scholarly journals Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Katherine A. Burns ◽  
Amelia M. Pearson ◽  
Jessica L. Slack ◽  
Elaine D. Por ◽  
Alicia N. Scribner ◽  
...  
Keyword(s):  
Murine Model ◽  
Human Disease ◽  
Cycle Phase ◽  
Preclinical Model ◽  
Model Parameters ◽  
Preclinical Research ◽  
Retrograde Menstruation ◽  
Anatomy And Physiology ◽  
Cost Efficient

Endometriosis is a prevalent gynecologic condition associated with pelvic pain and infertility characterized by the implantation and growth of endometrial tissue displaced into the pelvis via retrograde menstruation. The mouse is a molecularly well-annotated and cost-efficient species for modeling human disease in the therapeutic discovery pipeline. However, as a non-menstrual species with a closed tubo-ovarian junction, the mouse poses inherent challenges as a preclinical model for endometriosis research. Over the past three decades, numerous murine models of endometriosis have been described with varying degrees of fidelity in recapitulating the essential pathophysiologic features of the human disease. We conducted a search of the peer-reviewed literature to identify publications describing preclinical research using a murine model of endometriosis. Each model was reviewed according to a panel of ideal model parameters founded on the current understanding of endometriosis pathophysiology. Evaluated parameters included method of transplantation, cycle phase and type of tissue transplanted, recipient immune/ovarian status, iterative schedule of transplantation, and option for longitudinal lesion assessment. Though challenges remain, more recent models have incorporated innovative technical approaches such as in vivo fluorescence imaging and novel hormonal preparations to overcome the unique challenges posed by murine anatomy and physiology. These models offer significant advantages in lesion development and readout toward a high-fidelity mouse model for translational research in endometriosis.

scholarly journals A computational bio-chemo-mechanical model of in vivo tissue-engineered vascular graft development

2020 ◽  
Vol 12 (3) ◽  
pp. 47-63
Author(s):  
Ramak Khosravi ◽  
Abhay B Ramachandra ◽  
Jason M Szafron ◽  
Daniele E Schiavazzi ◽  
Christopher K Breuer ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Optimal Parameter ◽  
Mechanistic Model ◽  
Vena Cava ◽  
Model Parameters ◽  
Identifiability Analysis ◽  
Macrophage Activity ◽  
Cost Efficient

Abstract Stenosis is the primary complication of current tissue-engineered vascular grafts used in pediatric congenital cardiac surgery. Murine models provide considerable insight into the possible mechanisms underlying this situation, but they are not efficient for identifying optimal changes in scaffold design or therapeutic strategies to prevent narrowing. In contrast, computational modeling promises to enable time- and cost-efficient examinations of factors leading to narrowing. Whereas past models have been limited by their phenomenological basis, we present a new mechanistic model that integrates molecular- and cellular-driven immuno- and mechano-mediated contributions to in vivo neotissue development within implanted polymeric scaffolds. Model parameters are inferred directly from in vivo measurements for an inferior vena cava interposition graft model in the mouse that are augmented by data from the literature. By complementing Bayesian estimation with identifiability analysis and simplex optimization, we found optimal parameter values that match model outputs with experimental targets and quantify variability due to measurement uncertainty. Utility is illustrated by parametrically exploring possible graft narrowing as a function of scaffold pore size, macrophage activity, and the immunomodulatory cytokine transforming growth factor beta 1 (TGF-β1). The model captures salient temporal profiles of infiltrating immune and synthetic cells and associated secretion of cytokines, proteases, and matrix constituents throughout neovessel evolution, and parametric studies suggest that modulating scaffold immunogenicity with early immunomodulatory therapies may reduce graft narrowing without compromising compliance.

scholarly journals [18F]Fluorothymidine Uptake in the Porcine Pancreatic Elastase-Induced Model of Abdominal Aortic Aneurysm

2021 ◽  
Vol 7 (8) ◽  
pp. 130
Author(s):  
Richa Gandhi ◽  
Joanna Koch-Paszkowski ◽  
Charalampos Tsoumpas ◽  
Marc A. Bailey
Keyword(s):  
Murine Model ◽  
Ex Vivo ◽  
Aortic Rupture ◽  
Aortic Aneurysms ◽  
Preclinical Model ◽  
Pancreatic Elastase ◽  
Abdominal Aortic ◽  
Pet Ct ◽  
Porcine Pancreatic Elastase

