scholarly journals Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of zoledronic acid in vivo

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Marietta Landgraf ◽  
Christoph A. Lahr ◽  
Alvaro Sanchez-Herrero ◽  
Christoph Meinert ◽  
Ali Shokoohmand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastasis ◽  
Mouse Model ◽  
Cancer Metastasis ◽  
New Drugs ◽  
Therapeutic Effects ◽  
Humanized Mouse ◽  
Preclinical Research ◽  
Humanized Mouse Model

Abstract Advanced prostate cancer (PCa) is known for its high prevalence to metastasize to bone, at which point it is considered incurable. Despite significant effort, there is no animal model capable of recapitulating the complexity of PCa bone metastasis. The humanized mouse model for PCa bone metastasis used in this study aims to provide a platform for the assessment of new drugs by recapitulating the human–human cell interactions relevant for disease development and progression. The humanized tissue-engineered bone construct (hTEBC) was created within NOD-scid IL2rgnull (NSG) mice and was used for the study of experimental PC3-Luc bone metastases. It was confirmed that PC3-Luc cells preferentially grew in the hTEBC compared with murine bone. The translational potential of the humanized mouse model for PCa bone metastasis was evaluated with two clinically approved osteoprotective therapies, the non-species-specific bisphosphonate zoledronic acid (ZA) or the human-specific antibody Denosumab, both targeting Receptor Activator of Nuclear Factor Kappa-Β Ligand. ZA, but not Denosumab, significantly decreased metastases in hTEBCs, but not murine femora. These results highlight the importance of humanized models for the preclinical research on PCa bone metastasis and indicate the potential of the bioengineered mouse model to closely mimic the metastatic cascade of PCa cells to human bone. Eventually, it will enable the development of new effective antimetastatic treatments.

Abstract 1537: Characterization of tumor-infiltrating macrophages in humanized mouse model of prostate cancer.

2013 ◽  
Author(s):  
Vladimir Ryabov ◽  
David Kim ◽  
Rikka Saito ◽  
Richard B. Alexander ◽  
Elena Klyushnenkova
Keyword(s):  
Prostate Cancer ◽  
Mouse Model ◽  
Humanized Mouse ◽  
Humanized Mouse Model

scholarly journals Correction: Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of Zoledronic acid in vivo

Bone Research ◽  
2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Marietta Landgraf ◽  
Christoph A. Lahr ◽  
Alvaro Sanchez-Herrero ◽  
Christoph Meinert ◽  
Ali Shokoohmand ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Cancer Metastasis ◽  
Therapeutic Effects ◽  
Prostate Cancer Metastasis

scholarly journals Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Tianyun Qiao ◽  
Yanlu Xiong ◽  
Yangbo Feng ◽  
Wenwen Guo ◽  
Yongsheng Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Preclinical Model ◽  
Small Subset ◽  
Therapeutic Effects ◽  
Humanized Mouse ◽  
Humanized Mouse Model

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients, partly because of the lack of sufficient immune cells in the tumor. It is reported that targeted lactate dehydrogenase (LDH) to reduce lactic acid production can promote the infiltration and activity of immune cells and turn tumors into hot tumors. Therefore, we constructed a humanized mouse model to evaluate the efficacy of using classical LDH inhibitor oxamate and pembrolizumab alone or in combination in non-small cell lung cancer (NSCLC). We found that both oxamate and pembrolizumab monotherapy significantly delayed tumor growth; moreover, combination therapy showed better results. Immunofluorescence analysis showed that oxamate treatment increased the infiltration of activated CD8+ T cells in the tumor, which might have enhanced the therapeutic effects of pembrolizumab. Treatment of the humanized mice with anti-CD8 abrogated the therapeutic effects of oxamate, indicating CD8+ T cells as the main force mediating the effect of oxamate. In conclusion, Our preclinical findings position that oxamate not only inhibits tumor growth at a high safe dose but also enhances the efficacy of pembrolizumab in Hu-PBMC-CDX mice. Our study also provides a preclinical model for exploring the efficacy of other immune-based combination therapies for NSCLC.

