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  1. Article ; Online: Targeting the tumour microenvironment in platinum-resistant ovarian cancer.

    Cummings, M / Freer, C / Orsi, N M

    Seminars in cancer biology

    2021  Volume 77, Page(s) 3–28

    Abstract: Ovarian cancer typically presents at an advanced stage, and although the majority of cases initially respond well to platinum-based therapies, chemoresistance almost always occurs leading to a poor long-term prognosis. While various cellular autonomous ... ...

    Abstract Ovarian cancer typically presents at an advanced stage, and although the majority of cases initially respond well to platinum-based therapies, chemoresistance almost always occurs leading to a poor long-term prognosis. While various cellular autonomous mechanisms contribute to intrinsic or acquired platinum resistance, the tumour microenvironment (TME) plays a central role in resistance to therapy and disease progression by providing cancer stem cell niches, promoting tumour cell metabolic reprogramming, reducing chemotherapy drug perfusion and promoting an immunosuppressive environment. As such, the TME is an attractive therapeutic target which has been the focus of intense research in recent years. This review provides an overview of the unique ovarian cancer TME and its role in disease progression and therapy resistance, highlighting some of the latest preclinical and clinical data on TME-targeted therapies. In particular, it focuses on strategies targeting cancer-associated fibroblasts, tumour-associated macrophages, cancer stem cells and cancer cell metabolic vulnerabilities.
    MeSH term(s) Animals ; Carcinoma, Ovarian Epithelial/immunology ; Carcinoma, Ovarian Epithelial/pathology ; Drug Resistance, Neoplasm/physiology ; Female ; Humans ; Tumor Microenvironment/physiology
    Language English
    Publishing date 2021-02-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2021.02.007
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    Zs.A 2922: Show issues Location:
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  2. Article ; Online: Epithelial and stromal-specific immune pathway activation in the murine endometrium post-coitum.

    Field, S L / Cummings, M / Orsi, N M

    Reproduction (Cambridge, England)

    2015  Volume 150, Issue 2, Page(s) 127–138

    Abstract: The endometrium is a dynamic tissue, demonstrating cyclical growth/remodelling in preparation for implantation. In mice, seminal constituents trigger mechanisms to prepare the endometrium, a process dubbed 'seminal priming' that modifies immune system ... ...

    Abstract The endometrium is a dynamic tissue, demonstrating cyclical growth/remodelling in preparation for implantation. In mice, seminal constituents trigger mechanisms to prepare the endometrium, a process dubbed 'seminal priming' that modifies immune system components and mediates endometrial remodelling in preparation for pregnancy. An array of cytokines has been reported to mediate this interaction, although much of the literature relates to in vitro studies on isolated endometrial epithelial cells. This study measured changes in immune-related gene expression in endometrial epithelial and stromal cells in vivo following natural mating. CD1 mice were naturally mated and sacrificed over the first 4 days post-coitum (n=3 each day). Endometrial epithelial and stromal compartments were isolated by laser capture microdissection. Labelled cRNA was generated and hybridised to genome-wide expression microarrays. Pathway analysis identified several immune-related pathways active within epithelial and stromal compartments, in particular relating to cytokine networks, matrix metalloproteinases and prostaglandin synthesis. Cluster analysis demonstrated that the expression of factors involved in immunomodulation/endometrial remodelling differed between the epithelial and stromal compartments in a temporal fashion. This study is the first to examine the disparate responses of the endometrial epithelial and stromal compartments to seminal plasma in vivo in mice, and demonstrates the complexity of the interactions between these two compartments needed to create a permissive environment for implantation.
    MeSH term(s) Animals ; Cytokines/biosynthesis ; Cytokines/genetics ; Embryo Implantation/physiology ; Endometrium/cytology ; Endometrium/immunology ; Epithelium/immunology ; Female ; Gene Expression/immunology ; Genome-Wide Association Study ; Immunity/genetics ; Immunity/physiology ; Male ; Matrix Metalloproteinases/biosynthesis ; Matrix Metalloproteinases/genetics ; Mice ; Microarray Analysis ; Microdissection ; Pregnancy ; Prostaglandins/biosynthesis ; RNA, Complementary/biosynthesis ; RNA, Complementary/genetics ; Semen/metabolism ; Signal Transduction/genetics ; Signal Transduction/immunology ; Stromal Cells/immunology ; Uterus/cytology ; Uterus/metabolism
    Chemical Substances Cytokines ; Prostaglandins ; RNA, Complementary ; Matrix Metalloproteinases (EC 3.4.24.-)
    Language English
    Publishing date 2015-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2034501-X
    ISSN 1741-7899 ; 1470-1626 ; 1476-3990
    ISSN (online) 1741-7899
    ISSN 1470-1626 ; 1476-3990
    DOI 10.1530/REP-15-0087
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  3. Article: Embryotoxicity of the nitric oxide donor sodium nitroprusside in preimplantation bovine embryos in vitro

