS-like pathology in the brain.
Profiling the peripheral blood T cell receptor repertoires of gastric cancer patients
Authors: Wang Mengyao , Gao Peng , Ren Laifeng , Duan Jingjing , Yang Silu , Wang Haina , Wang Hongxia , Sun Junning , Gao Xiaoyan , Li Bo , Li Shuaicheng , Su Wen
Published: July 2022

Cancer driven by somatic mutations may express neoantigens that can trigger T-cell immune responses. Since T-cell receptor (TCR) repertoires play critical roles in anti-tumor immune responses for oncology, next-generation sequencing (NGS) was used to profile the hypervariable complementarity-determining region 3 (CDR3) of the TCR-beta chain in peripheral blood samples from 68 gastric cancer patients and 49 healthy controls. We found that most hyper-expanded CDR3 are individual-specific, and the gene usage of TRBV3-1 is more frequent in the tumor group regardless of tumor stage than in the healthy control group. We identified 374 hyper-expanded tumor-specific CDR3, which may play a vital role in anti-tumor immune responses. The patients with stage IV gastric cancer have higher EBV-specific CDR3 abundance than the control. In conclusion, analysis of the peripheral blood TCR repertoires may provide the biomarker for gastric cancer prognosis and guide future immunotherapy.
Distinct immune stimulatory effects of anti-human VISTA antibodies are determined by Fc-receptor interaction
Authors: Mostböck Sven , Wu Helen Haixia , Fenn Timothy , Riegler Bettina , Strahlhofer Susanne , Huang Yining , Hansen Gale , Kroe-Barrett Rachel , Tirapu Iñigo , Vogt Anne B.
Published: July 2022

VISTA (PD-1H) is an immune regulatory molecule considered part of the next wave of immuno-oncology targets. VISTA is an immunoglobulin (Ig) superfamily cell surface molecule mainly expressed on myeloid cells, and to some extent on NK cells and T cells. In previous preclinical studies, some VISTA-targeting antibodies provided immune inhibitory signals, while other antibodies triggered immune stimulatory signals. Importantly, for therapeutic antibodies, the isotype backbone can have a strong impact on antibody function. To elucidate the mode of action of immune stimulatory anti-VISTA antibodies, we studied three different anti-human VISTA antibody clones, each on three different IgG isotypes currently used for therapeutic antibodies: unaltered IgG1 (IgG1-WT), IgG1-KO (IgG1-LL234,235AA-variant with reduced Fc-effector function), and IgG4-Pro (IgG4- S228P-variant with stabilized hinge region). Antibody functionality was analysed in mixed leukocyte reaction (MLR) of human peripheral blood mononuclear cells (PBMCs), as a model system for ongoing immune reactions, on unstimulated human PBMCs, as a model system for a resting immune system, and also on acute myeloid leukemia (AML) patient samples to evaluate anti-VISTA antibody effects on primary tumor material. The functions of three anti-human VISTA antibodies were determined by their IgG isotype backbones. An MLR of healthy donor PBMCs was effectively augmented by anti-VISTA-IgG4-Pro and anti-VISTA-IgG1-WT antibodies, as indicated by increased levels of cytokines, T cell activation markers and T cell proliferation. However, in a culture of unstimulated PBMCs of single healthy donors, only anti-VISTA-IgG1-WT antibodies increased the activation marker HLA-DR on resting myeloid cells, and chemokine levels. Interestingly, interactions with different Fc-receptors were required for these effects, namely CD64 for augmentation of MLR, and CD16 for activation of resting myeloid cells. Furthermore, anti-VISTA-IgG1-KO antibodies had nearly no impact in any model system. Similarly, in AML patient samples, anti-VISTA-antibody on IgG4-Pro backbone, but not on IgG1-KO backbone, increased interactions, as a novel readout of activity, between immune cells and CD34+ AML cancer cells. In conclusion, the immune stimulatory effects of antagonistic anti-VISTA antibodies are defined by the antibody isotype and interaction with different Fc-gamma-receptors, highlighting the importance of understanding these interactions when designing immune stimulatory antibody therapeutics for immuno-oncology applications.
Proinflammatory mucosal-associated invariant CD8+ T cells react to gut flora yeasts and infiltrate multiple sclerosis brain
Authors: Gargano Francesca , Guerrera Gisella , Piras Eleonora , Serafini Barbara , Di Paola Monica , Rizzetto Lisa , Buscarinu Maria Chiara , Annibali Viviana , Vuotto Claudia , De Bardi Marco , D’Orso Silvia , Ruggieri Serena , Gasperini Claudio , Pavarini Lorenzo , Ristori Giovanni , Picozza Mario , Rosicarelli Barbara , Ballerini Clara , Mechelli Rosella , Vitali Francesco , Cavalieri Duccio , Salvetti Marco , Angelini Daniela F. , Borsellino Giovanna , De Filippo Carlotta , Battistini Luca
Published: July 2022

