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Article ; Online: Letter to the editor regarding Milchteim et al: "Subacromial dislocation of the acromioclavicular joint with associated fracture of the clavicle".

Fagg, James A / Davies, Emma J / Stanley, David

2019 Volume 28, Issue 9, Page(s) e323

Language	English
Publishing date	2019-05-02
Publishing country	United States
Document type	Letter
ZDB-ID	1170782-3
ISSN	1532-6500 ; 1058-2746
ISSN (online)	1532-6500
ISSN	1058-2746
DOI	10.1016/j.jse.2018.12.023
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Article ; Online: Perfusion Air Culture of Precision-Cut Tumor Slices: An Ex Vivo System to Evaluate Individual Drug Response under Controlled Culture Conditions.

Dong, Meng / Böpple, Kathrin / Thiel, Julia / Winkler, Bernd / Liang, Chunguang / Schueler, Julia / Davies, Emma J / Barry, Simon T / Metsalu, Tauno / Mürdter, Thomas E / Sauer, Georg / Ott, German / Schwab, Matthias / Aulitzky, Walter E

Cells

2023 Volume 12, Issue 5

Abstract: Precision-cut tumor slices (PCTS) maintain tissue heterogeneity concerning different cell types and preserve the tumor microenvironment (TME). Typically, PCTS are cultured statically on a filter support at an air-liquid interface, which gives rise to ... ...

Abstract	Precision-cut tumor slices (PCTS) maintain tissue heterogeneity concerning different cell types and preserve the tumor microenvironment (TME). Typically, PCTS are cultured statically on a filter support at an air-liquid interface, which gives rise to intra-slice gradients during culture. To overcome this problem, we developed a perfusion air culture (PAC) system that can provide a continuous and controlled oxygen medium, and drug supply. This makes it an adaptable ex vivo system for evaluating drug responses in a tissue-specific microenvironment. PCTS from mouse xenografts (MCF-7, H1437) and primary human ovarian tumors (primary OV) cultured in the PAC system maintained the morphology, proliferation, and TME for more than 7 days, and no intra-slice gradients were observed. Cultured PCTS were analyzed for DNA damage, apoptosis, and transcriptional biomarkers for the cellular stress response. For the primary OV slices, cisplatin treatment induced a diverse increase in the cleavage of caspase-3 and PD-L1 expression, indicating a heterogeneous response to drug treatment between patients. Immune cells were preserved throughout the culturing period, indicating that immune therapy can be analyzed. The novel PAC system is suitable for assessing individual drug responses and can thus be used as a preclinical model to predict in vivo therapy responses.
MeSH term(s)	Female ; Humans ; Mice ; Animals ; Ovarian Neoplasms ; Biological Phenomena ; Perfusion ; Tumor Microenvironment
Language	English
Publishing date	2023-03-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12050807
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Article: Subacromial, supracoracoid dislocation of the acromioclavicular joint with ipsilateral clavicle fracture: a case report with review of the literature and classification.

Davies, Emma J / Fagg, James A / Stanley, David

JRSM open

2014 Volume 5, Issue 7, Page(s) 2054270414527281

Abstract: A type VI acromioclavicular joint injury with a supracoracoid location of the distal end of the clavicle (VIa) may be associated with low energy injuries and, in association with a clavicle fracture, can successfully be treated with reduction of the ... ...

Abstract	A type VI acromioclavicular joint injury with a supracoracoid location of the distal end of the clavicle (VIa) may be associated with low energy injuries and, in association with a clavicle fracture, can successfully be treated with reduction of the dislocation, fixation of the clavicle, and may not require reconstruction of the acromioclavicular ligaments. An infracoracoid location (VIb) is highly suggestive of a higher energy injury.
Language	English
Publishing date	2014-06-09
Publishing country	England
Document type	Case Reports
ZDB-ID	2762955-7
ISSN	2054-2704
ISSN	2054-2704
DOI	10.1177/2054270414527281
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Article ; Online: Origin and maintenance of the intestinal cancer stem cell.

