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Article ; Online: Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

Zhao, Lan / Cunningham, Christine M / Andruska, Adam M / Schimmel, Katharina / Ali, Md Khadem / Kim, Dongeon / Gu, Shenbiao / Chang, Jason L / Spiekerkoetter, Edda / Nicolls, Mark R

Lab animal

2024 Volume 53, Issue 2, Page(s) 43–55

Abstract: The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of ... ...

Abstract	The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined the multitissue microbial biogeography of healthy Fischer 344 rats across their lifespan. Microbial community profiling data were extracted and integrated with host transcriptomic data from the Sequencing Quality Control consortium. Unsupervised machine learning, correlation, taxonomic diversity and abundance analyses were performed to determine and characterize the rat microbial biogeography and identify four intertissue microbial heterogeneity patterns (P1-P4). We found that the 11 body habitats harbored a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundance progressively declined in lungs from breastfed newborn to adolescence/adult, and was below detectable levels in elderly rats. Bioinformatics analyses indicate that the abundance of LAB may be modulated by the lung-immune axis. The presence and levels of LAB in lungs were further evaluated by PCR in two validation datasets. The lung, testes, thymus, kidney, adrenal and muscle niches were found to have age-dependent alterations in microbial abundance. The 357 microbial signatures were positively correlated with host genes in cell proliferation (P1), DNA damage repair (P2) and DNA transcription (P3). Our study established a link between the metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures could be useful for microbiome therapeutic approaches to human health and life quality enhancement.
MeSH term(s)	Humans ; Rats ; Animals ; Bacteria ; Lactobacillales ; Lung/microbiology ; Microbiota/genetics
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ISSN	1548-4475
ISSN (online)	1548-4475
DOI	10.1038/s41684-023-01322-x
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Article ; Online: Microvasculature in murine tracheal allografts after combined therapy with clopidogrel and everolimus.

Heim, Christian / Kuckhahn, Annika / Ramsperger-Gleixner, Martina / Nicolls, Mark R / Weyand, Michael / Ensminger, Stephan M

Interactive cardiovascular and thoracic surgery

2021 Volume 32, Issue 6, Page(s) 960–968

Abstract: Objectives: Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction. Previous studies have suggested T-cell mediated proliferation and microvascular changes in experimental small airways models as ... ...

Abstract	Objectives: Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction. Previous studies have suggested T-cell mediated proliferation and microvascular changes in experimental small airways models as potential therapeutic targets. The aim of this study was to assess microvascular changes in murine orthotopic tracheal allografts after treatment with everolimus alone or in combination with clopidogrel. Methods: C57Bl/6 (H-2b) donor tracheas were orthotopically transplanted into CBA (H-2k) recipients. Mice received daily injections of everolimus (0.05 mg/kg) alone or combined with clopidogrel (1 mg/kg). Twenty-eight days after transplantation, ratio of the thickness of tracheal epithelium and lamina propria was measured as an indicator for chronic rejection. Additionally, graft oxygenation and graft perfusion were detected on postoperative days 4, 10 and 28. Quantitative reverse transcription polymerase chain reaction analysis was used for gene expression analysis. Results: While syngeneic grafts showed a stable tissue pO2 and undisturbed microvascular perfusion, rejecting allografts had a drastic decline in both parameters as well as a flattened epithelium and an increased thickness of the lamina propria. Treatment with everolimus reduced allogeneic fibroproliferation, but had no protective effects on the microvasculature; polymerase chain reaction analysis indicated hypoxic stress and inflammation. Combining everolimus with clopidogrel improved microvascular integrity in the tracheal grafts, but had no synergistic effect in preventing obliterative bronchiolitis development. Conclusions: These data demonstrate that the ability of everolimus to reduce the development of post-transplant obliterative bronchiolitis is not caused by microvascular protection and has no synergistic effects with clopidogrel in acute airway rejection.
MeSH term(s)	Allografts ; Animals ; Bronchiolitis Obliterans ; Clopidogrel ; Everolimus ; Graft Rejection/prevention & control ; Lung Transplantation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Microvessels ; Trachea/surgery
Chemical Substances	Everolimus (9HW64Q8G6G) ; Clopidogrel (A74586SNO7)
Language	English
Publishing date	2021-02-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2095298-3
ISSN	1569-9285 ; 1569-9293
ISSN (online)	1569-9285
ISSN	1569-9293
DOI	10.1093/icvts/ivab021
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Article ; Online: VIEWING PULMONARY HYPERTENSION THROUGH A PEDIATRIC LENS.

