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  1. Article ; Online: Female reproductive tract pain

    PhillipJobling

    Frontiers in Pharmacology, Vol

    targets, challenges, and outcomes

    2014  Volume 5

    Abstract: Pain from the female reproductive tract (FRT) is a significant clinical problem for which there are few effective therapies. The complex neuroantomy of pelvic organs not only makes diagnosis of pelvic pain disorders difficult but represents a challenge ... ...

    Abstract Pain from the female reproductive tract (FRT) is a significant clinical problem for which there are few effective therapies. The complex neuroantomy of pelvic organs not only makes diagnosis of pelvic pain disorders difficult but represents a challenge to development of targeted therapies. A number of potential therapeutic targets have been identified on sensory neurons supplying the FRT but our knowledge on the basic neurophysiology of these neurons is limited compared with other viscera. Until this is addressed we can only guess if the new experimental therapies proposed for somatic, gastrointestinal or bladder pain will translate to the FRT. Once suitable therapeutic targets become clear, the next challenge is drug delivery. The FRT represents a promising system for topical drug delivery that could be tailored to act locally or systemically depending on formulation. Development of these therapies and their delivery systems will need to be done in concert with more robust in vivo and in vitro models of FRT pain.
    Keywords Pelvic Pain ; Uterus ; Vagina ; Cervix ; drug delivery. ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R
    Language English
    Publishing date 2014-02-01T00:00:00Z
    Publisher Frontiers
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Objective quantification of nerves in immunohistochemistry specimens of thyroid cancer utilising deep learning.

    Indriani P Astono / James S Welsh / Christopher W Rowe / Phillip Jobling

    PLoS Computational Biology, Vol 18, Iss 2, p e

    2022  Volume 1009912

    Abstract: Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However ... ...

    Abstract Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However the images are of a large size with nerves having substantial variation in morphology that renders accurate and objective quantification difficult using existing manual and automated counting techniques. Manual counting is precise, but time-consuming, susceptible to inconsistency and has a high rate of false negatives. Existing automated techniques using digitised tissue sections and colour filters are sensitive, however, have a high rate of false positives. In this paper we develop a new automated nerve detection approach, based on a deep learning model with an augmented classification structure. This approach involves pre-processing to extract the image patches for the deep learning model, followed by pixel-level nerve detection utilising the proposed deep learning model. Outcomes assessed were a) sensitivity of the model in detecting manually identified nerves (expert annotations), and b) the precision of additional model-detected nerves. The proposed deep learning model based approach results in a sensitivity of 89% and a precision of 75%. The code and pre-trained model are publicly available at https://github.com/IA92/Automated_Nerves_Quantification.
    Keywords Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Nerve growth factor and its receptor tyrosine kinase TrkA are overexpressed in cervical squamous cell carcinoma

    Sam Faulkner / Nathan Griffin / Christopher W. Rowe / Phillip Jobling / Janine M. Lombard / Sonia M. Oliveira / Marjorie M. Walker / Hubert Hondermarck

    FASEB BioAdvances, Vol 2, Iss 7, Pp 398-

    2020  Volume 408

    Abstract: Abstract Nerve growth factor (NGF) and its receptors are increasingly implicated in cancer progression, but their expression in cervical cancer is unclear. The objective of this study was to define the protein expression of NGF, its precursor (proNGF), ... ...

    Abstract Abstract Nerve growth factor (NGF) and its receptors are increasingly implicated in cancer progression, but their expression in cervical cancer is unclear. The objective of this study was to define the protein expression of NGF, its precursor (proNGF), as well as their receptors, the tyrosine kinase receptor TrkA, the common neurotrophin receptor p75NTR and the pro‐neurotrophin receptor sortilin in cervical cancer. Immunohistochemistry was performed in a cohort of cervical cancers (n = 287), including the two major subtypes of the disease: squamous cell carcinomas (SCC) and adenocarcinomas (AC). Normal cervical tissues (n = 28) were also analyzed. Protein expression was determined by computer‐based digital quantification of staining intensity and comparative statistical analyses were made with clinicopathological parameters including histological subtype, age, grade, tumor size, lymph node invasion, and stage. The expression of NGF, proNGF, TrkA, p75NTR, and sortilin was higher in cervical cancer compared to normal cervical tissues. NGF and TrkA were found overexpressed in SCC compared to AC (P = .0006 and P < .0001, respectively). The expression of NGF (P = .0053), proNGF (P = .0022), and p75NTR (P = .0002), but not that of TrkA or sortilin, was associated with increasing grade in SCC. In addition, nerve infiltration into the tumor microenvironment was assessed using the pan‐neuronal marker PGP9.5. Infiltrating nerves were detected in 27% of cervical tumors and expressed TrkA. Functional investigations using the HELA cervical cancer cell line indicated that the Trk tyrosine kinase inhibitor GNF‐5837 reduced cell viability through decreased ERK1/2 activation. Together, these data reveal the overexpression of NGF and TrkA in cervical SCC, suggesting a potential therapeutic value of targeting the NGF‐TrkA signaling pathway in this subtype of cervical cancer.
    Keywords cervical cancer ; nerves ; NGF ; p75NTR ; proNGF ; sortilin ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Tumor innervation and clinical outcome in pancreatic cancer

    Aysha Ferdoushi / Nathan Griffin / Mark Marsland / Xiaoyue Xu / Sam Faulkner / Fangfang Gao / Hui Liu / Simon J. King / James W. Denham / Dirk F. van Helden / Phillip Jobling / Chen Chen Jiang / Hubert Hondermarck

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Abstract Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the ...

