A simplified simulation model and virtual reality visualization of tumour growth in vitro

Melanoma is the more dangerous skin cancer, and metastatic melanoma still carries poor prognosis. Despite recent therapeutic advances, prolonged survival remains rare and research is still required. Propolis extracts from many countries have attracted a great deal of attention for their biological properties. We here investigated the ability of an ethanolic extract of Algerian propolis (EEP) to control melanoma tumour growth when given to mice bearing B16F1melanoma tumour either as preventive or as therapeutic treatment. EEP given after tumour occurrence increased mice survival (+30%) and reduced tumour growth (-75%). This was associated with a decrease of the Mitotic Index (-75%) and of Ki-67 (-50%) expression. When given either before or both before and after tumour occurrence, EEP reduced tumour growth but without prolonging mice life. Isolation of B16F1 melanoma cells from resected tumour showed that preventive and curative EEP treatments reduced invasiveness by 55% and 40% respectively compared to control. Galangin, one of the most abundant flavonoids in propolis, significantly reduced the number of melanoma cells in vitro and induced autophagy/apoptosis dose dependently. In conclusion, we showed that EEP reduced melanoma tumour progression/dissemination and could extend mice lifespan when used as therapeutic treatment. Then, EEP may help patients with melanoma when used as a complementary therapy to classical treatment for which autophagy is not contraindicated.

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Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

Cell Death and Disease ◽

10.1038/s41419-021-03940-0 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Yu Tian ◽

Bo Tang ◽

Chengye Wang ◽

Yan Wang ◽

Jiakai Mao ◽

...

Keyword(s):

Tumour Growth ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Sirtuin 1 ◽

Mesenchymal Transition ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

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STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

Endocrine Related Cancer ◽

10.1530/erc-12-0231 ◽

2012 ◽

Vol 20 (1) ◽

pp. 53-64 ◽

Cited By ~ 10

Author(s):

Joanna M Day ◽

Paul A Foster ◽

Helena J Tutill ◽

Fabien Schmidlin ◽

Christopher M Sharland ◽

...

Keyword(s):

Prostate Cancer ◽

Tumour Growth ◽

Plasma Testosterone ◽

Prostate Hyperplasia ◽

Testosterone Levels ◽

Concept Model ◽

Body Weights ◽

Type 3

17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC50 of ∼200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17β-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1×107 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17β-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

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Microvessel Chaste: An Open Library for Spatial Modelling of Vascularized Tissues

10.1101/105692 ◽

2017 ◽

Cited By ~ 2

Author(s):

J.A. Grogan ◽

A.J. Connor ◽

B. Markelc ◽

R.J. Muschel ◽

P.K. Maini ◽

...

Keyword(s):

Open Source ◽

Tumour Growth ◽

Spatial Models ◽

3D Models ◽

Tissue Growth ◽

Coronary Perfusion ◽

Analysis Model ◽

User Friendly

AbstractSpatial models of vascularized tissues are widely used in computational physiology, to study for example, tumour growth, angiogenesis, osteogenesis, coronary perfusion and oxygen delivery. Composition of such models is time-consuming, with many researchers writing custom software for this purpose. Recent advances in imaging have produced detailed three-dimensional (3D) datasets of vascularized tissues at the scale of individual cells. To fully exploit such data there is an increasing need for software that allows user-friendly composition of efficient, 3D models of vascularized tissue growth, and comparison of predictions with in vivo or in vitro experiments and other models. Microvessel Chaste is a new open-source library for building spatial models of vascularized tissue growth. It can be used to simulate vessel growth and adaptation in response to mechanical and chemical stimuli, intra- and extra-vascular transport of nutrient, growth factor and drugs, and cell proliferation in complex 3D geometries. The library provides a comprehensive Python interface to solvers implemented in C++, allowing user-friendly model composition, and integration with experimental data. Such integration is facilitated by interoperability with a growing collection of scientific Python software for image processing, statistical analysis, model annotation and visualization. The library is available under an open-source Berkeley Software Distribution (BSD) licence at https://jmsgrogan.github.io/MicrovesselChaste. This article links to two reproducible example problems, showing how the library can be used to model tumour growth and angiogenesis with realistic vessel networks.

