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Darius J. Bägli - One of the best experts on this subject based on the ideXlab platform.
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assessment of local structural disorders of the Bladder wall in partial Bladder outlet Obstruction using polarized light imaging
Biomedical Optics Express, 2014Co-Authors: Sanaz Alali, Annette Schroder, Adam Gribble, Karen Aitken, Darius J. Bägli, Alex I VitkinAbstract:Partial Bladder outlet Obstruction causes prominent morphological changes in the Bladder wall, which leads to Bladder dysfunction. In this paper, we demonstrate that polarized light imaging can be used to identify the location of Obstruction induced structural changes that other imaging modalities fail to detect. We induced 2-week and 6-week partial outlet Obstruction in rats, harvested obstructed Bladders, then measured their retardances while distended to high pressures and compared them to controls. Our results show that the retardance of the central part of the ventral side (above the ureters) closer to the urethra can be used as a potential metric of the distending Bladder Obstruction.
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modulation of dna methylation and phenotypic switching in smooth muscle cells by the extracellular matrix microenvironment
Epigenetics & Chromatin, 2013Co-Authors: Jiaxin Jiang, Karen Aitken, Tyler Kirwan, Nicole Zhang, Darius J. BägliAbstract:Background Partial Bladder outlet Obstruction due to neurogenic Bladder or mechanical Obstruction is common amongst the population and can cause Bladder injury and dysfunction. Bladder Smooth Muscle Cells (BSMCs) undergo phenotypic changes such as hyper-proliferation, de-differentiation and altered expression of integrins and ECM proteins.[1] Extracellular matrix changes are often crucial inciting events for fibroproliferative disease.[2] Epigenetic change, specifically DNA methylation, may be important factors underlying the persistent fibroproliferative phenotype. Previously, damaged matrix (heat-denatured collagen, DNC) induced hyper-proliferation of Bladder smooth muscle cells (BSMC) and the phenotype was not reverted upon a return to normal matrix. [3] We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methyltransferase activity. The cooperativity of matrix with other inciting stimuli (growth factors, hypoxia and strain) associated with Bladder Obstruction was also examined.
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mammalian target of rapamycin mtor induces proliferation and de differentiation responses to three coordinate pathophysiologic stimuli mechanical strain hypoxia and extracellular matrix remodeling in rat Bladder smooth muscle
American Journal of Pathology, 2010Co-Authors: Karen J Aitken, Cornelia Tolg, Trupti Panchal, Bruno Leslie, Mohamed Elkelini, Nesrin Sabha, Derrick Tse, Armando J Lorenzo, Magdy M Hassouna, Darius J. BägliAbstract:Maladaptive Bladder muscle overgrowth and de-differentiation in human Bladder obstructive conditions is instigated by coordinate responses to three stimuli: mechanical strain, tissue hypoxia, and extracellular matrix remodeling.1,2 Pathway analysis of genes induced by obstructive models of injury in Bladder smooth muscle cells (BSMCs) identified a mammalian target of rapamycin (mTOR)-specific inhibitor as a potential pharmacological inhibitor. Strain-induced mTOR-specific S6K activation segregated differently from ERK1/2 activation in intact Bladder ex vivo. Though rapamycin's antiproliferative effects in vascular smooth muscle cells are well known, its effects on BSMCs were previously unknown. Rapamycin significantly inhibited proliferation of BSMCs in response to mechanical strain, hypoxia, and denatured collagen. Rapamycin inhibited S6K at mTOR-sensitive phosphorylation sites in response to strain and hypoxia. Rapamycin also supported smooth muscle actin expression in response to strain or hypoxia-induced de-differentiation. Importantly, strain plus hypoxia synergistically augmented mTOR-dependent S6K activation, Mmp7 expression and proliferation. Forced expression of wild-type and constitutively active S6K resulted in loss of smooth muscle actin expression. Decreased smooth muscle actin, increased Mmp7 levels and mTOR pathway activation during in vivo partial Bladder Obstruction paralleled our in vitro studies. These results point to a coordinate role for mTOR in BSMCs responses to the three stimuli and a potential new therapeutic target for myopathic Bladder disease.
Karen Aitken - One of the best experts on this subject based on the ideXlab platform.