Davies, Emma J / Marsh, Victoria / Clarke, Alan R

Molecular carcinogenesis

2011 Volume 50, Issue 4, Page(s) 254–263

Abstract: Colorectal cancer is one of the most common cancers in the western world and its incidence is steadily increasing. Understanding the basic biology of both the normal intestine and of intestinal tumorigenesis is vital for developing appropriate and ... ...

Abstract	Colorectal cancer is one of the most common cancers in the western world and its incidence is steadily increasing. Understanding the basic biology of both the normal intestine and of intestinal tumorigenesis is vital for developing appropriate and effective cancer therapies. However, relatively little is known about the normal intestinal stem cell or the hypothetical intestinal cancer stem cell, and there is much debate surrounding these areas. This review briefly describes our current understanding of the properties of both the intestinal stem cell and the intestinal cancer stem cell. We also discuss recent theories regarding the origin of the intestinal cancer stem cell, and the signals required for its maintenance and proliferation. Finally, we place the relevance of cancer stem cell research into context by discussing potential clinical applications of targeting the intestinal cancer stem cell.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Lineage ; Colorectal Neoplasms/pathology ; Humans ; Intestines/cytology ; Neoplastic Stem Cells/pathology ; Signal Transduction ; Stem Cells/cytology
Language	English
Publishing date	2011-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1004029-8
ISSN	1098-2744 ; 0899-1987
ISSN (online)	1098-2744
ISSN	0899-1987
DOI	10.1002/mc.20631
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Zs.A 2664: Show issues

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Article ; Online: PTEN loss and KRAS activation cooperate in murine biliary tract malignancies.

Marsh, Victoria / Davies, Emma J / Williams, Geraint T / Clarke, Alan R

The Journal of pathology

2013 Volume 230, Issue 2, Page(s) 165–173

Abstract: Carcinomas of the biliary tract are aggressive malignancies in humans. Loss of the tumour suppressor PTEN has previously been associated with cholangiocarcinoma development in a murine model. Activation of KRAS is reported in up to one-third of human ... ...

Abstract	Carcinomas of the biliary tract are aggressive malignancies in humans. Loss of the tumour suppressor PTEN has previously been associated with cholangiocarcinoma development in a murine model. Activation of KRAS is reported in up to one-third of human cholangiocarcinomas and 50% of gall bladder carcinomas. In this study we aimed to test the potential interaction between PTEN and KRAS mutation in biliary tract malignancy. We used an inducible Cre-LoxP-based approach to coordinately delete PTEN and activate KRAS within the adult mouse biliary epithelium. We found that activation of KRAS alone has little effect upon biliary epithelium. Loss of PTEN alone results in the development of low-grade neoplastic lesions, following long latency and at low incidence. Combination of both mutations causes rapid development of biliary epithelial proliferative lesions, which progress through dysplasia to invasive carcinoma. We conclude that activation of the PI3'K pathway following loss of PTEN is sufficient to drive slow development of low-grade biliary lesions in mice. In contrast, mutational activation of KRAS does not result in a similar phenotype, despite a prediction that this should activate both the RAF-MEK-ERK and PI3'-kinase pathways. However, mutation of both genes results in rapid tumourigenesis, arguing that PTEN normally functions as a 'brake' on the PI3'-kinase pathway, limiting the influence of KRAS activation. Mutation of both genes creates a 'permissive' environment, allowing the full effects of both mutations to be manifested. These data reveal an in vivo synergy between these mutations and provides a new mouse model of biliary tract malignancy.
MeSH term(s)	Animals ; Animals, Outbred Strains ; Bile Duct Neoplasms/genetics ; Bile Duct Neoplasms/metabolism ; Bile Duct Neoplasms/mortality ; Biliary Tract/cytology ; Biliary Tract/metabolism ; Cholangiocarcinoma/genetics ; Cholangiocarcinoma/metabolism ; Cholangiocarcinoma/mortality ; Epithelial Cells/metabolism ; Extracellular Signal-Regulated MAP Kinases/genetics ; Female ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Kaplan-Meier Estimate ; Male ; Mice ; Mitogen-Activated Protein Kinase Kinases/genetics ; Mutation ; PTEN Phosphohydrolase/deficiency ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/biosynthesis ; Proto-Oncogene Proteins p21(ras)/genetics ; Survival Rate
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67) ; Hras protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2013-03-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.4189
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Article ; Online: A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

PLoS biology

2022 Volume 20, Issue 5, Page(s) e3001624

Abstract: Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive ... ...