    Orsi, N.M

    Animal reproduction science. 2006 Feb., v. 91, issue 3-4

    2006  

    Keywords cows ; blastocyst ; embryotoxicity ; nitric oxide ; embryogenesis ; metabolism ; in vitro fertilization ; glucose ; pyruvic acid ; lactic acid ; amino acids ; nutrient uptake ; nutrient retention ; adenosine triphosphate
    Language English
    Dates of publication 2006-02
    Size p. 225-236.
    Document type Article
    ZDB-ID 429674-6
    ISSN 1873-2232 ; 0378-4320
    ISSN (online) 1873-2232
    ISSN 0378-4320
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  4. Article ; Online: Cytokine networks and the regulation of uterine function in pregnancy and parturition.

    Orsi, N M / Tribe, R M

    Journal of neuroendocrinology

    2008  Volume 20, Issue 4, Page(s) 462–469

    Abstract: Complex cytokine networks play an important role in a wide range of reproductive and pregnancy related processes. Here, we review the current knowledge concerning the impact of cytokines on uterine physiology and pathophysiology. Cytokines influence a ... ...

    Abstract Complex cytokine networks play an important role in a wide range of reproductive and pregnancy related processes. Here, we review the current knowledge concerning the impact of cytokines on uterine physiology and pathophysiology. Cytokines influence a range of uterine functions during the menstrual cycle, implantation, pregnancy and labour. The synergistic interactions between individual cytokines are intricate and dynamic, and modulated by pregnancy hormones. It is not surprising therefore, that perturbations to cytokine signalling are associated with adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, preterm labour and foetal brain injury. Further insight into the complexity of cytokine networks will be required to develop novel therapeutic strategies for the treatment of cytokine imbalances in pregnancy.
    MeSH term(s) Animals ; Biomarkers/blood ; Cervix Uteri/immunology ; Cytokines/blood ; Cytokines/physiology ; Embryo Implantation/immunology ; Embryo Implantation/physiology ; Female ; Humans ; Immune Tolerance/physiology ; Inflammation/etiology ; Inflammation/physiopathology ; Labor, Obstetric/physiology ; Models, Biological ; Parturition/physiology ; Placentation/immunology ; Placentation/physiology ; Pregnancy/physiology ; Pregnancy Complications/etiology ; Pregnancy Complications/immunology ; Seminal Plasma Proteins/physiology ; Uterus/growth & development ; Uterus/immunology ; Uterus/physiology
    Chemical Substances Biomarkers ; Cytokines ; Seminal Plasma Proteins
    Language English
    Publishing date 2008-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/j.1365-2826.2008.01668.x
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    Zs.A 2634: Show issues Location:
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  5. Article: Mammalian embryo co-culture: Trials and tribulations of a misunderstood method

    Orsi, N.M / Reischl, J.B

    Theriogenology. 2007 Feb., v. 67, issue 3

    2007  

    Abstract: Embryo-somatic cell co-culture was devised over 40 years ago in an attempt to improve the development and viability of mammalian preimplantation embryos generated and cultured in vitro. While initial endeavours were successful in this respect, other ... ...