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human murine concordance of molecular signatures in nerve sparing murine partial Bladder outlet Obstruction nemo
bioRxiv, 2021Co-Authors: Martin Sidler, Jiaxin Jiang, Abdalla Ahmed, Dursa Koshkebaghi, Priyank Yadav, Dariush Davani, Ryan Huang, Rosanna Weksberg, Paul Delgadoolguin, Karen AitkenAbstract:Recently we demonstrated the utility of a nerve-sparing mid-urethra model of partial outlet Obstruction (NeMO) that has high consistency and minimal mortalities, unlike the traditional model proximal to the Bladder neck. Our goal was to uncover potential therapeutic targets by investigating the genome wide transcriptional changes and pathways altered in NeMO to compare with published human Bladder Obstruction data. We performed RNAseq and analysed the differentially upregulated and downregulated genes for associated pathways, transcription factor binding site analysis (TFBS), upstream regulators and Gene Set Enrichment Analysis (GSEA). NeMO increased Bladder mass, relative Bladder mass and hyperactivity, and decreased voiding efficiency. In NeMO vs. sham, 831 genes were differentially expressed (adjusted p<0.05) and correlated significantly with at least one physiologic parameter. Gene ontology revealed an enrichment for matrix pathways in the upregulated genes, and for cardiac contraction, oxidative phosphorylation and pyruvate metabolism in downregulated genes. TFBS analysis revealed a differential regulation of up vs downregulated genes, with KLF4 strongly associated with the downregulated genes. Downregulated genes of Human Bladder Obstruction were also associated with the TFBS of KLF4. GSEA of the NeMO gene set confirmed the DAVID results, but also showed a cluster of cytokine activation genes. In human Bladder underactive Obstruction, cytokines were also highly upregulated. The common cytokine pathway upregulation provided an example of the use of RNAseq for uncovering potential new therapeutic targets. As TNF and the innate immune pathways were strongly implicated in both human and mouse, and TNF is produced by macrophages, we depletion macrophages with clodronate (CL) during NeMO. Although CL did not block hypertrophy, it significantly decreased NeMO-induced hyperactive voiding (p<0.01) and increased voiding efficiency (p<0.05). The expression of several cytokines/chemokines correlated significantly with Bladder functional parameters such as residual volumes, and hyperactivity. Conclusions: Gene expression signatures of NeMO were consistent with human Bladder Obstruction, supporting the use of the nerve-sparing mouse Obstruction model for therapeutic exploration.
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dna methylation reduces the yes associated protein 1 ww domain containing transcription regulator 1 pathway and prevents pathologic remodeling during Bladder Obstruction by limiting expression of bdnf
American Journal of Pathology, 2018Co-Authors: Martin Sidler, Chris Sotiropoulos, Prateek Aggarwal, Arsalan Anees, Cynthia Chong, Aliza Siebenaller, Thenuka Thanabalasingam, Jiaxin Jiang, Karen Aitken, Maxwell J WhiteAbstract:Chronic Bladder Obstruction and Bladder smooth muscle cell (SMC) stretch provide fibrotic and mechanical environments that can lead to epigenetic change. Therefore, we examined the role of DNA methylation in Bladder pathology and transcriptional control. Sprague-Dawley female rats underwent partial Bladder Obstruction by ligation of a silk suture around the proximal urethra next to a 0.9-mm steel rod. Sham operation comprised passing the suture around the urethra. After 2 weeks, rats were randomized to normal saline or DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (DAC) at 1 mg/kg, three times/week intraperitoneally. After 6 weeks, Bladders were weighed and divided for histology and RNA analysis by high-throughput real-time quantitative PCR arrays. DAC treatment during Obstruction in vivo profoundly augmented brain-derived neurotrophic factor (BDNF) expression compared with the Obstruction with vehicle group, which was statistically correlated with pathophysiologic parameters. BDNF, cysteine rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF) expression clustered tightly together using Pearson's correlation analysis. Their promoters were associated with the TEA domain family member 1 (TEAD1) and Yes-associated protein 1/WW domain containing transcription regulator 1 pathways. Interestingly, DAC treatment increased BDNF expression in Bladder SMCs (P
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assessment of local structural disorders of the Bladder wall in partial Bladder outlet Obstruction using polarized light imaging
Biomedical Optics Express, 2014Co-Authors: Sanaz Alali, Annette Schroder, Adam Gribble, Karen Aitken, Darius J. Bägli, Alex I VitkinAbstract:Partial Bladder outlet Obstruction causes prominent morphological changes in the Bladder wall, which leads to Bladder dysfunction. In this paper, we demonstrate that polarized light imaging can be used to identify the location of Obstruction induced structural changes that other imaging modalities fail to detect. We induced 2-week and 6-week partial outlet Obstruction in rats, harvested obstructed Bladders, then measured their retardances while distended to high pressures and compared them to controls. Our results show that the retardance of the central part of the ventral side (above the ureters) closer to the urethra can be used as a potential metric of the distending Bladder Obstruction.
