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Article: Elusive physiological role of prostatic acid phosphatase (PAP): generation of choline for sperm motility via auto-and paracrine cholinergic signaling.

Hanley, Peter J

2023 Volume 14, Page(s) 1327769

Abstract: Prostatic acid phosphatase (PAP) exists as two splice variants, secreted PAP and transmembrane PAP, the latter of which is implicated in antinociceptive signaling in dorsal root ganglia. However, PAP is predominantly expressed in the prostate gland and ... ...

Abstract	Prostatic acid phosphatase (PAP) exists as two splice variants, secreted PAP and transmembrane PAP, the latter of which is implicated in antinociceptive signaling in dorsal root ganglia. However, PAP is predominantly expressed in the prostate gland and the physiological role of seminal PAP, first identified in 1938, is largely unknown. Here, the author proposes that PAP, following ejaculation, functions to hydrolyze phosphocholine (PC) in seminal fluid and generate choline, which is imported by sperm via a choline transporter and converted to acetylcholine (ACh) by choline acetyltransferase. Auto- and paracrine cholinergic signaling, or choline directly, may subsequently stimulate sperm motility via α7 nicotinic ACh receptors (nAChRs) and contractility of the female reproductive tract through muscarinic ACh receptors (mAChRs). Consistent with a role of PAP in cholinergic signaling, 1) seminal vesicles secrete PC, 2) the prostate gland secretes PAP, 3) PAP specifically catalyzes the hydrolysis of PC into inorganic phosphate and choline, 4) seminal choline levels increase post-ejaculation, 5) pharmacological inhibition of choline acetyltransferase inhibits sperm motility, 6) inhibition or genetic deletion of α7 nAChRs impairs sperm motility, and 7) mAChRs are expressed in the uterus and oviduct (fallopian tube). Notably, PAP does not degrade glycerophosphocholine (GPC), the predominant choline source in the semen of rats and other mammals. Instead, uterine GPC phosphodiesterases may liberate choline from seminal GPC. In summary, the author deduces that PAP in humans, and uterine GPC phosphodiesterases in other mammals, function to generate choline for sperm cholinergic signaling, which promotes sperm motility and possibly contractility of the female reproductive tract.
Language	English
Publishing date	2023-12-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1327769
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Article ; Online: Changes in lung epithelial cell volatile metabolite profile induced by pro-fibrotic stimulation with TGF-

Hayton, Conal / Ahmed, Waqar / Cunningham, Peter / Piper-Hanley, Karen / Pearmain, Laurence / Chaudhuri, Nazia / Leonard, Colm / Blaikley, John F / Fowler, Stephen J

Journal of breath research

2023 Volume 17, Issue 4

Abstract: Volatile organic compounds (VOCs) have shown promise as potential biomarkers in idiopathic pulmonary fibrosis. Measuring VOCs in the headspace ... ...

Abstract	Volatile organic compounds (VOCs) have shown promise as potential biomarkers in idiopathic pulmonary fibrosis. Measuring VOCs in the headspace of
MeSH term(s)	Humans ; Transforming Growth Factor beta1 ; Volatile Organic Compounds ; Breath Tests ; Epithelial Cells ; Idiopathic Pulmonary Fibrosis ; Lung
Chemical Substances	Transforming Growth Factor beta1 ; Volatile Organic Compounds
Language	English
Publishing date	2023-09-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2381007-5
ISSN	1752-7163 ; 1752-7155
ISSN (online)	1752-7163
ISSN	1752-7155
DOI	10.1088/1752-7163/acf391
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Article ; Online: Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

Tewkesbury, Daniel H / Scott, Jennifer / Barry, Peter J / Bright-Thomas, Rowland J / Hanley, Karen Piper / Athwal, Varinder / Jones, Andrew M

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

2023

Abstract: Background: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after ... ...

Abstract	Background: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. Methods: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. Results: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). Conclusions: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.
Language	English
Publishing date	2023-09-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2084724-5
ISSN	1873-5010 ; 1569-1993
ISSN (online)	1873-5010
ISSN	1569-1993
DOI	10.1016/j.jcf.2023.09.006
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Article: Class IX Myosins: Motorized RhoGAP Signaling Molecules.

Hanley, Peter J / Vollmer, Veith / Bähler, Martin

Advances in experimental medicine and biology

2020 Volume 1239, Page(s) 381–389

Abstract: Class IX myosins are simultaneously motor and signaling molecules. In addition to myosin class-specific functions of the tail region, they feature unique motor properties. Within their motor region they contain a long insertion with a calmodulin- and a F- ...