    Abstract Embryo-somatic cell co-culture was devised over 40 years ago in an attempt to improve the development and viability of mammalian preimplantation embryos generated and cultured in vitro. While initial endeavours were successful in this respect, other studies soon highlighted a number of significant long-term detrimental impacts of this approach. Surprisingly little is known about the mechanisms underlying the beneficial effects of co-culture, although the production of embryotrophic compounds, modulation of nutrient profile, protection against culture-induced stress and/or toxin clearance are all contenders. The extent to which the inadvertent exposure of embryos to serum accounts for many of these effects remains open to question. Although the popularity of somatic cell co-culture has recently declined in favour of the use of sequential media due to concerns associated with its risk of disease transmission and long-term sequelae, we argue that complete dismissal of this technique is ill advised, given that our limited understanding of basic somatic cell interactions has prevented us from fully exploiting its potential. In this respect, there is some merit in focussing future research strategies based on reconstructed maternal tract tissue. Although the use of co-culture in clinical practice is unacceptable and its implementation in domestic species for commercial purposes should be viewed with diffidence, this technique can still provide a wealth of information on the development of novel, more physiological embryo in vitro culture systems. The proviso for acquiring such information is to gain a fuller understanding of the culture requirements/biochemistry of somatic cells and their interaction with the early conceptus.
    Keywords mammals ; embryo (animal) ; somatic cells ; embryo culture ; coculture ; embryogenesis ; viability
    Language English
    Dates of publication 2007-02
    Size p. 441-458.
    Document type Article
    ZDB-ID 189232-0
    ISSN 1879-3231 ; 0093-691X
    ISSN (online) 1879-3231
    ISSN 0093-691X
    DOI 10.1016/j.theriogenology.2006.10.011
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    Zs.A 3929: Show issues Location:
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  6. Article: Protection against reactive oxygen species during mouse preimplantation embryo development: role of EDTA, oxygen tension, catalase, superoxide dismutase and pyruvate.

    Orsi, N M / Leese, H J

    Molecular reproduction and development

    2001  Volume 59, Issue 1, Page(s) 44–53

    Abstract: Oxidative damage due to the production of reactive oxygen species (ROS) is one of a number of culture-induced stresses which may compromise preimplantation embryo development in vitro. Ethylenediaminetetraacetic acid (EDTA), reduced oxygen tension, ... ...

    Abstract Oxidative damage due to the production of reactive oxygen species (ROS) is one of a number of culture-induced stresses which may compromise preimplantation embryo development in vitro. Ethylenediaminetetraacetic acid (EDTA), reduced oxygen tension, superoxide dismutase (SOD) and catalase (CAT) offer protection against oxidative stress, but few attempts have been made to determine which of these agents, or which combination, is the most effective. In particular, no systematic investigation of their actions and interactions has been made using a multifactorial experimental design. Murine zygotes were cultured in the presence or absence of 10 miccroM EDTA, SOD (100-7,000 U/ml) and CAT (50-100 U/ml) at atmospheric (20%) and reduced (5%) oxygen tensions. Blastocyst formation and hatching rates (at various time points), and cell numbers were recorded, whilst parallel groups of embryos had their consumption of pyruvate, a hydrogen peroxide scavenger, measured. All parameters interacted significantly and affected blastocyst formation, hatching rate and cell numbers but the effect of EDTA was the most pronounced. There were beneficial effects of 5% O2, CAT and SOD, while 20% O2 had a deleterious effect on development. EDTA improved blastocyst formation and hatching rates but paradoxically led to a reduction in cell number. 5% O2 was the next most significant parameter to enhance embryo development and also increased cell numbers. No differences in pyruvate uptake were apparent between the various treatment groups. The results suggest that embryo culture in EDTA-free medium under 5% O2 provides the most practical and physiological conditions for in vitro murine embryo culture.
    MeSH term(s) Animals ; Blastocyst/drug effects ; Blastocyst/physiology ; Catalase/metabolism ; Chelating Agents/pharmacology ; Culture Media/chemistry ; Culture Techniques/methods ; Edetic Acid/pharmacology ; Embryonic and Fetal Development ; Female ; Free Radical Scavengers/metabolism ; Humans ; Male ; Mice ; Oxidoreductases/metabolism ; Oxygen/metabolism ; Pyruvic Acid/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Time Factors
    Chemical Substances Chelating Agents ; Culture Media ; Free Radical Scavengers ; Reactive Oxygen Species ; Pyruvic Acid (8558G7RUTR) ; Edetic Acid (9G34HU7RV0) ; Oxidoreductases (EC 1.-) ; Catalase (EC 1.11.1.6) ; Superoxide Dismutase (EC 1.15.1.1) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2001-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 20321-x
    ISSN 1098-2795 ; 1040-452X
    ISSN (online) 1098-2795
    ISSN 1040-452X
    DOI 10.1002/mrd.1006
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    Zs.A 2759: Show issues Location:
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  7. Article: Ammonium exposure and pyruvate affect the amino acid metabolism of bovine blastocysts in vitro