The porcine pancreatic elastase (PPE) model is a common preclinical model of abdominal aortic aneurysms (AAA). Some notable characteristics of this model include the low aortic rupture rate, non-progressive disease course, and infra-renal AAA formation. Enhanced [18F]fluorothymidine ([18F]FLT) uptake on positron emission tomography/computed tomography (PET/CT) has previously been reported in the angiotensin II-induced murine model of AAA. Here, we report our preliminary findings of investigating [18F]FLT uptake in the PPE murine model of AAA. [18F]FLT uptake was found to be substantially increased in the abdominal areas recovering from the surgery, whilst it was not found to be significantly increased within the PPE-induced AAA, as confirmed using in vivo PET/CT and ex vivo whole-organ gamma counting (PPE, n = 7; controls, n = 3). This finding suggests that the [18F]FLT may not be an appropriate radiotracer for this specific AAA model, and further studies with larger sample sizes are warranted to elucidate the pathobiology contributing to the reduced uptake of [18F]FLT in this model.

Murine Model of Aggressive Systemic Mastocytosis: A Disease Caused by Oncogenic Kit.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2426-2426 ◽  
Author(s):  
Shadmehr Demehri ◽  
Amie S. Corbin ◽  
Marc Loriaux ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Disease Progression ◽  
Murine Model ◽  
Human Disease ◽  
Systemic Mastocytosis ◽  
Animal Cell ◽  
Hematopoietic Organs

Abstract Background : Systemic mastocytosis (SM) is characterized by infiltration of extracutanous tissues by neoplastic mast cells. Primary target organs are liver, spleen and bone marrow. In some instances, SM progresses to aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL), which are associated with extensive mast cell infiltration into various organs and their failure. Almost all cases of SM exhibit point mutations at codon 816 of Kit, a receptor tyrosine kinase. These mutations (most commonly D816V) lead to constitutive activation of the kinase and are the causative lesion of SM. Here, we describe a novel murine model of SM/ASM that shares many characteristics with the human disease and may be useful for in vivo drug testing, including targeted therapy of D816 mutant Kit with small molecule inhibitors. Materials and methods : P815 cells, a cell line expressing D814Y Kit (homologous to human D816V kit) that was established in DBA2 mice (Dunn T, Bap M. J Natl Cancer Inst1957;18:587–95) were injected retro-orbitally into two groups (n = 4) of 8–10 week-old syngeneic mice, at a dose of 1x102 and 5x104 cells. Using an automated animal cell counter, the mice were monitored at 48h intervals with full blood counts, including white cell differential and platelets. The presence of mast cells was assessed by FACS for mast cell markers (CD117-PE and CD45-APC) as well as Giemsa staining. The animals were evaluated daily for signs of morbidity. Moribund mice were sacrificed and subjected to autopsy. Liver, spleen and bone marrow were analyzed by histopathology, and the expression and phophorylation status of Kit was assessed by FACS and immunoblotting. Results : Both cell doses induced an aggressive disease, with all animals reaching a moribund stage on day 9 (5x104 cells) and 16 (1x102 cells). A significant (p<0.001, student’s t test) drop in the platelet count regularly accompanied the appearance of mast cells in the peripheral blood (PB) (figure 1A). Subsequently, the animals developed marked granulocytosis. Autopsy demonstrated gross enlargement of liver and spleen, while lungs and kidneys were unaffected. Histopathology and FACS showed extensive infiltration of spleen, liver and bone marrow by Kit-positive cells (figure 1B). Immunoblotting revealed high levels of tyrosine phosphorylated Kit protein in whole cell lysates from PB, BM and spleen. Conclusion : We have established a highly reproducible model of SM/ASM that resembles the human disease. A particular advantage of this model is that the onset of disease can conveniently be monitored by serial PB counts. In addition, the latency of the disease can be modified by the size of the initial inoculum. Its extremely predictable course together with the parameters it provides for monitoring disease progression should make this model useful for the study of small molecules that target D816 mutant Kit. Figure 1. The infiltration of Kit-positive P815 cells into various organs of DBA/2 mouse. (A) PB over the course of the disease progression. (B) Hematopoietic organs at death. Figure 1. The infiltration of Kit-positive P815 cells into various organs of DBA/2 mouse. (A) PB over the course of the disease progression. (B) Hematopoietic organs at death.

scholarly journals Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 210
Author(s):  
Kamal Pandey ◽  
Nar Bahadur Katuwal ◽  
Nahee Park ◽  
Jin Hur ◽  
Young Bin Cho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cytotoxic Chemotherapy ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Preclinical Model ◽  
M Cell ◽  
Proliferating Cells ◽  
Positive Breast Cancer

Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer.