    Abstract Abstract Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77–4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19–0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The neurotrophic tyrosine kinase receptor TrkA and its ligand NGF are increased in squamous cell carcinomas of the lung

    Fangfang Gao / Nathan Griffin / Sam Faulkner / Christopher W. Rowe / Lily Williams / Severine Roselli / Rick F. Thorne / Aysha Ferdoushi / Phillip Jobling / Marjorie M. Walker / Hubert Hondermarck

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: Abstract The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of ...

    Abstract Abstract The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the neurotrophin co-receptor p75NTR and the proneurotrophin co-receptor sortilin, remains unclear. In the present study, analysis of these proteins was conducted by immunohistochemistry and digital quantification in a series of 204 lung cancers of different histological subtypes versus 121 normal lung tissues. TrkA immunoreactivity was increased in squamous cell carcinoma compared with benign and other malignant lung cancer histological subtypes (p < 0.0001). NGF and proNGF were also increased in squamous cell carcinoma, as well as in adenocarcinoma (p < 0.0001). In contrast, p75NTR was increased across all lung cancer histological subtypes compared to normal lung (p < 0.0001). Sortilin was higher in adenocarcinoma and small cell carcinoma (p < 0.0001). Nerves in the tumor microenvironment were negative for TrkA, NGF, proNGF, p75NTR and sortilin. In conclusion, these data suggest a preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2018-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

    Kelly M Smith / Tyler J Browne / Olivia C Davis / A Coyle / Kieran A Boyle / Masahiko Watanabe / Sally A Dickinson / Jacqueline A Iredale / Mark A Gradwell / Phillip Jobling / Robert J Callister / Christopher V Dayas / David I Hughes / Brett A Graham

    eLife, Vol

    2019  Volume 8

    Abstract: Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to ... ...

    Abstract Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.
    Keywords pain ; optogenetics ; spinal cord ; patch clamp ; interneuron ; projection neurons ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2019-11-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Phasic contractions of the mouse vagina and cervix at different phases of the estrus cycle and during late pregnancy.

    Fernanda S Gravina / Dirk F van Helden / Karen P Kerr / Ramatis B de Oliveira / Phillip Jobling

    PLoS ONE, Vol 9, Iss 10, p e

    2014  Volume 111307

    Abstract: The pacemaker mechanisms activating phasic contractions of vaginal and cervical smooth muscle remain poorly understood. Here, we investigate properties of pacemaking in vaginal and cervical tissues by determining whether: 1) functional pacemaking is ... ...

    Abstract The pacemaker mechanisms activating phasic contractions of vaginal and cervical smooth muscle remain poorly understood. Here, we investigate properties of pacemaking in vaginal and cervical tissues by determining whether: 1) functional pacemaking is dependent on the phase of the estrus cycle or pregnancy; 2) pacemaking involves Ca2+ release from sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) -dependent intracellular Ca2+ stores; and 3) c-Kit and/or vimentin immunoreactive ICs have a role in pacemaking.Vaginal and cervical contractions were measured in vitro, as was the distribution of c-Kit and vimentin positive interstitial cells (ICs). Cervical smooth muscle was spontaneously active in estrus and metestrus but quiescent during proestrus and diestrus. Vaginal smooth muscle was normally quiescent but exhibited phasic contractions in the presence of oxytocin or the K+ channel blocker tetraethylammonium (TEA) chloride. Spontaneous contractions in the cervix and TEA-induced phasic contractions in the vagina persisted in the presence of cyclopiazonic acid (CPA), a blocker of the SERCA that refills intracellular SR Ca2+ stores, but were inhibited in low Ca2+ solution or in the presence of nifedipine, an inhibitor of L-type Ca2+channels. ICs were found in small numbers in the mouse cervix but not in the vagina.Cervical smooth muscle strips taken from mice in estrus, metestrus or late pregnancy were generally spontaneously active. Vaginal smooth muscle strips were normally quiescent but could be induced to exhibit phasic contractions independent on phase of the estrus cycle or late pregnancy. Spontaneous cervical or TEA-induced vaginal phasic contractions were not mediated by ICs or intracellular Ca2+ stores. Given that vaginal smooth muscle is normally quiescent then it is likely that increases in hormones such as oxytocin, as might occur through sexual stimulation, enhance the effectiveness of such pacemaking until phasic contractile activity emerges.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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