    Orsi, N.M / Leese, H.J

    Reproduction : the Journal of the Society for Reproduction and Fertility. 2004 Jan., v. 127, no. 1

    2004  

    Keywords cattle ; blastocyst ; amino acid metabolism ; pyruvic acid ; ammonium compounds
    Language English
    Dates of publication 2004-01
    Size p. 131-140.
    Document type Article
    ZDB-ID 2034501-X
    ISSN 1741-7899 ; 1470-1626 ; 1476-3990
    ISSN (online) 1741-7899
    ISSN 1470-1626 ; 1476-3990
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    Z 2067: Show issues

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  8. Article: Amino acid metabolism of preimplantation bovine embryos cultured with bovine serum albumin or polyvinyl alcohol

    Orsi, N.M / Leese, H.J

    Theriogenology. 2004 Jan. 15, v. 61, no. 2-3

    2004  

    Abstract: Bovine serum albumin (BSA) is an embryotrophic macromolecule used in embryo culture media, which is commonly replaced with synthetic compounds, such as polyvinyl alcohol (PVA). This study compared the effect of BSA and PVA on the development, blastocyst ... ...

    Abstract Bovine serum albumin (BSA) is an embryotrophic macromolecule used in embryo culture media, which is commonly replaced with synthetic compounds, such as polyvinyl alcohol (PVA). This study compared the effect of BSA and PVA on the development, blastocyst cell number and amino acid metabolism of preimplantation bovine embryos in vitro. Embryos were produced by in vitro maturation and fertilization of immature oocytes from abattoir-derived ovaries. Zygotes were cultured in synthetic oviduct fluid with either 4 mg/ml BSA (SOFaaBSA) or 1 mg/ml PVA (SOFaaPVA) in microdrops with a mineral oil overlay at 39 degrees C under a 5% O2/5% CO2/90% N2 atmosphere. Blastocyst rate and cell numbers were determined after 123 h of culture. In parallel, single expanding blastocysts grown in either medium were incubated in microdrops for 12 h. Amino acid profile of spent drops was determined by high performance liquid chromatography. Replacing BSA with PVA depressed blastocyst rate and cell numbers, and led to quantitative and qualitative differences in amino acid appearance, disappearance and turnover. These differences could partly be due to an increase in free intracellular amino acid concentration in SOFaaBSA embryos derived from hydrolysis of endocytosed BSA, and argue against the inclusion of PVA in bovine embryo culture media.
    Keywords embryo culture ; embryogenesis ; cattle ; culture media
    Language English
    Dates of publication 2004-0115
    Size p. 561-572.
    Document type Article
    ZDB-ID 189232-0
    ISSN 1879-3231 ; 0093-691X
    ISSN (online) 1879-3231
    ISSN 0093-691X
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    Zs.A 3929: Show issues Location:
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  9. Article: An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease.

    Girn, H R S / Orsi, N M / Homer-Vanniasinkam, S

    Vascular medicine (London, England)

    2007  Volume 12, Issue 4, Page(s) 299–309

    Abstract: Over the last three decades, a surge in research into the inflammatory pathophysiology of atherosclerosis has highlighted an array of cytokines and other inflammatory mediators associated with underlying inflammatory burden. The ability to identify and ... ...