The composition of the intestinal microbiota plays a critical role in shaping the immune system. Modern lifestyle, the inappropriate use of antibiotics, and exposure to pollution have significantly affected the composition of commensal microorganisms. The intestinal microbiota has been shown to sustain inappropriate autoimmune responses at distant sites in animal models of disease, and may also have a role in immune-mediated central nervous system (CNS) diseases such as multiple sclerosis (MS). We studied the composition of the gut mycobiota in fecal samples from 27 persons with MS (pwMS) and in 18 healthy donors (HD), including 5 pairs of homozygous twins discordant for MS. We found a tendency towards higher fungal abundance and richness in the MS group, and we observed that MS twins showed a higher rate of food-associated strains, such as Saccharomyces cerevisiae. We then found that in pwMS, a distinct population of cells with antibacterial and antifungal activity is expanded during the remitting phase and markedly decreases during clinically and/or radiologically active disease. These cells, named MAIT (mucosal-associated invariant T cells) lymphocytes, were significantly more activated in pwMS compared to HD in response to S. cerevisiae and Candida albicans strains isolated from fecal samples. This activation was also mediated by fungal-induced IL-23 secretion by innate immune cells. Finally, immunofluorescent stainings of MS post-mortem brain tissues from persons with the secondary progressive form of the disease showed that MAIT cells cross the blood–brain barrier (BBB) and produce pro-inflammatory cytokines in the brain. These results were in agreement with the hypothesis that dysbiosis of the gut microbiota might determine the inappropriate response of a subset of pathogenic mucosal T cells and favor the development of systemic inflammatory and autoimmune diseases.
Susceptibility to Infections During Acute Liver Injury Depends on Transient Disruption of Liver Macrophage Niche
Authors: Lopes Mateus Eustáquio , Nakagaki Brenda Naemi , Mattos Matheus Silvério , Campolina-Silva Gabriel Henrique , Meira Raquel de Oliveira , Paixão Pierre Henrique de Menezes , Oliveira André Gustavo , Faustino Lucas D. , Gonçalves Ricardo , Menezes Gustavo Batista
Published: July 2022

Kupffer cells are the primary liver resident immune cell responsible for the liver firewall function, including clearance of bacterial infection from the circulation, as they are strategically positioned inside the liver sinusoid with intimate contact with the blood. Disruption in the tissue-resident macrophage niche, such as in Kupffer cells, can lead to a window of susceptibility to systemic infections, which represents a significant cause of mortality in patients with acetaminophen (APAP) overdose-induced acute liver injury (ALI). However, how Kupffer cell niche disruption increases susceptibility to systemic infections in ALI is not fully understood. Using a mouse model of ALI induced by APAP overdose, we found that Kupffer cells upregulated the apoptotic cell death program and were markedly reduced in the necrotic areas during the early stages of ALI, opening the niche for the infiltration of neutrophils and monocyte subsets. In addition, during the resolution phase of ALI, the remaining tissue macrophages with a Kupffer cell morphology were observed forming replicating cell clusters closer to necrotic areas devoid of Kupffer cells. Interestingly, mice with APAP-induced liver injury were still susceptible to infections despite the dual cellular input of circulating monocytes and proliferation of remaining Kupffer cells in the damaged liver. Therapy with bone marrow-derived macrophages (BMDM) was shown to be effective in occupying the niche devoid of Kupffer cells following APAP-induced ALI. The rapid BMDM migration to the liver and their positioning within necrotic areas enhanced the healing of the tissue and restored the liver firewall function after BMDM therapy. Therefore, we showed that disruption in the Kupffer cell niche and its impaired function during acute liver injury are key factors for the susceptibility to systemic bacterial infections. In addition, modulation of the liver macrophage niche was shown to be a promising therapeutic strategy for liver injuries that reduce the Kupffer cell number and compromise the organ function.
Polyethylene glycol 20 kDa-induced vacuolation does not impair phagocytic function of human monocyte-derived macrophages
Authors: Schoenbrunn Anne , Juelke Kerstin , Reipert Birgit M. , Horling Frank , Turecek Peter L.
Published: July 2022

