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Article ; Online: Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice.

Arellano, Danna L / Juárez, Patricia / Verdugo-Meza, Andrea / Almeida-Luna, Paloma S / Corral-Avila, Juan A / Drescher, Florian / Olvera, Felipe / Jiménez, Samanta / Elzey, Bennett D / Guise, Theresa A / Fournier, Pierrick G J

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2022 Volume 37, Issue 8, Page(s) 1446–1463

Abstract: Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and ... patients. The bone microenvironment combines various immunosuppressive factors, and combined with T ... tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell ...

Abstract	Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1)
MeSH term(s)	Animals ; Bone Neoplasms/metabolism ; Bone Resorption/metabolism ; Humans ; Male ; Mice ; Myeloid-Derived Suppressor Cells/metabolism ; Osteoclasts ; Prostatic Neoplasms ; Tumor Microenvironment
Language	English
Publishing date	2022-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632783-7
ISSN	1523-4681 ; 0884-0431
ISSN (online)	1523-4681
ISSN	0884-0431
DOI	10.1002/jbmr.4615
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Article ; Online: T Helper Cell Subsets and Their Functions in Common Bottlenose Dolphins (

De Guise, Sylvain / Levin, Milton / Jasperse, Lindsay / Risatti, Guillermo / Wells, Randall S

Frontiers in immunology

2019 Volume 10, Page(s) 1578

Abstract: ... functionality of the Th1, Th2, and Treg T helper cell subsets in bottlenose dolphins. The present study aimed ... at validating assays and reagents to identify T helper cell subsets and their functions in a subset of dolphins ... could it significantly contribute to predicting the variability of T lymphocyte proliferation, suggesting that not ...

Abstract	Considerable efforts have been made to better understand the immune system of bottlenose dolphins in view of the common environmental challenges they encounter, such as exposure to polychlorinated biphenyls, oil spills, or harmful algal bloom biotoxins. However, little is known about the identity and functionality of the Th1, Th2, and Treg T helper cell subsets in bottlenose dolphins. The present study aimed at validating assays and reagents to identify T helper cell subsets and their functions in a subset of dolphins from Sarasota Bay, Florida, USA, which have been long studied and often used as a reference population. A population of CD4+ FOXP3+ lymphocytes was identified representing an average <1% of blood lymphocyte population, which is in the range observed in for Treg cells in other species. The use of porcine reagents to measure TGFß, one of the key Treg cytokines, was further validated using the relatively high-throughput and highly standardized Luminex technology. The proportion of circulating Treg cells was not correlated with the serum concentrations of the Treg effector cytokines TGFß and IL-10, nor could it significantly contribute to predicting the variability of T lymphocyte proliferation, suggesting that not all dolphin circulating Treg cells are functional and active. However, stimulation of dolphin lymphocytes with TGFß and IL-2 increased the expression of the gene for TGFß and IL-10, and stimulation with IL-12 and IFNγ induced a robust increase in the expression of the gene for IFNγ, suggesting the potential for polarization and differentiation of dolphin T helper cells toward a Treg and Th1 response, respectively. The lack of an increase in the expression of the genes for the Th2 cytokines IL-4 and IL-13 upon stimulation with IL-4 may be due to the requirement for IL-2 for a Th2 polarization as described in mice. However, regression analysis and PCA suggested the potential ability of both the Th1 and Th2 response to be triggered upon acute inflammatory signals. These results may be useful in better understanding the mechanisms by which the dolphin immune system is affected upon exposure to environmental challenges and how it responds to pathogen challenges.
MeSH term(s)	Animals ; Bottle-Nosed Dolphin/immunology ; Cytokines/immunology ; T-Lymphocyte Subsets/immunology ; Th1 Cells/immunology ; Th2 Cells/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2019-08-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2019.01578
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Article ; Online: T lymphocyte-proliferative responses of harbor seal (Phoca vitulina) peripheral blood mononuclear cells (PBMCs) exposed to pharmaceuticals in vitro.