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Calibration and validation of a novel hybrid model of the lumbosacral spine in ArtiSynth–The passive structures

PLoS ONE ◽

10.1371/journal.pone.0250456 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0250456

Author(s):

Robin Remus ◽

Andreas Lipphaus ◽

Marc Neumann ◽

Beate Bender

Keyword(s):

Simulation Model ◽

Facet Joint ◽

Contact Forces ◽

Combined Loading ◽

Sensitivity Analyses ◽

Lumbosacral Spine ◽

Mechanical Responses ◽

Functional Spinal Unit ◽

Starting Point

In computational biomechanics, two separate types of models have been used predominantly to enhance the understanding of the mechanisms of action of the lumbosacral spine (LSS): Finite element (FE) and musculoskeletal multibody (MB) models. To combine advantages of both models, hybrid FE-MB models are an increasingly used alternative. The aim of this paper is to develop, calibrate, and validate a novel passive hybrid FE-MB open-access simulation model of a ligamentous LSS using ArtiSynth. Based on anatomical data from the Male Visible Human Project, the LSS model is constructed from the L1-S1 rigid vertebrae interconnected with hyperelastic fiber-reinforced FE intervertebral discs, ligaments, and facet joints. A mesh convergence study, sensitivity analyses, and systematic calibration were conducted with the hybrid functional spinal unit (FSU) L4/5. The predicted mechanical responses of the FSU L4/5, the lumbar spine (L1-L5), and the LSS were validated against literature data from in vivo and in vitro measurements and in silico models. Spinal mechanical responses considered when loaded with pure moments and combined loading modes were total and intervertebral range of motions, instantaneous axes and centers of rotation, facet joint contact forces, intradiscal pressures, disc bulges, and stiffnesses. Undesirable correlations with the FE mesh were minimized, the number of crisscrossed collagen fiber rings was reduced to five, and the individual influences of specific anatomical structures were adjusted to in vitro range of motions. Including intervertebral motion couplings for axial rotation and nonlinear stiffening under increasing axial compression, the predicted kinematic and structural mechanics responses were consistent with the comparative data. The results demonstrate that the hybrid simulation model is robust and efficient in reproducing valid mechanical responses to provide a starting point for upcoming optimizations and extensions, such as with active skeletal muscles.

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Novel cyclometalated iridium(iii) phosphine-imine (P^N) complexes: highly efficient anticancer and anti-lung metastasis agents in vivo

Inorganic Chemistry Frontiers ◽

10.1039/c9qi01492f ◽

2020 ◽

Vol 7 (5) ◽

pp. 1273-1283 ◽

Cited By ~ 2

Author(s):

Zhishan Xu ◽

Yuliang Yang ◽

Xianglei Jia ◽

Lihua Guo ◽

Xingxing Ge ◽

...

Keyword(s):

Lung Metastasis ◽

Tumour Growth ◽

Combined Treatment ◽

Highly Efficient

Iridium(iii)-based complexes with phosphine-imine (P^N) ligands are synthesized and authenticated. The combined treatment with Ir(iii) and BIX01294 potently inhibited tumour growth and lung metastasis in vitro and in vivo.

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Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2

Cell Death and Disease ◽

10.1038/s41419-019-2030-2 ◽

2019 ◽

Vol 10 (11) ◽

Cited By ~ 13

Author(s):

Xuan Zhang ◽

Yi Zhang ◽

Zhongyuan He ◽

Kai Yin ◽

Bowen Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Chronic Stress ◽

Adrenergic Receptor ◽

Tumour Growth ◽

Mapk Pathway ◽

Rt Pcr ◽

Expression Levels

Abstract An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.

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