    Abstract Over the last three decades, a surge in research into the inflammatory pathophysiology of atherosclerosis has highlighted an array of cytokines and other inflammatory mediators associated with underlying inflammatory burden. The ability to identify and simultaneously measure multiple cytokines in peripheral blood highlights their potential as biomarkers of atherosclerosis. This has prompted much research in vascular medicine to identify the ;at-risk' groups for atherostenotic or atheroaneurysmal disease. This review is compiled with similar intentions and aims to discern the relevant evidence for cytokine profiling in peripheral arterial disease (PAD), where such information is lacking, while providing a holistic overview of cytokine interactions in atherosclerosis. This is pertinent given that cytokine profiles from coronary artery disease and aortic aneurysm studies cannot be directly extrapolated to PAD due to differences in inflammatory environments that exist in these conditions. Whilst plaque morphology and blood rheology play an important role in the cardiac manifestations of atherosclerosis, tissue thrombogenecity is very important in PAD. Further, cytokines act in concert rather than in isolation in a disease process, and no single cytokine in a cross-sectional model is able to serve as an absolute screening marker. Thus, it is essential to understand the regulation of cytokine production in atherosclerosis prior to evaluating the viability and merits of a multimarker approach for clinical risk stratification in PAD.
    MeSH term(s) Atherosclerosis/metabolism ; Chemokines/metabolism ; Cytokines/metabolism ; Humans ; Interferons/metabolism ; Interleukins/metabolism ; Peripheral Vascular Diseases/metabolism ; Signal Transduction ; Transforming Growth Factors/metabolism ; Tumor Necrosis Factors/metabolism
    Chemical Substances Chemokines ; Cytokines ; Interleukins ; Tumor Necrosis Factors ; Transforming Growth Factors (76057-06-2) ; Interferons (9008-11-1)
    Language English
    Publishing date 2007-11
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1311628-9
    ISSN 1477-0377 ; 1358-863X
    ISSN (online) 1477-0377
    ISSN 1358-863X
    DOI 10.1177/1358863X07083387
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    Zs.A 4409: Show issues Location:
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  10. Article ; Online: Three-dimensional digital reconstruction of human placental villus architecture in normal and complicated pregnancies.

    McCarthy, R / Orsi, N M / Treanor, D / Moran, O / Vernooij, M / Magee, D R / Roberts, N / Stahlschmidt, J / Simpson, N A B

    European journal of obstetrics, gynecology, and reproductive biology

    2016  Volume 197, Page(s) 130–135

    Abstract: Objective: This study aimed to examine the use of digital technology in the three-dimensional reconstruction of human placentas.: Study design: Placentas obtained at term elective caesarean section were sampled, formalin-fixed and embedded in ... ...

    Abstract Objective: This study aimed to examine the use of digital technology in the three-dimensional reconstruction of human placentas.
    Study design: Placentas obtained at term elective caesarean section were sampled, formalin-fixed and embedded in paraffin. Two hundred 5 μm consecutive sections were cut from each specimen and the resultant slides stained with haematoxylin and eosin. Slides were then scanned and the digitised images reconstructed using customised software.
    Results: Three-dimensional reconstructions were successfully achieved in placentas from normal pregnancies and those complicated by pre-eclampsia, growth restriction, and gestational diabetes. Marked morphological differences were readily identifiable, most clearly in the stem villus architecture.
    Conclusion: This method is an emerging research tool for examining placental histoarchitecture at high resolution and gaining clinically relevant insight into the placental pathology allied to pregnancy complications such as PET, IUGR and GD.
    MeSH term(s) Case-Control Studies ; Cesarean Section ; Chorionic Villi/pathology ; Diabetes, Gestational/pathology ; Female ; Fetal Growth Retardation/pathology ; Humans ; Imaging, Three-Dimensional ; Pilot Projects ; Placenta/pathology ; Pre-Eclampsia/pathology ; Pregnancy
    Language English
    Publishing date 2016-02
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190605-7
    ISSN 1872-7654 ; 0301-2115 ; 0028-2243
    ISSN (online) 1872-7654
    ISSN 0301-2115 ; 0028-2243
    DOI 10.1016/j.ejogrb.2015.12.015
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