Abstract	Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.
MeSH term(s)	Animals ; Cell Culture Techniques ; DNA ; Humans ; Mice ; Microfluidics ; Models, Biological
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3001624
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Article ; Online: PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine.

Davies, Emma J / Marsh Durban, Victoria / Meniel, Valerie / Williams, Geraint T / Clarke, Alan R

The Journal of pathology

2014 Volume 233, Issue 1, Page(s) 27–38

Abstract: Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal ... ...

Abstract	Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/secondary ; Adenoma/genetics ; Adenoma/metabolism ; Adenoma/pathology ; Animals ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Disease Models, Animal ; Female ; Genes, APC ; Genetic Predisposition to Disease ; Hyperplasia ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Intestinal Neoplasms/genetics ; Intestinal Neoplasms/metabolism ; Intestinal Neoplasms/pathology ; Intestinal Polyps/genetics ; Intestinal Polyps/metabolism ; Intestinal Polyps/pathology ; Intestine, Small/metabolism ; Intestine, Small/pathology ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mutation ; Neoplasm Invasiveness ; PTEN Phosphohydrolase/deficiency ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism ; Phenotype ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction ; Time Factors ; Tumor Burden
Chemical Substances	Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67) ; Kras2 protein, mouse (EC 3.6.5.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2014-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.4312
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Article ; Online: Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.

Sale, Matthew J / Minihane, Emma / Monks, Noel R / Gilley, Rebecca / Richards, Frances M / Schifferli, Kevin P / Andersen, Courtney L / Davies, Emma J / Vicente, Mario Aladren / Ozono, Eiko / Markovets, Aleksandra / Dry, Jonathan R / Drew, Lisa / Flemington, Vikki / Proia, Theresa / Jodrell, Duncan I / Smith, Paul D / Cook, Simon J

Nature communications

2019 Volume 10, Issue 1, Page(s) 5167

Abstract: BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family ... ...

Abstract	BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X
MeSH term(s)	Animals ; Apoptosis ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; Macrocyclic Compounds/pharmacology ; Melanoma/pathology ; Mice ; Molecular Targeted Therapy ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/metabolism ; bcl-X Protein/metabolism
Chemical Substances	AZD5991 ; MCL1 protein, human ; Macrocyclic Compounds ; Myeloid Cell Leukemia Sequence 1 Protein ; Protein Kinase Inhibitors ; bcl-X Protein ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2019-11-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-12409-w
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Article ; Online: Development of an ObLiGaRe Doxycycline Inducible Cas9 system for pre-clinical cancer drug discovery.

Lundin, Anders / Porritt, Michelle J / Jaiswal, Himjyot / Seeliger, Frank / Johansson, Camilla / Bidar, Abdel Wahad / Badertscher, Lukas / Wimberger, Sandra / Davies, Emma J / Hardaker, Elizabeth / Martins, Carla P / James, Emily / Admyre, Therese / Taheri-Ghahfarokhi, Amir / Bradley, Jenna / Schantz, Anna / Alaeimahabadi, Babak / Clausen, Maryam / Xu, Xiufeng /

Mayr, Lorenz M / Nitsch, Roberto / Bohlooly-Y, Mohammad / Barry, Simon T / Maresca, Marcello

Nature communications

2020 Volume 11, Issue 1, Page(s) 4903

Abstract: The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with ...