Conjugation to polyethylene glycol (PEG) is commonly used to enhance drug delivery and efficacy by extending the half-life of the drug molecule. This has important implications for reducing treatment burden in diseases that require chronic prophylaxis, such as hemophilia. Clearance of PEG molecules with high molecular weights (≥ 40 kDa) has been reported to cause cellular vacuolation in mammals. Rurioctocog alfa pegol (PEGylated recombinant coagulation factor VIII) contains a 20-kDa PEG. This study investigated the effects of exposure to 20-kDa PEG (10 μg/ml to 10 mg/ml) on the morphology and function of human monocyte-derived macrophages (MDMs) in vitro. Exposure to PEG for 24 hours was associated with significant vacuolation only at concentrations of 1 mg/ml or more, which far exceed the levels associated with clinically relevant doses of rurioctocog alfa pegol. Immunofluorescence staining of PEG was detected in the cytoplasm of MDMs, indicating uptake into the cells. No impairment of MDM phagocytic activity (ability to ingest fluorescently labeled Escherichia coli) was observed with 24-hour exposure to PEG, even at concentrations associated with significant vacuolation. Furthermore, PEG exposure did not have significant effects on cytokine secretion in resting or lipopolysaccharide-stimulated MDMs, or on the expression of cell surface markers in stimulated MDMs. Cell viability was not affected by 24-hour exposure to PEG. In conclusion, vacuolation of human MDMs after exposure to 20-kDa PEG only occurred with PEG concentrations far in excess of those equivalent to clinically relevant doses of rurioctocog alfa pegol and did not affect MDM viability or functionality. Together, these results support the concept that PEG-mediated vacuolation is an adaptive cellular response rather than a toxic effect.
May the force be with your (immune) cells: an introduction to traction force microscopy in Immunology
Authors: Mustapha Farah , Sengupta Kheya , Puech Pierre-Henri
Published: July 2022

For more than a couple of decades now, “force” has been recognized as an important physical parameter that cells employ to adapt to their microenvironment. Whether it is externally applied, or internally generated, cells use force to modulate their various actions, from adhesion and migration to differentiation and immune function. T lymphocytes use such mechano-sensitivity to decipher signals when recognizing cognate antigens presented on the surface of antigen presenting cells (APCs), a critical process in the adaptive immune response. As such, many techniques have been developed and used to measure the forces felt/exerted by these small, solitary and extremely reactive cells to decipher their influence on diverse T cell functions, primarily activation. Here, we focus on traction force microscopy (TFM), in which a deformable substrate, coated with the appropriate molecules, acts as a force sensor on the cellular scale. This technique has recently become a center of interest for many groups in the “ImmunoBiophysics” community and, as a consequence, has been subjected to refinements for its application to immune cells. Here, we present an overview of TFM, the precautions and pitfalls, and the most recent developments in the context of T cell immunology.
Case Report: Successful treatment of late-onset immune checkpoint inhibitor-associated membranous nephropathy in a patient with advanced renal cell carcinoma
Authors: Ratanasrimetha Praveen , Reddy Vikas D. , Kala Jaya , Tchakarov Amanda , Glass William F. , Msaouel Pavlos , Lin Jamie S.
Published: July 2022

Background

Diagnosing immune checkpoint inhibitor (ICI)-associated nephritis can be challenging since it is a rare complication of therapy, associated with a spectrum of immune-mediated pathologies, and can present months after ICI therapy discontinuation (i.e., late-onset). ICIs are increasingly administered in combination with other cancer therapies with associated nephrotoxicity, further obfuscating the diagnosis of ICI-associated nephritis. In this report, we describe the first suspected case of late-onset ICI-associated membranous nephropathy (MN) in a patient with metastatic clear cell renal cell carcinoma (RCC) who had discontinued ICI therapy 6 months prior to presentation. Prompt recognition of the suspected late-onset immune-related adverse event (irAE) resulted in the successful treatment of MN and continuation of RCC therapy.