Agarwal, Stuti / Fineman, Jeffrey / Cornfield, David N / Alvira, Cristina M / Zamanian, Roham T / Goss, Kara / Yuan, Ke / Bonnet, Sebastien / Boucherat, Olivier / Pullamsetti, Soni / Alcázar, Miguel A / Goncharova, Elena / Kudryashova, Tatiana V / Nicolls, Mark R / de Jesús Pérez, Vinicio

The European respiratory journal

2024

Language	English
Publishing date	2024-04-04
Publishing country	England
Document type	Journal Article
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.01518-2023
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Article: Rat microbial biogeography and age-dependent lactic acid bacteria in healthy lungs.

Zhao, Lan / Cunningham, Christine M / Andruska, Adam M / Schimmel, Katharina / Ali, Md Khadem / Kim, Dongeon / Gu, Shenbiao / Chang, Jason L / Spiekerkoetter, Edda / Nicolls, Mark R

bioRxiv : the preprint server for biology

2023

Abstract	The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearman's correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LAB's presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life.
Language	English
Publishing date	2023-05-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.19.541527
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Article ; Online: Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy.

Ferrian, Selena / Cao, Aiqin / McCaffrey, Erin F / Saito, Toshie / Greenwald, Noah F / Nicolls, Mark R / Bruce, Trevor / Zamanian, Roham T / Del Rosario, Patricia / Rabinovitch, Marlene / Angelo, Michael

American journal of respiratory and critical care medicine

2023 Volume 209, Issue 2, Page(s) 206–218

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Humans ; Pulmonary Arterial Hypertension ; Hypertension, Pulmonary ; Hepatitis A Virus Cellular Receptor 2/metabolism ; Endothelial Cells/metabolism ; Familial Primary Pulmonary Hypertension/genetics ; Pulmonary Artery ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Cell Proliferation ; Hydralazine/analogs & derivatives ; Hydrazones
Chemical Substances	Hepatitis A Virus Cellular Receptor 2 ; hydralazine 4-anisaldehyde hydrazone (61641-43-8) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30) ; Hydralazine (26NAK24LS8) ; Hydrazones
Language	English
Publishing date	2023-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202209-1761OC
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Article ; Online: HIGH LIVER FAT ASSOCIATES WITH HIGHER RISK OF DEVELOPING SYMPTOMATIC COVID-19 INFECTION - INITIAL UK BIOBANK OBSERVATIONS

Roca-Fernandez, A. / Dennis, A. / Nicolls, R. / McGonigle, J. / Kelly, M. / Banerjee, R.

Abstract: Background A high proportion of COVID-19 patients develop acute liver dysfunction. Early research has suggested that pre-existing fatty liver disease may be a significant risk factor for hospitalisation. Liver fat, in particular, is a modifiable ... ...

Abstract	Background A high proportion of COVID-19 patients develop acute liver dysfunction. Early research has suggested that pre-existing fatty liver disease may be a significant risk factor for hospitalisation. Liver fat, in particular, is a modifiable parameter and can be a target for public health policy and individual patient plans. In this study we aimed to assess pre-existing liver disease as a risk factor for developing symptomatic COVID-19. Methods From 502,506 participants from the UK Biobank, 42,146 underwent MRI (aged 45-82), and had measures of liver fat, liver fibroinflammatory disease and liver iron. Patients were censored on May 28th to determine how many had tested for COVID-19 with symptomatic disease. UK testing was restricted to those with symptoms in hospital. COVID-19 symptoms included fever, dry cough, sore throat, diarrhoea and fatigue. Univariate analysis was performed on liver phenotypic biomarkers to determine if these variables increased risk of symptomatic COVID-19, and compared to previously described risk factors associated with severe COVID-19, including to age, ethnicity, gender and obesity, Findings Increased liver fat was associated with a higher risk for symptomatic confirmed COVID-19 in this population in univariate analysis(OR:1.85, p=0.03). In obese participants, only those with concomitant fatty liver([≥]10%) were at increased risk(OR:2.96, p=0.02), with those having normal liver fat (<5%) showing no increased risk(OR:0.36, p=0.09). Conclusions UK Biobank data demonstrated an association between pre-existing liver disease and obesity with severe COVID-19, with higher proportions of liver fat in obese individuals a likely risk factor for symptomatic disease and severity. Public policy measures to protect patients with liver disease who may have almost double the risk of the general population should be considered, especially as dietary and pharmacological strategies to reduce body weight and liver fat already exist. Funding University of Oxford, Innovate UK, UK Biobank. Authors are employees of Perspectum Ltd.
Keywords	covid19
Publisher	MedRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.06.04.20122457
Database	COVID19

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Article ; Online: The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis-ten years later.

Cool, Carlyne D / Kuebler, Wolfgang M / Bogaard, Harm Jan / Spiekerkoetter, Edda / Nicolls, Mark R / Voelkel, Norbert F

American journal of physiology. Lung cellular and molecular physiology

2020 Volume 318, Issue 6, Page(s) L1115–L1130

Abstract: Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the ... ...