scholarly journals Combined cART Including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir Has Potent Therapeutic Effects in HIV-1 Infected Humanized Mice

2021 ◽  
Author(s):  
Matthew Weichseldorfer ◽  
Yvonne Affram ◽  
Alonso Heredia ◽  
Zahra Rikhtegaran-Tehrani ◽  
Mohammad M Sajadi ◽  
...  
Keyword(s):  
Animal Models ◽  
Mouse Model ◽  
Core Protein ◽  
Therapeutic Effects ◽  
Cell Recovery ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Clinical Model ◽  
Mouse Tissues ◽  
Hiv 1

Abstract HIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed to identify specific solid tissue reservoirs of human T-cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34 humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies.

scholarly journals Zoledronic acid decreased osteolysis but not bone metastasis in a nude mouse model of canine prostate cancer with mixed bone lesions

The Prostate ◽  
2008 ◽  
Vol 68 (10) ◽  
pp. 1116-1125 ◽  
Author(s):  
Nanda K. Thudi ◽  
Chelsea K. Martin ◽  
Murali V.P. Nadella ◽  
Soledad A. Fernandez ◽  
Jillian L. Werbeck ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastasis ◽  
Mouse Model ◽  
Nude Mouse ◽  
Bone Lesions ◽  
Nude Mouse Model

scholarly journals Combined cART including Tenofovir Disoproxil, Emtricitabine, and Dolutegravir has potent therapeutic effects in HIV-1 infected humanized mice

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Matthew Weichseldorfer ◽  
Yvonne Affram ◽  
Alonso Heredia ◽  
Zahra Rikhtegaran-Tehrani ◽  
Mohammad M. Sajadi ◽  
...  
Keyword(s):  
Animal Models ◽  
Mouse Model ◽  
Core Protein ◽  
Therapeutic Effects ◽  
Cell Recovery ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Clinical Model ◽  
Mouse Tissues ◽  
Hiv 1

AbstractHIV-1 reservoirs persist in the presence of combined antiretroviral therapy (cART). However, cART has transformed HIV-1 infection into a chronic disease marked by control of HIV-1 viral load and mortality reduction. Major challenges remain, including viral resistance upon termination of cART and persistence and identification of tissue distribution of HIV-1 reservoirs. Thus, appropriate animal models that best mimic HIV-1 pathogenesis are important, and the current study complements our previously published validation of the CD34+ hematopoietic humanized mouse model for this purpose. Here we analyze viral suppression using the recently developed combination of antiretrovirals that include Tenofovir Disoproxil (TDF), Emtricitabine (FTC), and Dolutegravir (DTG), a choice based on recent clinical outcomes showing its improved antiretroviral potency, CD4+ T cell preservation, tolerability, and prevention of viral drug resistance compared to that of previous regimens. We used quantitative Airyscan-based super resolution confocal microscopy of selected mouse tissues. Our data allowed us to identify specific solid tissue reservoirs of human T cells expressing the HIV-1 core protein p24. In particular, lymph node, brain, spleen, and liver were visualized as reservoirs for residual infected cells. Marked reduction of viral replication was evident. Considering that detection and visualization of cryptic sites of HIV-1 infection in tissues are clearly crucial steps towards HIV-1 eradication, appropriate animal models with pseudo-human immune systems are needed. In fact, current studies with humans and non-human primates have limited sample availability at multiple stages of infection and cannot easily analyze the effects of differently administered combined antiretroviral treatments on multiple tissues. That is easier to manage when working with humanized mouse models, although we realize the limitations due to low human cell recovery and thus the number of cells available for thorough and comprehensive analyses. Nonetheless, our data further confirm that the CD34+ humanized mouse model is a potentially useful pre-clinical model to study and improve current anti-HIV-1 therapies.

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
New Drugs ◽  
Imaging Data ◽  
Wild Type ◽  
Preclinical Research ◽  
Standardized Uptake Values ◽  
Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

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