Kleinert, Christine / Lacaze, Emilie / Fortier, Marlène / Hammill, Mike / De Guise, Sylvain / Fournier, Michel

Marine pollution bulletin

2018 Volume 127, Page(s) 225–234

Abstract: The ubiquity of pharmaceuticals in the aquatic environment and the accumulation in organisms of lower trophic levels have been documented. The immunotoxicity of these xenobiotics has however been little investigated. This study assessed the effects of ... ...

Abstract	The ubiquity of pharmaceuticals in the aquatic environment and the accumulation in organisms of lower trophic levels have been documented. The immunotoxicity of these xenobiotics has however been little investigated. This study assessed the effects of pharmaceuticals on the immune responses of harbor seal lymphocytes. Peripheral blood mononuclear cells isolated from harbor seal pups were exposed to varying concentrations of 17α-ethinyl estradiol (250-50,000μg/L), naproxen (500-100,000μg/L), carbamazepine (500-100,000μg/L), erythromycin (750-150,000μg/L) and binary mixtures thereof in vitro. All individual compounds and mixtures inhibited lymphocyte proliferation. Mixture effects were non-additive and predictive values overestimated the inhibition of proliferation. Male pups were more sensitive to erythromycin exposure. Comparison with the sensitivity of the 11B7501 cell line showed a higher sensitivity of pups to individual compounds and the inverse trend for mixtures. Based on our results, we hypothesize that pharmaceuticals may have the potential to interrupt immune functions in harbor seals.
MeSH term(s)	Animals ; Carbamazepine/toxicity ; Cell Proliferation/drug effects ; Erythromycin/toxicity ; Ethinyl Estradiol/toxicity ; Female ; Leukocytes, Mononuclear/drug effects ; Male ; Naproxen/toxicity ; Phoca/blood ; T-Lymphocytes/drug effects ; Water Pollutants, Chemical/toxicity
Chemical Substances	Water Pollutants, Chemical ; Carbamazepine (33CM23913M) ; Ethinyl Estradiol (423D2T571U) ; Naproxen (57Y76R9ATQ) ; Erythromycin (63937KV33D)
Language	English
Publishing date	2018-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2001296-2
ISSN	1879-3363 ; 0025-326X
ISSN (online)	1879-3363
ISSN	0025-326X
DOI	10.1016/j.marpolbul.2017.12.001
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Article ; Online: Coping facilitated troponin T increases and hypo-responsivity in the copeptin-HPA-axis during acute mental stress in a black cohort: The SABPA study.

Myburgh, Catharina Elizabeth / Malan, Leoné / Möller, Marisa / Magnusson, Martin / Melander, Olle / Rauch, Henri Guise Laurie / Steyn, Faans / Malan, Nicolaas Theodor

Physiology & behavior

2019 Volume 207, Page(s) 159–166

Abstract: ... cardiac troponin T (cTnT)] and cardiac wall-stress [N-terminal pro-brain natriuretic peptide (NT-proBNP ...