Spectroscopic imaging of human disease

1996 ◽  
Vol 54 ◽  
pp. 884-885
Author(s):  
D.J. Meyerhoff
Keyword(s):  
Magnetic Field ◽  
Magnetic Resonance ◽  
Field Gradient ◽  
Human Disease ◽  
Morphological Changes ◽  
Magnetic Field Gradient ◽  
Spectroscopic Imaging ◽  
Resonance Spectroscopy ◽  
Tissue Water

Magnetic Resonance Imaging (MRI) observes tissue water in the presence of a magnetic field gradient to study morphological changes such as tissue volume loss and signal hyperintensities in human disease. These changes are mostly non-specific and do not appear to be correlated with the range of severity of a certain disease. In contrast, Magnetic Resonance Spectroscopy (MRS), which measures many different chemicals and tissue metabolites in the millimolar concentration range in the absence of a magnetic field gradient, has been shown to reveal characteristic metabolite patterns which are often correlated with the severity of a disease. In-vivo MRS studies are performed on widely available MRI scanners without any “sample preparation” or invasive procedures and are therefore widely used in clinical research. Hydrogen (H) MRS and MR Spectroscopic Imaging (MRSI, conceptionally a combination of MRI and MRS) measure N-acetylaspartate (a putative marker of neurons), creatine-containing metabolites (involved in energy processes in the cell), choline-containing metabolites (involved in membrane metabolism and, possibly, inflammatory processes),

In vivo imaging reveals prostate pathology in the PTEN knockout murine model of prostate cancer

2016 ◽  
Author(s):  
Alysha Bhatti ◽  
Almeida Gilberto Serrano de ◽  
Serena Tommasini Ghelfi ◽  
Alwyn Dart ◽  
Anabel Varela-Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Murine Model ◽  
In Vivo Imaging

255-LB: Impaired Gsa/cAMP Signaling Exclusive to Pancreatic ß-Cells Exhibits a Unique Urinary Metabolome via Nontargeted Metabolomics in a Murine Model of Diabetes In Vivo

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 255-LB
Author(s):  
AMRO ILAIWY ◽  
MEGAN CAPOZZI ◽  
JENNIFER L. BROWN ◽  
DAVID D’ALESSIO ◽  
JONATHAN CAMPBELL
Keyword(s):  
Murine Model ◽  
Camp Signaling

2056-P: In Vivo Human Islet Compensation and Dysfunction to Diet-Induced Obesity: A Phase 0 Preclinical Model

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2056-P
Author(s):  
JULIE A. KERR-CONTE ◽  
JULIEN THEVENET ◽  
GIANNI PASQUETTI ◽  
PAULINE PETIT ◽  
CLARA CLABAUT ◽  
...  
Keyword(s):  
Human Islet ◽  
Preclinical Model ◽  
Diet Induced Obesity ◽  
Phase 0

[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.

scholarly journals High-Performance Liquid Chromatography-Tandem Mass Spectrometry for Buprenorphine Evaluation in Plasma—Application to Pharmacokinetic Studies in Rabbits

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 437
Author(s):  
Marta Tikhomirov ◽  
Błażej Poźniak ◽  
Tomasz Śniegocki
Keyword(s):  
High Performance ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Studies ◽  
Limit Of Quantification ◽  
Reliable Determination ◽  
Main Challenge ◽  
Analytical Protocol ◽  
Liquid Chromatography Tandem Mass ◽  
Cost Efficient

The precise and reliable determination of buprenorphine concentration is fundamental in certain medical or research applications, particularly in pharmacokinetic studies of this opioid. The main challenge is, however, the development of an analytical method that is sensitive enough, as the detected in vivo concentrations often fall in very low ranges. Thus, in this study we aimed at developing a sensitive, repeatable, cost-efficient, and easy HPLC analytical protocol for buprenorphine in rabbit plasma. In order to obtain this, the HPLC-MS2 system was used to elaborate and validate the method for samples purified with liquid-liquid extraction. Fragment ions 468.6→396.2 and 468.6→414.2 were monitored, and the method resulted in a high repeatability and reproducibility and a limit of quantification of 0.25 µg/L with a recovery of 98.7–109.0%. The method was linear in a range of 0.25–2000 µg/L. The suitability of the analytical procedure was tested in rabbits in a pilot pharmacokinetic study, and it was revealed that the method was suitable for comprehensively describing the pharmacokinetic profile after buprenorphine intravenous administration at a dose of 300 µg/kg. Thus, the method suitability for pharmacokinetic application was confirmed by both the good validation results of the method and successful in vivo tests in rabbits.

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