Abstract	Class IX myosins are simultaneously motor and signaling molecules. In addition to myosin class-specific functions of the tail region, they feature unique motor properties. Within their motor region they contain a long insertion with a calmodulin- and a F-actin-binding site. The rate-limiting step in the ATPase cycle is ATP hydrolysis rather than, typical for other myosins, the release of either product. This means that class IX myosins spend a large fraction of their cycle time in the ATP-bound state, which is typically a low F-actin affinity state. Nevertheless, class IX myosins in the ATP-bound state stochastically switch between a low and a high F-actin affinity state. Single motor domains even show characteristics of processive movement towards the plus end of actin filaments. The insertion thereby acts as an actin tether. The motor domain transports as intramolecular cargo a signaling Rho GTPase-activating protein domain located in the tail region. Rho GTPase-activating proteins catalyze the conversion of active GTP-bound Rho to inactive GDP-bound Rho by stimulating GTP hydrolysis. In cells, Rho activity regulates actin cytoskeleton organization and actomyosin II contractility. Thus, class IX myosins regulate cell morphology, cell migration, cell-cell junctions and membrane trafficking. These cellular functions affect embryonic development, adult organ homeostasis and immune responses. Human diseases associated with mutations in the two class IX myosins, Myo9a and Myo9b, have been identified, including hydrocephalus and congenital myasthenic syndrome in connection with Myo9a and autoimmune diseases in connection with Myo9b.
MeSH term(s)	Actins/metabolism ; GTPase-Activating Proteins/metabolism ; Humans ; Myosins/metabolism ; Protein Binding ; Signal Transduction
Chemical Substances	Actins ; GTPase-Activating Proteins ; MYO9A protein, human ; myosin IXB ; rho GTPase-activating protein ; Myosins (EC 3.6.4.1)
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-38062-5_16
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Article: Improving detection of cystic fibrosis related liver disease using liver fibrosis assessment tools.

Scott, Jennifer A / Jones, Andrew M / Jokl, Elliot / Gordon-Walker, Timothy / Barry, Peter J / Hanley, Neil A / Piper Hanley, Karen / Athwal, Varinder S

Heliyon

2023 Volume 9, Issue 11, Page(s) e21861

Abstract: Background & aims: Cystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may ... ...

Abstract	Background & aims: Cystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may underdiagnose liver fibrosis, particularly in its early stages. Newer modalities for the assessment of fibrosis may provide a more accurate assessment. FibroScan is validated in assessing fibrosis for several aetiologies including alcohol and fatty liver, the CFLD cohort have an entirely different phenotype so the cut off values are not transferrable. We appraised fibrosis assessment tools to improve diagnosis of CFLD. Methods: A prospective cohort (n = 114) of patients from the Manchester Adult Cystic Fibrosis Centre, UK were identified at annual assessment. Demographic data including co-morbidity, Results: 12 of 114 patient classified as CFLD according to the European Cystic Fibrosis Society best practice guidelines. No specific risk factors for development of CFLD were identified. Liver enzymes were elevated in patients with CFLD. Serum biomarker panels did not improve diagnostic criteria. LSM accurately predicted CFLD. A new diagnostic criterion was proposed and validated in a separate cohort, accurately predicating CFLD in 10 of 32 patients (31 %). Conclusion: We present a cohort of patients with CF assessed for the presence of liver fibrosis using blood biomarkers and LSM based platforms. We propose a new, simplified diagnostic criteria, capable of accurately predicting liver disease in patients with CF.Clinical trials number: NCT04277819.
Language	English
Publishing date	2023-11-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e21861
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Article ; Online: Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

Tewkesbury, Daniel / Jones, Andrew M / Bright-Thomas, Rowland / Cratchley, Alyn / Hanley, Karen Piper / Wyatt, Judith / Athwal, Varinder / Barry, Peter J

Drugs

2023 Volume 83, Issue 18, Page(s) 1699–1707

Abstract: Background: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, ... ...

Abstract	Background: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. Objective: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. Methods: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. Results: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. Conclusions: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.
MeSH term(s)	Adult ; Humans ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Aminophenols/adverse effects ; Benzodioxoles/adverse effects ; Liver Diseases ; Chemical and Drug Induced Liver Injury/etiology ; Transaminases/therapeutic use ; Necrosis/chemically induced ; Mutation
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; elexacaftor (RRN67GMB0V) ; ivacaftor (1Y740ILL1Z) ; tezacaftor ; Aminophenols ; Benzodioxoles ; Transaminases (EC 2.6.1.-)
Language	English
Publishing date	2023-11-15
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	120316-2
ISSN	1179-1950 ; 0012-6667
ISSN (online)	1179-1950
ISSN	0012-6667
DOI	10.1007/s40265-023-01969-3
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Article: Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet.

Hanley, Sarah / Brown, Jonathan / Timmins, Peter / Davies, Catrin / Dennis, Andrew

Pharmaceutics

2022 Volume 14, Issue 10

Abstract: The uptake of alkaline phosphate present in dissolution medium into a hydrating hydroxypropyl methylcellulose matrix tablet and that its activity was retained therein was demonstrated. This presents a risk to the stability of prodrugs that are substrates ...

