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  1. Article ; Online: Modulation of Progesterone Receptor Isoform Expression in Pregnant Human Myometrium

    Marina Ilicic / Tamas Zakar / Jonathan W. Paul

    BioMed Research International, Vol

    2017  Volume 2017

    Abstract: Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant ... ...

    Abstract Background. Regulation of myometrial progesterone receptor (PR) expression is an unresolved issue central to understanding the mechanism of functional progesterone withdrawal and initiation of labor in women. Objectives. To determine whether pregnant human myometrium undergoes culture-induced changes in PR isoform expression ex situ and, further, to determine if conditions approaching the in vivo environment stabilise PR isoform expression in culture. Methods. Term nonlaboring human myometrial tissues were cultured under specific conditions: serum supplementation, steroids, stretch, cAMP, PMA, PGF2α, NF-κB inhibitors, or TSA. Following 48 h culture, PR-T, PR-A, and PR-B mRNA levels were determined using qRT-PCR. PR-A/PR-B ratios were calculated. Results. PR-T and PR-A expression and the PR-A/PR-B ratio significantly increased in culture. Steroids prevented the culture-induced increase in PR-T and PR-A expression. Stretch blocked the effects of steroids on PR-T and PR-A expression. PMA further increased the PR-A/PR-B ratio, while TSA blocked culture-induced increases of PR-A expression and the PR-A/PR-B ratio. Conclusion. Human myometrial tissue in culture undergoes changes in PR gene expression consistent with transition toward a laboring phenotype. TSA maintained the nonlaboring PR isoform expression pattern. This suggests that preserving histone and/or nonhistone protein acetylation is critical for maintaining the progesterone dependent quiescent phenotype of human myometrium in culture.
    Keywords Medicine ; R
    Subject code 570
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Innervation of papillary thyroid cancer and its association with extra-thyroidal invasion

    Christopher W. Rowe / Tony Dill / Nathan Griffin / Phil Jobling / Sam Faulkner / Jonathan W. Paul / Simon King / Roger Smith / Hubert Hondermarck

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 9

    Abstract: Abstract Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated ... ...

    Abstract Abstract Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated the presence of nerves in thyroid cancers and the potential associations with clinicopathological parameters. Nerves were detected by immunohistochemistry using the pan-neuronal marker PGP9.5 in whole-slide sections of papillary thyroid cancer (PTC) (n = 75), compared to follicular thyroid cancer (FTC) (n = 13), and benign thyroid tissues (n = 26). Nerves were detected in most normal thyroid tissues and thyroid cancers, but nerve density was increased in PTC (12 nerves/cm2 [IQR 7–21]) compared to benign thyroid (6 nerves/cm2 [IQR: 3–10]) (p = 0.001). In contrast, no increase in nerve density was observed in FTC. In multivariate analysis, nerve density correlated positively with extrathyroidal invasion (p < 0.001), and inversely with tumour size (p < 0.001). The majority of nerves were adrenergic, although cholinergic and peptidergic innervation was detected. Perineural invasion was present in 35% of PTC, and was independently associated with extrathyroidal invasion (p = 0.008). This is the first report of infiltration of nerves into the tumour microenvironment of thyroid cancer and its association with tumour aggressiveness. The role of nerves in thyroid cancer pathogenesis should be further investigated.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 610
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Misleading Westerns

    Trent A. J. Butler / Jonathan W. Paul / Eng-Cheng Chan / Roger Smith / Jorge M. Tolosa

    BioMed Research International, Vol

    Common Quantification Mistakes in Western Blot Densitometry and Proposed Corrective Measures

    2019  Volume 2019

    Abstract: Densitometry data generated for Western blots are commonly used to compare protein abundance between samples. In the last decade, it has become apparent that assumptions underpinning these comparisons are often violated in studies reporting Western blot ... ...