Abstract	Background: Defensive coping (DefS) was associated with a vulnerable cardiovascular profile in blacks. The copeptin/vasopressin system is a manifestation of hypothalamic-pituitary-adrenal-axis activity and may act as an acute compensatory mechanism when there is a disruption in volume-loading homeostasis, i.e. when cardiac stress is evident. Whether DefS will influence associations between copeptin and cardiac stress markers, remains unclear. Here we aimed to determine associations between acute mental stress responses of copeptin, vascular responsiveness and biomarkers of cardiomyocyte injury [cardiac troponin T (cTnT)] and cardiac wall-stress [N-terminal pro-brain natriuretic peptide (NT-proBNP)] in DefS race groups. Methods: South African black and white teachers (n = 378) of both sexes, participated in this target population study. Cases with a history of myocardial infarction, stroke and atrial fibrillation were excluded. We obtained coping scores (Coping Strategy Indicator), beat-to-beat blood pressure and fasting blood samples at rest and after 1-min exposure to the Stroop-Colour-Word-Conflict-test. Results: Interaction effects (p < .05) for copeptin percentage change (%) during the Stroop-Colour-Word-Conflict-test determined stratification of participants into race and DefS (≥26, above-median score) groups. In DefS blacks, Stroop-Colour-Word-Conflict-test exposure elicited increases in cTnT%, NT-proBNP% and diastolic-blood pressure%. Again, in these individuals, multiple regression analyses showed positive associations between copeptin% and total peripheral resistance%; with inverse associations between copeptin% and cTnT% (p < .05). None of these associations were found in DefS whites. Conclusions: Utilisation of DefS in blacks provoked vascular hyper-responsiveness and cardiac wall stress (elevated cTnT and NT-proBNP); possibly mediated via the copeptin/vasopressin system. However, a presumably hypo-responsive hypothalamic-pituitary-adrenal-axis during stress exposure could not counteract coronary perfusion deficits via additional copeptin/vasopressin release. The presence of defensiveness may have clinical implications in preventive cardiology.
MeSH term(s)	Adaptation, Psychological ; Adult ; African Continental Ancestry Group/psychology ; Aged ; Biomarkers ; Blood Pressure ; Cross-Sectional Studies ; European Continental Ancestry Group ; Female ; Glycopeptides/metabolism ; Humans ; Hypothalamo-Hypophyseal System/physiopathology ; Male ; Middle Aged ; Natriuretic Peptide, Brain/metabolism ; Peptide Fragments/metabolism ; South Africa ; Stress, Psychological/metabolism ; Stress, Psychological/physiopathology ; Stress, Psychological/psychology ; Stroop Test ; Troponin T/metabolism ; Vascular Resistance ; Young Adult
Chemical Substances	Biomarkers ; Glycopeptides ; Peptide Fragments ; Troponin T ; copeptins ; pro-brain natriuretic peptide (1-76) ; Natriuretic Peptide, Brain (114471-18-0)
Language	English
Publishing date	2019-05-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2019.05.012
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Article: T lymphocyte-proliferative responses of harbor seal (Phoca vitulina) peripheral blood mononuclear cells (PBMCs) exposed to pharmaceuticals in vitro

Kleinert, Christine / Emilie Lacaze / Marlène Fortier / Michel Fournier / Mike Hammill / Sylvain De Guise

Elsevier Ltd Marine pollution bulletin. 2018 Feb., v. 127

2018

Abstract	The ubiquity of pharmaceuticals in the aquatic environment and the accumulation in organisms of lower trophic levels have been documented. The immunotoxicity of these xenobiotics has however been little investigated. This study assessed the effects of pharmaceuticals on the immune responses of harbor seal lymphocytes. Peripheral blood mononuclear cells isolated from harbor seal pups were exposed to varying concentrations of 17α-ethinyl estradiol (250–50,000μg/L), naproxen (500–100,000μg/L), carbamazepine (500–100,000μg/L), erythromycin (750–150,000μg/L) and binary mixtures thereof in vitro. All individual compounds and mixtures inhibited lymphocyte proliferation. Mixture effects were non-additive and predictive values overestimated the inhibition of proliferation. Male pups were more sensitive to erythromycin exposure. Comparison with the sensitivity of the 11B7501 cell line showed a higher sensitivity of pups to individual compounds and the inverse trend for mixtures. Based on our results, we hypothesize that pharmaceuticals may have the potential to interrupt immune functions in harbor seals.
Keywords	aquatic environment ; cell lines ; drugs ; erythromycin ; estradiol ; immune response ; immunotoxicity ; lymphocyte proliferation ; lymphocytes ; males ; Phoca vitulina ; pups ; trophic levels ; water pollution ; xenobiotics
Language	English
Dates of publication	2018-02
Size	p. 225-234.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2001296-2
ISSN	1879-3363 ; 0025-326X
ISSN (online)	1879-3363
ISSN	0025-326X
DOI	10.1016/j.marpolbul.2017.12.001
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Article: Coping facilitated troponin T increases and hypo-responsivity in the copeptin-HPA-axis during acute mental stress in a black cohort: The SABPA study

Myburgh, Catharina Elizabeth / Malan, Leoné / Möller, Marisa / Magnusson, Martin / Melander, Olle / Rauch, Henri Guise Laurie / Steyn, Faans / Malan, Nicolaas Theodor

Physiology & behavior. 2019 Aug. 01, v. 207

2019

Abstract: ... vascular responsiveness and biomarkers of cardiomyocyte injury [cardiac troponin T (cTnT)] and cardiac wall ...