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modulation of dna methylation and phenotypic switching in smooth muscle cells by the extracellular matrix microenvironment
Epigenetics & Chromatin, 2013Co-Authors: Jiaxin Jiang, Karen Aitken, Tyler Kirwan, Nicole Zhang, Darius J. BägliAbstract:Background Partial Bladder outlet Obstruction due to neurogenic Bladder or mechanical Obstruction is common amongst the population and can cause Bladder injury and dysfunction. Bladder Smooth Muscle Cells (BSMCs) undergo phenotypic changes such as hyper-proliferation, de-differentiation and altered expression of integrins and ECM proteins.[1] Extracellular matrix changes are often crucial inciting events for fibroproliferative disease.[2] Epigenetic change, specifically DNA methylation, may be important factors underlying the persistent fibroproliferative phenotype. Previously, damaged matrix (heat-denatured collagen, DNC) induced hyper-proliferation of Bladder smooth muscle cells (BSMC) and the phenotype was not reverted upon a return to normal matrix. [3] We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methyltransferase activity. The cooperativity of matrix with other inciting stimuli (growth factors, hypoxia and strain) associated with Bladder Obstruction was also examined.
Jiaxin Jiang - One of the best experts on this subject based on the ideXlab platform.
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human murine concordance of molecular signatures in nerve sparing murine partial Bladder outlet Obstruction nemo
bioRxiv, 2021Co-Authors: Martin Sidler, Jiaxin Jiang, Abdalla Ahmed, Dursa Koshkebaghi, Priyank Yadav, Dariush Davani, Ryan Huang, Rosanna Weksberg, Paul Delgadoolguin, Karen AitkenAbstract:Recently we demonstrated the utility of a nerve-sparing mid-urethra model of partial outlet Obstruction (NeMO) that has high consistency and minimal mortalities, unlike the traditional model proximal to the Bladder neck. Our goal was to uncover potential therapeutic targets by investigating the genome wide transcriptional changes and pathways altered in NeMO to compare with published human Bladder Obstruction data. We performed RNAseq and analysed the differentially upregulated and downregulated genes for associated pathways, transcription factor binding site analysis (TFBS), upstream regulators and Gene Set Enrichment Analysis (GSEA). NeMO increased Bladder mass, relative Bladder mass and hyperactivity, and decreased voiding efficiency. In NeMO vs. sham, 831 genes were differentially expressed (adjusted p<0.05) and correlated significantly with at least one physiologic parameter. Gene ontology revealed an enrichment for matrix pathways in the upregulated genes, and for cardiac contraction, oxidative phosphorylation and pyruvate metabolism in downregulated genes. TFBS analysis revealed a differential regulation of up vs downregulated genes, with KLF4 strongly associated with the downregulated genes. Downregulated genes of Human Bladder Obstruction were also associated with the TFBS of KLF4. GSEA of the NeMO gene set confirmed the DAVID results, but also showed a cluster of cytokine activation genes. In human Bladder underactive Obstruction, cytokines were also highly upregulated. The common cytokine pathway upregulation provided an example of the use of RNAseq for uncovering potential new therapeutic targets. As TNF and the innate immune pathways were strongly implicated in both human and mouse, and TNF is produced by macrophages, we depletion macrophages with clodronate (CL) during NeMO. Although CL did not block hypertrophy, it significantly decreased NeMO-induced hyperactive voiding (p<0.01) and increased voiding efficiency (p<0.05). The expression of several cytokines/chemokines correlated significantly with Bladder functional parameters such as residual volumes, and hyperactivity. Conclusions: Gene expression signatures of NeMO were consistent with human Bladder Obstruction, supporting the use of the nerve-sparing mouse Obstruction model for therapeutic exploration.