Abstract	The uptake of alkaline phosphate present in dissolution medium into a hydrating hydroxypropyl methylcellulose matrix tablet and that its activity was retained therein was demonstrated. This presents a risk to the stability of prodrugs that are substrates of this enzyme such as phosphonooxymethyl derivative prodrugs. It was found that fostemsavir, a phosphonooxymethyl derivative prodrug being developed for the treatment of HIV-1 infection, was unexpectedly resistant to hydrolysis within a hydrated HPMC matrix when subjected to drug release testing in media containing alkaline phosphatase. Studies indicated that this was not due to microenvironmental pH effects, osmolality effects or effective phosphate concentration effects associated with the presence of the prodrug. That the prodrug and not its parent could affect enzyme activity in a concentration dependent manner, and that another phosphate ester prodrug fosphenytoin did not inhibit alkaline phosphatase activity within a hydrated HPMC matrix suggested that the unexpected stability of the HIV-1 therapy prodrug may be associated with the ability of the phosphate group-containing compound itself to inhibit the enzyme at the concentrations it exists at in the hydrated dosage form and so enables the development of the compound in this type of dosage form.
Language	English
Publishing date	2022-10-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14102222
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Article ; Online: Quantifying Nature: Introducing NatureScore

Browning, Matthew H E M / Hanley, Jared R / Bailey, Christopher R / Beatley, Timothy / Gailey, Samantha / Hipp, J Aaron / Larson, Lincoln R / James, Peter / Jennings, Viniece / Jimenez, Marcia Pescador / Kahn, Peter H / Li, Dongying / Reuben, Aaron / Rigolon, Alessandro / Sachs, Naomi A / Pearson, Amber L / Minson, Christopher T

American journal of health promotion : AJHP

2023 Volume 38, Issue 1, Page(s) 126–134

Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	645160-3
ISSN	2168-6602 ; 0890-1171
ISSN (online)	2168-6602
ISSN	0890-1171
DOI	10.1177/08901171231210806b
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Article ; Online: Is teaching work? A heuristic study of the views of teachers.

Graydon, Joanne / Coman, Robyn / Hanley, Natalia / Caputi, Peter

Work (Reading, Mass.)

2020 Volume 66, Issue 1, Page(s) 95–107

Abstract: Background: Teachers can be at risk of exposure to psychosocial hazards. Improving workplace safety for teachers, within a 'systems thinking' context, should begin with understanding the work.: Objective: While much is known about what teachers do, ... ...

Abstract	Background: Teachers can be at risk of exposure to psychosocial hazards. Improving workplace safety for teachers, within a 'systems thinking' context, should begin with understanding the work. Objective: While much is known about what teachers do, little is known about how teachers conceptualize 'work'. Knowing how teachers conceptualize 'work' provides a reference point for exploring attitudes towards work health and safety. Methods: The paper presents a review of the literature, an overview of heuristic methodology describing and interpreting the lived experience of teachers as workers, and analysis of teachers' accounts of work. The heuristic approach allowed the author to compare their lived experiences and perceptions as a teacher with the lived experience of teachers in the NSW school system. Results: Teaching is work that is both rewarding and hazardous. It is argued that teachers draw on battle motifs, perceive a need for safety within a workplace context, and have an ability to conduct personal risk assessments. Conclusions: Findings from the study provided direction for the second phase of the project that is aimed at exploring the ways in which teachers conceptualize psychosocial work- related hazards and the extent to which they are visible in teaching practice and policy.
MeSH term(s)	Attitude ; Employment ; Female ; Heuristics ; Humans ; Male ; New South Wales ; School Teachers/psychology ; Socioeconomic Factors ; Surveys and Questionnaires ; Teaching/classification ; Teaching/psychology
Language	English
Publishing date	2020-05-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1394194-x
ISSN	1875-9270 ; 1051-9815
ISSN (online)	1875-9270
ISSN	1051-9815
DOI	10.3233/WOR-203154
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Article ; Online: High-Grade Endometrial Stromal Sarcomas With YWHAE::NUTM2 Gene Fusion Exhibit Recurrent CDKN2A Alterations and Absence of p16 Staining is a Poor Prognostic Marker.

Kommoss, Felix K F / Mar, Lisa-Marie / Howitt, Brooke E / Hanley, Krisztina / Turashvilli, Gulisa / Buslei, Rolf / Irving, Julie A / Dickson, Brendan C / Koelsche, Christian / Sinn, Hans-Peter / Schirmacher, Peter / von Deimling, Andreas / Chiang, Sarah / McCluggage, W Glenn / Croce, Sabrina / Stewart, Colin J R / Lee, Cheng-Han

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2023 Volume 36, Issue 3, Page(s) 100044

Abstract: High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these ... ...

Abstract	High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker.
MeSH term(s)	Female ; Humans ; Endometrial Neoplasms/pathology ; Prognosis ; In Situ Hybridization, Fluorescence ; Sarcoma, Endometrial Stromal/genetics ; Sarcoma, Endometrial Stromal/pathology ; Homozygote ; Sequence Deletion ; Sarcoma/genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Gene Fusion ; 14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism
Chemical Substances	Cyclin-Dependent Kinase Inhibitor p16 ; YWHAE protein, human ; 14-3-3 Proteins ; CDKN2A protein, human
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1016/j.modpat.2022.100044
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