Abstract	Defensive coping (DefS) was associated with a vulnerable cardiovascular profile in blacks. The copeptin/vasopressin system is a manifestation of hypothalamic-pituitary-adrenal-axis activity and may act as an acute compensatory mechanism when there is a disruption in volume-loading homeostasis, i.e. when cardiac stress is evident. Whether DefS will influence associations between copeptin and cardiac stress markers, remains unclear. Here we aimed to determine associations between acute mental stress responses of copeptin, vascular responsiveness and biomarkers of cardiomyocyte injury [cardiac troponin T (cTnT)] and cardiac wall-stress [N-terminal pro-brain natriuretic peptide (NT-proBNP)] in DefS race groups.South African black and white teachers (n = 378) of both sexes, participated in this target population study. Cases with a history of myocardial infarction, stroke and atrial fibrillation were excluded. We obtained coping scores (Coping Strategy Indicator), beat-to-beat blood pressure and fasting blood samples at rest and after 1-min exposure to the Stroop-Colour-Word-Conflict-test.Interaction effects (p < .05) for copeptin percentage change (%) during the Stroop-Colour-Word-Conflict-test determined stratification of participants into race and DefS (≥26, above-median score) groups. In DefS blacks, Stroop-Colour-Word-Conflict-test exposure elicited increases in cTnT%, NT-proBNP% and diastolic-blood pressure%. Again, in these individuals, multiple regression analyses showed positive associations between copeptin% and total peripheral resistance%; with inverse associations between copeptin% and cTnT% (p < .05). None of these associations were found in DefS whites.Utilisation of DefS in blacks provoked vascular hyper-responsiveness and cardiac wall stress (elevated cTnT and NT-proBNP); possibly mediated via the copeptin/vasopressin system. However, a presumably hypo-responsive hypothalamic-pituitary-adrenal-axis during stress exposure could not counteract coronary perfusion deficits via additional copeptin/vasopressin release. The presence of defensiveness may have clinical implications in preventive cardiology.
Keywords	Blacks ; atrial fibrillation ; biomarkers ; blood pressure ; blood sampling ; cardiomyocytes ; homeostasis ; myocardial infarction ; natriuretic peptides ; psychological stress ; regression analysis ; stress response ; stroke ; teachers ; troponin T ; vasopressin
Language	English
Dates of publication	2019-0801
Size	p. 159-166.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3907-x
ISSN	1873-507X ; 0031-9384
ISSN (online)	1873-507X
ISSN	0031-9384
DOI	10.1016/j.physbeh.2019.05.012
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: X-Ray to DRR Images Translation for Efficient Multiple Objects Similarity Measures in Deformable Model 3D/2D Registration.

Aubert, B / Cresson, T / de Guise, J A / Vazquez, C

IEEE transactions on medical imaging

2023 Volume 42, Issue 4, Page(s) 897–909

Abstract: The robustness and accuracy of the intensity-based 3D/2D registration of a 3D model on planar X-ray image(s) is related to the quality of the image correspondences between the digitally reconstructed radiographs (DRR) generated from the 3D models ( ... ...