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dna methylation reduces the yes associated protein 1 ww domain containing transcription regulator 1 pathway and prevents pathologic remodeling during Bladder Obstruction by limiting expression of bdnf
American Journal of Pathology, 2018Co-Authors: Martin Sidler, Chris Sotiropoulos, Prateek Aggarwal, Arsalan Anees, Cynthia Chong, Aliza Siebenaller, Thenuka Thanabalasingam, Jiaxin Jiang, Karen Aitken, Maxwell J WhiteAbstract:Chronic Bladder Obstruction and Bladder smooth muscle cell (SMC) stretch provide fibrotic and mechanical environments that can lead to epigenetic change. Therefore, we examined the role of DNA methylation in Bladder pathology and transcriptional control. Sprague-Dawley female rats underwent partial Bladder Obstruction by ligation of a silk suture around the proximal urethra next to a 0.9-mm steel rod. Sham operation comprised passing the suture around the urethra. After 2 weeks, rats were randomized to normal saline or DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (DAC) at 1 mg/kg, three times/week intraperitoneally. After 6 weeks, Bladders were weighed and divided for histology and RNA analysis by high-throughput real-time quantitative PCR arrays. DAC treatment during Obstruction in vivo profoundly augmented brain-derived neurotrophic factor (BDNF) expression compared with the Obstruction with vehicle group, which was statistically correlated with pathophysiologic parameters. BDNF, cysteine rich angiogenic inducer 61 (CYR61), and connective tissue growth factor (CTGF) expression clustered tightly together using Pearson's correlation analysis. Their promoters were associated with the TEA domain family member 1 (TEAD1) and Yes-associated protein 1/WW domain containing transcription regulator 1 pathways. Interestingly, DAC treatment increased BDNF expression in Bladder SMCs (P
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modulation of dna methylation and phenotypic switching in smooth muscle cells by the extracellular matrix microenvironment
Epigenetics & Chromatin, 2013Co-Authors: Jiaxin Jiang, Karen Aitken, Tyler Kirwan, Nicole Zhang, Darius J. BägliAbstract:Background Partial Bladder outlet Obstruction due to neurogenic Bladder or mechanical Obstruction is common amongst the population and can cause Bladder injury and dysfunction. Bladder Smooth Muscle Cells (BSMCs) undergo phenotypic changes such as hyper-proliferation, de-differentiation and altered expression of integrins and ECM proteins.[1] Extracellular matrix changes are often crucial inciting events for fibroproliferative disease.[2] Epigenetic change, specifically DNA methylation, may be important factors underlying the persistent fibroproliferative phenotype. Previously, damaged matrix (heat-denatured collagen, DNC) induced hyper-proliferation of Bladder smooth muscle cells (BSMC) and the phenotype was not reverted upon a return to normal matrix. [3] We examined the dependency of matrix-induced fibroproliferation and SMC phenotype on DNA methyltransferase activity. The cooperativity of matrix with other inciting stimuli (growth factors, hypoxia and strain) associated with Bladder Obstruction was also examined.
A Zaloszyc - One of the best experts on this subject based on the ideXlab platform.
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fetal intervention for severe lower urinary tract Obstruction a multicenter case control study comparing fetal cystoscopy with vesicoamniotic shunting
Ultrasound in Obstetrics & Gynecology, 2015Co-Authors: N Sananes, Haleh Sangihaghpeykar, S Hernandezruano, R Moog, F Becmeur, A ZaloszycAbstract:Objective To evaluate the efficacy of fetal intervention using fetal cystoscopy or vesicoamniotic shunting in the treatment of severe lower urinary Obstruction (LUTO). Methods A cohort of 111 fetuses with severe LUTO attending two centers between January 1990 and August 2013 were included retrospectively. Fetuses were categorized into three groups based on the method of intervention: (1) fetal cystoscopy, (2) vesicoamniotic shunting or (3) no intervention. Multivariate analyses were performed to determine the probability of survival and normal renal function until 6 months of age by comparing fetal cystoscopy and vesicoamniotic shunting to no fetal intervention. Results Of the 111 fetuses with severe LUTO that were included in the analysis, fetal cystoscopy was performed in 34, vesicoamniotic shunting was performed in 16 and there was no fetal intervention in 61. Gestational age at diagnosis, method of fetal intervention and cause