Case presentation

A 57-year-old man with metastatic clear cell RCC was responsive to third-line RCC therapy with lenvatinib (oral TKI) and everolimus (oral mTOR inhibitor) when he presented with nephrotic range proteinuria and acute kidney injury (AKI). His kidney biopsy revealed probable secondary MN with subendothelial and mesangial immune complex deposits and negative staining for both phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A). While a diagnosis of paraneoplastic MN could not be excluded, the patient was responding to cancer therapy and had tumor regression. However, 6 months prior to presentation, the patient had received pembrolizumab, an ICI, with his first-line RCC treatment. Due to concern that the patient may be presenting with late-onset ICI-associated MN, he was effectively treated with rituximab, which allowed for his continued RCC therapy.

Conclusion

This report highlights the first case of suspected late-onset ICI-associated MN and the increasing complexity of recognizing renal irAEs. With the growing indications for the use of ICIs in combination with other cancer therapies, recognizing the various presentations of ICI-immune nephritis can help guide patient management and treatment.
Evidence for histamine release in chronic inducible urticaria – A systematic review
Authors: Kulthanan Kanokvalai , Church Martin K. , Grekowitz Eva Maria , Hawro Tomasz , Kiefer Lea Alice , Munprom Kanyalak , Nanchaipruek Yanisorn , Rujitharanawong Chuda , Terhorst-Molawi Dorothea , Maurer Marcus
Published: July 2022

Background

Chronic inducible urticaria (CIndU) constitutes a group of nine different CIndUs in which pruritic wheals and/or angioedema occur after exposure to specific and definite triggers. Histamine released from activated and degranulating skin mast cells is held to play a key role in the pathogenesis of CIndU, but evidence to support this has, as of yet, not been reviewed systematically or in detail. We aim to characterize the role and relevance of histamine in CIndU.

Methods

We systematically searched 3 electronic databases (PubMed, Scopus, and Embase) for studies that reported increased serum or skin histamine concentration (direct evidence) orin vitroorex vivohistamine release (indirect evidence) following trigger exposure.

Results

An initial total of 3,882 articles was narrowed down to 107 relevant studies of which 52 were in cold urticaria, 19 in cholinergic urticaria, 14 in heat urticaria, 10 in contact urticaria, 7 each in solar urticaria and vibratory angioedema, 4 each in symptomatic dermographism and aquagenic urticaria, and 3 in delayed pressure urticaria. The results of our review support that histamine has a key pathogenic role in the pathogenesis of all CIndUs, but it is not the sole mediator as evidenced by the often poor relationship between the level of histamine and severity of symptoms and the variable clinical efficacy of H1-antihistamines.

Conclusions

Histamine released from skin mast cells is a key driver of the development of signs and symptoms and a promising therapeutic target in CIndU.
Intervertebral disc cell chondroptosis elicits neutrophil response in Staphylococcus aureus spondylodiscitis
Authors: Schweizer Tiziano A. , Andreoni Federica , Acevedo Claudio , Scheier Thomas C. , Heggli Irina , Maggio Ewerton Marques , Eberhard Nadia , Brugger Silvio D. , Dudli Stefan , Zinkernagel Annelies S.
Published: July 2022