Abstract	The robustness and accuracy of the intensity-based 3D/2D registration of a 3D model on planar X-ray image(s) is related to the quality of the image correspondences between the digitally reconstructed radiographs (DRR) generated from the 3D models (varying image) and the X-ray images (fixed target). While much effort may be devoted to generating realistic DRR that are similar to real X-rays (using complex X-ray simulation, adding densities information in 3D models, etc.), significant differences still remain between DRR and real X-ray images. Differences such as the presence of adjacent or superimposed soft tissue and bony or foreign structures lead to image matching difficulties and decrease the 3D/2D registration performance. In the proposed method, the X-ray images were converted into DRR images using a GAN-based cross-modality image-to-images translation. With this added prior step of XRAY-to-DRR translation, standard similarity measures become efficient even when using simple and fast DRR projection. For both images to match, they must belong to the same image domain and essentially contain the same kind of information. The XRAY-to-DRR translation also addresses the well-known issue of registering an object in a scene composed of multiple objects by separating the superimposed or/and adjacent objects to avoid mismatching across similar structures. We applied the proposed method to the 3D/2D fine registration of vertebra deformable models to biplanar radiographs of the spine. We showed that the XRAY-to-DRR translation enhances the registration results, by increasing the capture range and decreasing dependence on the similarity measure choice since the multi-modal registration becomes mono-modal.
MeSH term(s)	X-Rays ; Imaging, Three-Dimensional/methods ; Radiography ; Spine/diagnostic imaging
Language	English
Publishing date	2023-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	622531-7
ISSN	1558-254X ; 0278-0062
ISSN (online)	1558-254X
ISSN	0278-0062
DOI	10.1109/TMI.2022.3218568
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Zs.A 2546: Show issues

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Article: New insights into the role of T cells in the vicious cycle of bone metastases.

Fournier, Pierrick G J / Chirgwin, John M / Guise, Theresa A

Current opinion in rheumatology

2006 Volume 18, Issue 4, Page(s) 396–404

Abstract: ... to secondary stimulation of tumor development. Recent findings suggest the involvement of T ... such as parathyroid hormone-related protein, interleukin-7, and interleukin-8 that can recruit or activate T cells. T cells are involved ... however, which could suppress T-cell antitumor immune responses. Bisphosphonate antiresorptive drugs are the approved treatment ...

Abstract	Purpose of review: Bone metastases interact with the bone microenvironment. Cancer cells modulate the functions of osteoblasts and osteoclasts to induce new bone formation or bone resorption, leading to secondary stimulation of tumor development. Recent findings suggest the involvement of T cells in this process. Recent findings: Bone metastatic cancer cells produce factors such as parathyroid hormone-related protein, interleukin-7, and interleukin-8 that can recruit or activate T cells. T cells are involved in bone remodeling and can induce osteoclastic resorption. Bone resorption releases transforming growth factor-beta, however, which could suppress T-cell antitumor immune responses. Bisphosphonate antiresorptive drugs are the approved treatment for solid tumor bone metastases. They have recently been found to activate the cytolytic activity of gammadelta T cells. Thus, inhibitors of transforming growth factor-beta or antiresorptive therapies may be effective enhancers of antitumor immune responses in bone. Summary: T cells at the site of bone metastases may be functionally suppressed by factors in the bone microenvironment. Instead of acting against tumor cells, they may increase bone resorption, making bone a privileged site for tumor growth.
MeSH term(s)	Bone Neoplasms/immunology ; Bone Neoplasms/pathology ; Humans ; Interleukin-7/immunology ; Interleukin-8/immunology ; Lymphocyte Activation ; Models, Immunological ; Neoplasm Metastasis/immunology ; Parathyroid Hormone-Related Protein/physiology ; T-Lymphocytes/immunology
Chemical Substances	Interleukin-7 ; Interleukin-8 ; Parathyroid Hormone-Related Protein
Language	English
Publishing date	2006-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1045317-9
ISSN	1531-6963 ; 1040-8711
ISSN (online)	1531-6963
ISSN	1040-8711
DOI	10.1097/01.bor.0000231909.35043.da
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Article ; Online: Systemic effects of abnormal bone resorption on muscle, metabolism, and cognition.

Trivedi, Trupti / Guise, Theresa A

Bone

2021 Volume 154, Page(s) 116245

Abstract: Skeletal tissue is dynamic, undergoing constant remodeling to maintain musculoskeletal integrity and balance in the human body. Recent evidence shows that apart from maintaining homeostasis in the local microenvironment, the skeleton systemically affects ...