Abstract	Severe forms of pulmonary arterial hypertension (PAH) are most frequently the consequence of a lumen-obliterating angiopathy. One pathobiological model is that the initial pulmonary vascular endothelial cell injury and apoptosis is followed by the evolution of phenotypically altered, apoptosis-resistant, proliferating cells and an inflammatory vascular immune response. Although there may be a vasoconstrictive disease component, the increased pulmonary vascular shear stress in established PAH is caused largely by the vascular wall pathology. In this review, we revisit the "quasi-malignancy concept" of severe PAH and examine to what extent the hallmarks of PAH can be compared with the hallmarks of cancer. The cancer model of severe PAH, based on the growth of abnormal vascular and bone marrow-derived cells, may enable the emergence of novel cell-based PAH treatment strategies.
MeSH term(s)	Animals ; Apoptosis ; Autoimmunity ; Humans ; Lung Neoplasms/pathology ; Models, Biological ; Neoplasm Proteins/metabolism ; Pulmonary Arterial Hypertension/pathology
Chemical Substances	Neoplasm Proteins
Language	English
Publishing date	2020-02-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00476.2019
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Article ; Online: Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis.

de Bourcy, Charles F A / Dekker, Cornelia L / Davis, Mark M / Nicolls, Mark R / Quake, Stephen R

Science immunology

2018 Volume 2, Issue 15

Abstract: Systemic sclerosis with pulmonary arterial hypertension (SSc-PAH) is a debilitating and frequently lethal disease of unknown cause lacking effective treatment options. Lymphocyte anomalies and autoantibodies observed in systemic sclerosis have suggested ... ...

Abstract	Systemic sclerosis with pulmonary arterial hypertension (SSc-PAH) is a debilitating and frequently lethal disease of unknown cause lacking effective treatment options. Lymphocyte anomalies and autoantibodies observed in systemic sclerosis have suggested an autoimmune character. We study the clonal structure of the B cell repertoire in SSc-PAH using immunoglobulin heavy chain (IGH) sequencing before and after B cell depletion. We found SSc-PAH to be associated with anomalies in B cell development, namely, altered VDJ rearrangement frequencies (reduced IGHV2-5 segment usage) and an increased somatic mutation-fixation probability in expanded B cell lineages. SSc-PAH was also characterized by anomalies in B cell homeostasis, namely, an expanded immunoglobulin D-positive (IgD
MeSH term(s)	Aged ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/immunology ; B-Lymphocytes/immunology ; Double-Blind Method ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/immunology ; Immune Reconstitution/immunology ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Heavy Chains/immunology ; Immunologic Factors/therapeutic use ; Longitudinal Studies ; Lymphocyte Depletion ; Middle Aged ; Placebos ; Plasma Cells/immunology ; Rituximab/therapeutic use ; Scleroderma, Systemic/drug therapy ; Scleroderma, Systemic/immunology ; Sequence Analysis, DNA ; Time Factors ; V(D)J Recombination/immunology
Chemical Substances	Immunoglobulin Heavy Chains ; Immunologic Factors ; Placebos ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2018-01-16
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.aan8289
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Article ; Online: Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

Kim, Dongeon / Tian, Wen / Wu, Timothy Ting-Hsuan / Xiang, Menglan / Vinh, Ryan / Chang, Jason Lon / Gu, Shenbiao / Lee, Seunghee / Zhu, Yu / Guan, Torrey / Schneider, Emilie Claire / Bao, Evan / Dixon, J Brandon / Kao, Peter / Pan, Junliang / Rockson, Stanley G / Jiang, Xinguo / Nicolls, Mark Robert

Circulation

2023 Volume 148, Issue 16, Page(s) 1231–1249

Abstract: Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) ... ...

Abstract	Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. Methods: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific Results: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC Conclusions: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.
MeSH term(s)	Humans ; Mice ; Animals ; P-Selectin ; Signal Transduction ; Inflammation/pathology ; Lymphedema/pathology
Chemical Substances	sphingosine 1-phosphate (26993-30-6) ; P-Selectin
Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.123.064181
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Article: Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

Kim, Dongeon / Tian, Wen / Wu, Timothy Ting-Hsuan / Xiang, Menglan / Vinh, Ryan / Chang, Jason / Gu, Shenbiao / Lee, Seunghee / Zhu, Yu / Guan, Torrey / Schneider, Emilie Claire / Bao, Evan / Dixon, J Brandon / Kao, Peter / Pan, Junliang / Rockson, Stanley G / Jiang, Xinguo / Nicolls, Mark Robert

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) ... ...

Abstract	Background: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies. Methods: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific Results: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC Conclusion: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition. Clinical perspective: What is New?:
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.08.23291175
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