To understand the pathophysiology of spondylodiscitis due to Staphylococcus aureus, an emerging infectious disease of the intervertebral disc (IVD) and vertebral body with a high complication rate, we combined clinical insights and experimental approaches. Clinical data and histological material of nine patients suffering from S. aureus spondylodiscitis were retrospectively collected at a single center. To mirror the clinical findings experimentally, we developed a novel porcine ex vivo model mimicking acute S. aureus spondylodiscitis and assessed the interaction between S. aureus and IVD cells within their native environment. In addition, the inflammatory features underlying this interaction were assessed in primary human IVD cells. Finally, mirroring the clinical findings, we assessed primary human neutrophils for their ability to respond to secreted inflammatory modulators of IVD cells upon the S. aureus challenge. Acute S. aureus spondylodiscitis in patients was characterized by tissue necrosis and neutrophil infiltration. Additionally, the presence of empty IVD cells’ lacunae was observed. This was mirrored in the ex vivo porcine model, where S. aureus induced extensive IVD cell death, leading to empty lacunae. Concomitant engagement of the apoptotic and pyroptotic cell death pathways was observed in primary human IVD cells, resulting in cytokine release. Among the released cytokines, functionally intact neutrophil-priming as well as broad pro- and anti-inflammatory cytokines which are known for their involvement in IVD degeneration were found. In patients as well as ex vivo in a novel porcine model, S. aureus IVD infection caused IVD cell death, resulting in empty lacunae, which was accompanied by the release of inflammatory markers and recruitment of neutrophils. These findings offer valuable insights into the important role of inflammatory IVD cell death during spondylodiscitis and potential future therapeutic approaches.
Multidimensional overview of neurofilament light chain contribution to comprehensively understanding multiple sclerosis
Authors: Kölliker Frers Rodolfo A. , Otero-Losada Matilde , Kobiec Tamara , Udovin Lucas D. , Aon Bertolino María Laura , Herrera María I. , Capani Francisco
Published: July 2022

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by demyelination, progressive axonal loss, and varying clinical presentations. Axonal damage associated with the inflammatory process causes neurofilaments, the major neuron structural proteins, to be released into the extracellular space, reaching the cerebrospinal fluid (CSF) and the peripheral blood. Methodological advances in neurofilaments’ serological detection and imaging technology, along with many clinical and therapeutic studies in the last years, have deepened our understanding of MS immunopathogenesis. This review examines the use of light chain neurofilaments (NFLs) as peripheral MS biomarkers in light of the current clinical and therapeutic evidence, MS immunopathology, and technological advances in diagnostic tools. It aims to highlight NFL multidimensional value as a reliable MS biomarker with a diagnostic-prognostic profile while improving our comprehension of inflammatory neurodegenerative processes, mainly RRMS, the most frequent clinical presentation of MS.
Prevention of omalizumab for seasonal allergic rhinoconjunctivitis: a retrospective cohort study
Authors: Tang Rui , Lei Shubin , Zhu Liping , Lv Yuzhen , Li Hong
Published: July 2022

Background

Allergic rhinoconjunctivitis (ARC) is an allergic disease that is characterized by conjunctival and nasal symptoms such as edema and congestion of conjunctiva, rhinorrhea, sneezing, and blocked nose. Seasonal ARC (SARC) is usually induced by seasonal allergens and often occurs at specific times during the year. Traditional treatments of SARC include nasal corticosteroids, antihistamines, and mast cell membrane stabilizers. Biological agents such as omalizumab have also been proved effective in the treatment of SARC.

Objectives

We aim to certify the preventative efficacy of omalizumab for SARC and explore its influence factors.

Methods

Medical records of 64 SARC patients were retrospectively analyzed, and generalized linear models were used to analyze influence factors of efficacy of omalizumab.

Results

Compared with forepassed pollen season without omalizumab treatment, the combined symptom and medication score (CSMS) of ARC with pre-seasonal omalizumab was significantly lower (with omalizumab: 0.67[0.00,1.83], without omalizumab: 4.00[2.83,4.96], p<0.001, max score=6). Subgroup analysis was conducted to explore the influence factor of preventative efficacy of omalizumab. The CSMS with omalizumab treatment were not significantly different among different age, gender, dosage, number of injections, and injection date subgroups (p>0.05).

Conclusion

Pre-seasonal omalizumab treatment could significantly relieve SARC related symptoms and reduce medication use. This preventative efficacy would not be influenced by the dosage and number of injections of omalizumab. A single dose of 150mg omalizumab could achieve a satisfactory outcome.