    Abstract Densitometry data generated for Western blots are commonly used to compare protein abundance between samples. In the last decade, it has become apparent that assumptions underpinning these comparisons are often violated in studies reporting Western blot data in the literature. These violations can lead to erroneous interpretations of data and may contribute to poor reproducibility of research. We assessed the reliability of Western blot data obtained to study human myometrial tissue proteins. We ran dilution series of protein lysates to explore the linearity of densitometry data. Proteins analysed included αSMA, HSP27, ERK1/2, and GAPDH. While ideal densitometry data are directly proportional to protein abundance, our data confirm that densitometry data often deviate from this ideal, in which case they can fit nonproportional linear or hyperbolic mathematical models and can reach saturation. Nonlinear densitometry data were observed when Western blots were detected using infrared fluorescence or chemiluminescence, and under different SDS-PAGE conditions. We confirm that ghosting artefacts associated with overabundance of proteins of interest in Western blots can skew findings. We also confirm that when data to be normalised are not directly proportional to protein abundance, it is a mistake to use the normalisation technique of dividing densitometry data from the protein-of-interest with densitometry data from loading control protein(s), as this can cause the normalised data to be unusable for making comparisons. Using spiked proteins in a way that allowed us to control the total protein amount per lane, while only changing the amount of spiked proteins, we confirm that nonlinearity and saturation of densitometry data, and errors introduced from normalisation processes, can occur in routine assays that compare equal amounts of lysate. These findings apply to all Western blot studies, and we highlight quality control checks that should be performed to make Western blot data more quantitative.
    Keywords Medicine ; R
    Subject code 310
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Landscape of Preterm Birth Therapeutics and a Path Forward

    Brahm Seymour Coler / Oksana Shynlova / Adam Boros-Rausch / Stephen Lye / Stephen McCartney / Kelycia B. Leimert / Wendy Xu / Sylvain Chemtob / David Olson / Miranda Li / Emily Huebner / Anna Curtin / Alisa Kachikis / Leah Savitsky / Jonathan W. Paul / Roger Smith / Kristina M. Adams Waldorf

    Journal of Clinical Medicine, Vol 10, Iss 2912, p

    2021  Volume 2912

    Abstract: Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal ... ...

    Abstract Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics.
    Keywords tocolytic ; preterm birth ; preterm labor ; neonate ; prematurity ; pregnancy ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A Hypothesis for Self-Organization and Symmetry Reduction in the Synchronization of Organ-Level Contractions in the Human Uterus during Labor

    David Banney / Roger Young / Jonathan W. Paul / Mohammad Imtiaz / Roger Smith

    Symmetry, Vol 7, Iss 4, Pp 1981-

    2015  Volume 1988

    Abstract: We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contractions in human labor. This view is in contrast to the long-held presumption that the synchronized ... ...

    Abstract We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contractions in human labor. This view is in contrast to the long-held presumption that the synchronized behavior of the uterus is subject to well-defined internal organization (as is found in the heart) that exists prior to the onset of labor. The contractile units of the uterus are myocytes, which contract in response to both mechanical stretch and electrical stimulation. Throughout pregnancy progesterone maintains quiescence by suppression of “contraction-associated proteins” (CAPs). At the end of pregnancy a functional withdrawal of progesterone and an increasingly estrogenic environment leads to an increase in the production of CAPs. One CAP of particular importance is connexin 43, which creates gap junctions between the myocytes that cause them to become electrically coupled. The electrical connectivity between myocytes, combined with an increase in intrauterine pressure at the end of pregnancy shifts the uterus towards an increasingly unstable critical point, characterized by irregular, uncoordinated contractions. We propose that synchronous, coordinated contractions emerge from this critical point through a process of self-organization, and that the search for a uterine pacemaker has been unfruitful for the sole reason that it is non-existent.
    Keywords uterus ; contractions ; human labor ; symmetry reduction ; self-organization ; connexin 43 ; mechanotransduction ; emergence ; Physics ; QC1-999 ; Science ; Q
    Language English
    Publishing date 2015-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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