of Bladder Obstruction were associated with prognosis. In multivariate analysis and after adjustment for potential confounders (considering all causes of LUTO) the overall probability of survival was significantly higher with fetal cystoscopy and vesicoamniotic shunting when compared to no intervention (adjusted relative risk (ARR), 1.86 (95% CI, 1.01–3.42; P = 0.048) and ARR, 1.73 (95% CI, 1.01–3.08; P = 0.04) respectively). A clear trend for normal renal function was present in the fetal cystoscopy group (ARR, 1.73 (95% CI, 0.97–3.08; P = 0.06)) but was not observed in the vesicoamniotic shunt group (ARR, 1.16 (95% CI, 0.86–1.55; P = 0.33)). In cases in which there was a postnatal diagnosis of posterior urethral valves, fetal cystoscopy was effective in improving both the 6-month survival rate and renal function (ARR, 4.10 (95% CI, 1.75–9.62; P < 0.01) and 2.66 (95% CI, 1.25–5.70; P = 0.01) respectively) while vesicoamniotic shunting was associated only with an improvement in the 6-month survival rate (ARR, 3.76 (95% CI, 1.42–9.97; P < 0.01)) with no effect on renal function (ARR, 1.03 (95% CI, 0.49–2.17, P = 0.93)). Conclusion Fetal cystoscopy and vesicoamniotic shunting improve the 6-month survival rate in cases of severe LUTO. However, only fetal cystoscopy may prevent impairment of renal function in fetuses with posterior urethral valves. Our data support the idea of performing a subsequent randomized controlled trial to compare the effectiveness of fetal cystoscopy vs vesicoamniotic shunting for severe fetal LUTO. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
Haleh Sangihaghpeykar - One of the best experts on this subject based on the ideXlab platform.
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fetal intervention for severe lower urinary tract Obstruction a multicenter case control study comparing fetal cystoscopy with vesicoamniotic shunting
Ultrasound in Obstetrics & Gynecology, 2015Co-Authors: N Sananes, Haleh Sangihaghpeykar, S Hernandezruano, R Moog, F Becmeur, A ZaloszycAbstract:Objective To evaluate the efficacy of fetal intervention using fetal cystoscopy or vesicoamniotic shunting in the treatment of severe lower urinary Obstruction (LUTO). Methods A cohort of 111 fetuses with severe LUTO attending two centers between January 1990 and August 2013 were included retrospectively. Fetuses were categorized into three groups based on the method of intervention: (1) fetal cystoscopy, (2) vesicoamniotic shunting or (3) no intervention. Multivariate analyses were performed to determine the probability of survival and normal renal function until 6 months of age by comparing fetal cystoscopy and vesicoamniotic shunting to no fetal intervention. Results Of the 111 fetuses with severe LUTO that were included in the analysis, fetal cystoscopy was performed in 34, vesicoamniotic shunting was performed in 16 and there was no fetal intervention in 61. Gestational age at diagnosis, method of fetal intervention and cause of Bladder Obstruction were associated with prognosis. In multivariate analysis and after adjustment for potential confounders (considering all causes of LUTO) the overall probability of survival was significantly higher with fetal cystoscopy and vesicoamniotic shunting when compared to no intervention (adjusted relative risk (ARR), 1.86 (95% CI, 1.01–3.42; P = 0.048) and ARR, 1.73 (95% CI, 1.01–3.08; P = 0.04) respectively). A clear trend for normal renal function was present in the fetal cystoscopy group (ARR, 1.73 (95% CI, 0.97–3.08; P = 0.06)) but was not observed in the vesicoamniotic shunt group (ARR, 1.16 (95% CI, 0.86–1.55; P = 0.33)). In cases in which there was a postnatal diagnosis of posterior urethral valves, fetal cystoscopy was effective in improving both the 6-month survival rate and renal function (ARR, 4.10 (95% CI, 1.75–9.62; P < 0.01) and 2.66 (95% CI, 1.25–5.70; P = 0.01) respectively) while vesicoamniotic shunting was associated only with an improvement in the 6-month survival rate (ARR, 3.76 (95% CI, 1.42–9.97; P < 0.01)) with no effect on renal function (ARR, 1.03 (95% CI, 0.49–2.17, P = 0.93)). Conclusion Fetal cystoscopy and vesicoamniotic shunting improve the 6-month survival rate in cases of severe LUTO. However, only fetal cystoscopy may prevent impairment of renal function in fetuses with posterior urethral valves. Our data support the idea of performing a subsequent randomized controlled trial to compare the effectiveness of fetal cystoscopy vs vesicoamniotic shunting for severe fetal LUTO. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.