Abstract	Skeletal tissue is dynamic, undergoing constant remodeling to maintain musculoskeletal integrity and balance in the human body. Recent evidence shows that apart from maintaining homeostasis in the local microenvironment, the skeleton systemically affects other tissues. Several cancer-associated and noncancer-associated bone disorders can disrupt the physiological homeostasis locally in the bone microenvironment and indirectly contribute to dysregulation of systemic body function. The systemic effects of bone on the regulation of distant organ function have not been widely explored. Recent evidence suggests that bone can interact with skeletal muscle, pancreas, and brain by releasing factors from mineralized bone matrix. Currently available bone-targeting therapies such as bisphosphonates and denosumab inhibit bone resorption, decrease morbidity associated with bone destruction, and improve survival. Bisphosphonates have been a standard treatment for bone metastases, osteoporosis, and cancer treatment-induced bone diseases. The extraskeletal effects of bisphosphonates on inhibition of tumor growth are known. However, our knowledge of the effects of bisphosphonates on muscle weakness, hyperglycemia, and cognitive defects is currently evolving. To be able to identify the molecular link between bone and distant organs during abnormal bone resorption and then treat these abnormalities and prevent their systemic effects could improve survival benefits. The current review highlights the link between bone resorption and its systemic effects on muscle, pancreas, and brain.
MeSH term(s)	Bone Neoplasms/secondary ; Bone Resorption/drug therapy ; Cognition ; Diphosphonates/pharmacology ; Diphosphonates/therapeutic use ; Humans ; Muscles ; Tumor Microenvironment
Chemical Substances	Diphosphonates
Language	English
Publishing date	2021-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	632515-4
ISSN	1873-2763 ; 8756-3282
ISSN (online)	1873-2763
ISSN	8756-3282
DOI	10.1016/j.bone.2021.116245
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Article ; Online: Suppression of Th2 cytokines as a potential mechanism for reduced antibody response following PFOA exposure in female B6C3F1 mice.

De Guise, Sylvain / Levin, Milton

Toxicology letters

2021 Volume 351, Page(s) 155–162

Abstract: ... in the IgM antibody response to the T cell dependent antigen keyhole limpet hemocyanin (KLH) at a dose lower ... in antibody response, pointing to a potential role for T helper cells in the immunotoxicity of PFOA. Further ...

Abstract	Perfluorooctanoic acid (PFOA), a member of the Per- and polyfluoroalkyl substances, is a highly persistent "forever" chemicals with increasing concern for its potential health effects. However, the mechanisms of PFOA immunotoxic effects are poorly understood. We assessed the antibody response to a physiological antigen stimulation and associated cytokine response upon PFOA exposure. The significant decrease in the IgM antibody response to the T cell dependent antigen keyhole limpet hemocyanin (KLH) at a dose lower than the previously documented LOAEL was accompanied by a significant reduction of the Th2 serum cytokines IL-5 and IL-13, a non-significant dose-response reduction of IL-4, a significant reduction of the Th1 cytokine IL-12, and a non-significant dose-response increase in IL-2 and IFNγ. PFOA significantly decreased the pro-inflammatory cytokines IL-17α and IL-1α, decreased (non-significantly but dose-response) IL-6, and a significantly increased TNFα. Overall, the modulation of serum Th1/Th2 cytokines could explain the reduction in antibody response, pointing to a potential role for T helper cells in the immunotoxicity of PFOA. Further, the higher than anticipated weight loss and increased liver weight, compared to previous studies using similar doses, highlight the potential importance of the route and duration of exposure, contributing to the total accumulated dose, in assessing the toxicity of PFOA.
MeSH term(s)	Animals ; Caprylates/toxicity ; Corticosterone/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Dose-Response Relationship, Drug ; Female ; Fluorocarbons/toxicity ; Gene Expression Regulation/drug effects ; Hemocyanins/immunology ; Immunoglobulin M/metabolism ; Mice
Chemical Substances	Caprylates ; Cytokines ; Fluorocarbons ; Immunoglobulin M ; Hemocyanins (9013-72-3) ; perfluorooctanoic acid (947VD76D3L) ; keyhole-limpet hemocyanin (FV4Y0JO2CX) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2021-09-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2021.09.002
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