Abstract	The CRISPR-Cas9 system has increased the speed and precision of genetic editing in cells and animals. However, model generation for drug development is still expensive and time-consuming, demanding more target flexibility and faster turnaround times with high reproducibility. The generation of a tightly controlled ObLiGaRe doxycycline inducible SpCas9 (ODInCas9) transgene and its use in targeted ObLiGaRe results in functional integration into both human and mouse cells culminating in the generation of the ODInCas9 mouse. Genomic editing can be performed in cells of various tissue origins without any detectable gene editing in the absence of doxycycline. Somatic in vivo editing can model non-small cell lung cancer (NSCLC) adenocarcinomas, enabling treatment studies to validate the efficacy of candidate drugs. The ODInCas9 mouse allows robust and tunable genome editing granting flexibility, speed and uniformity at less cost, leading to high throughput and practical preclinical in vivo therapeutic testing.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Cell Line, Tumor ; Doxycycline/pharmacology ; Drug Discovery/methods ; Drug Screening Assays, Antitumor/methods ; Female ; Gene Editing/methods ; Gene Expression/drug effects ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Genetic Vectors/genetics ; HEK293 Cells ; High-Throughput Screening Assays/methods ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Male ; Mice ; Mice, Transgenic ; RNA, Guide, CRISPR-Cas Systems/genetics ; Recombination, Genetic/drug effects ; Reproducibility of Results ; Transcriptional Activation/drug effects ; Transfection/methods ; Transgenes/genetics
Chemical Substances	Antineoplastic Agents ; RNA, Guide, CRISPR-Cas Systems ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Cas9 endonuclease Streptococcus pyogenes (EC 3.1.-) ; Doxycycline (N12000U13O)
Language	English
Publishing date	2020-09-29
Publishing country	England
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-020-18548-9
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Article: The relationships between local muscular endurance and kinematic changes during a run to exhaustion at vVO2max.

Hayes, Philip R / Bowen, Sarah J / Davies, Emma J

Journal of strength and conditioning research

2004 Volume 18, Issue 4, Page(s) 898–903

Abstract: The relationships between local muscular endurance and kinematic changes during a run to exhaustion at vVo2max. J Strength Cond. Res. 18(4):000-000. 2004.-A recent study suggested that runners who maintain a stable running style are able to run for ... ...

Abstract	The relationships between local muscular endurance and kinematic changes during a run to exhaustion at vVo2max. J Strength Cond. Res. 18(4):000-000. 2004.-A recent study suggested that runners who maintain a stable running style are able to run for longer at vVo2max velocity (vVo2max). This may be because of the capacity of various muscle groups to maintain their functions despite the onset of fatigue. The purpose of this study was to examine the relationship between local muscular endurance of both the hip and knee extensor and flexor muscle groups and the kinematic changes during a run to exhaustion at vVo2max. Six subelite runners (age 24.2 + 4.2) participated in this study;they were considered as a homogeneous group based upon theirvVo2max scores (coefficient of variation = 3.9%). They performed an incremental protocol to determine vVo2max, a series of isokinetic tests to determine the local muscular endurance of both knee and hip flexors and extensors, and a run to exhaustion at vVo2max. The change in kinematic variables between the beginning and the end of the run were correlated with the measures of muscular endurance. Several statistically significant negative correlations emerged between the change in stride length and concentric hip extension (HE(con)), r = -0.934; eccentric hip extension (HE(ecc)), r = -0.818; eccentric knee flexion(KF(ecc)), r = -0.957; and change in maximum hip extension (Delta max HE), r - -0.857; and Delta max HE with HE(con), r = -0.846.We concluded that the local muscular endurance of both HE(con) and KF(ecc) are important in maintaining a stable running style.
MeSH term(s)	Adult ; Anaerobic Threshold ; Biomechanical Phenomena ; Exercise Tolerance ; Humans ; Leg/physiology ; Male ; Oxygen Consumption/physiology ; Physical Endurance/physiology ; Running/physiology
Language	English
Publishing date	2004-11-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1156349-7
ISSN	1533-4287 ; 1064-8011
ISSN (online)	1533-4287
ISSN	1064-8011
DOI	10.1519/r-13503.1
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