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Survivin in the human hair follicleBotchkareva, Natalia V., Ahluwalia, G., Kahn, M., Shander, D. January 2007 (has links)
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The roles of prostate progenitor cells and survivin in inflammation-induced prostate epithelial hyperplasiaWang, Liang 06 September 2016 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Prostate inflammation is a common health concern as an important risk factor
for prostate cancer and Benign Prostatic Hyperplasia (BPH). Inflammation
induces epithelial apoptosis and epithelial hyperplasia, suggesting that
inflammation promotes the tissue repair and regeneration process. Progenitor
cells are critical in maintaining epithelial homeostasis in adult tissues. However,
the roles of prostate progenitor cells, especially during prostate inflammation, are
understudied. I proposed that prostate epithelial progenitor cells (PEPCs) are
involved in inflammation-induced epithelial hyperplasia, and are driven by
regulation from inflammatory pathways.
Here, we showed that sphere formation ability of prostate epithelial cells is
increased by inflammation. We identified that a population of prostate progenitor
cells, named prostate epithelial progenitor cells, were expanded by inflammation
under the regulation of IL-1/insulin-like growth factor 1 (IGF-1) signaling pathway,
a previously identified critical regulation pathway of inflammation-induced epithelial hyperplasia. The expansion of PEPCs also correlated with the intensity of inflammation.
We then identified that survivin was upregulated in prostate epithelial cells by
inflammation and was mainly co-localized with proliferation markers in prostate
epithelial cells. This upregulation depended on IL-1/IGF-1 signaling. In vivo
treatment with the survivin inhibitor LQZ-7F reduced both survivin expression and
proliferation in prostate epithelial cells during inflammation. Using our label
retaining strategy, we compared the survivin expression pattern in two prostate
regeneration models. We discovered that different populations of progenitor cells
may be involved in different regeneration processes. We identified that survivin
was expressed in a specific population of reactivated cells that respond to the
inflammatory environment and was independent of the known slow-cycling stem
cells found in the prostate epithelium. In summary, I have identified that PEPCs
are involved in epithelial hyperplasia and are dependent on survivin signaling. My
work defines how survivin serves as a key regulator of epithelial hyperplasia in
an inflammatory environment.
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Estudo imunoistoquímico da proteína inibidora de apoptose, survivina no processo de carcinogênese quimicamente induzida pela 4NQO (4-nitroquinolina 1-óxido) em mucosa lingual de ratos WistarKitakawa, Dárcio [UNESP] 03 August 2006 (has links) (PDF)
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kitakawa_d_dr_sjc.pdf: 747579 bytes, checksum: a564a7ffad24123335cf349a22a13f34 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A carcinogênese em mucosa lingual de rato induzida pela 4-nitroquinolina 1-óxido (4NQO) é um modelo interessante para o estudo da evolução do carcinoma epidermóide fase por fase. Considerando-se que a apoptose tem um papel importante na carcinogênese, o objetivo deste trabalho foi investigar a expressão da survivina, membro da família das proteínas inibidoras de apoptose, através da imunoistoquímica, durante o ensaio de carcinogênese lingual induzida pela 4NQO. Ratos Wistar do sexo masculino foram divididos em três grupos de 10 animais cada e tratados com 50 ppm de 4NQO na água de beber durante quatro, 12 e 20 semanas. Um total de 10 animais foi utilizado como controle negativo. Embora não tenha sido observada alteração histopatológica após 4 semanas de exposição ao carcinógeno, detectou-se survivina no citoplasma das células das camadas granulares e superficiais do epitélio. Nas lesões com atipias após 12 semanas de exposição ao carcinógeno, observou-se survivina citoplasmática apenas na camada superficial do epitélio. Nos carcinomas epidermóides bem diferenciados induzidos após 20 semanas de tratamento com a 4NQO, detectou-se a expressão de survivina citoplasmática nas células adjacentes as pérolas córneas. Não houve imunorreatividade no grupo controle negativo. Diante destes achados, os resultados sugerem que a expressão da survivina citoplasmática é um evento inicial durante a carcinogênese lingual de ratos induzida pela 4NQO, e pode ser uma ferramenta interessante para a identificação de lesões com grande risco de progredir para carcinoma epidermóide das estruturas de revestimento bucal. / 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinogenesis is a useful model for studying the development of squamous cell carcinoma phase by phase. Taking into consideration apoptosis plays an important role in tumorigenesis, the aim of this study was to investigate the expressivity of survivin, a member of the inhibitor apoptotic protein family, during tongue carcinogenesis induced by 4NQO through immunohistochemistry. Male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO by drinking water for four, 12 or 20 weeks. A total of ten animals were used as negative control. Although no histological changes were induced in the epithelium after 4 weeds of carcinogen exposure, survivin was detected in the cytoplasm within granular and superficial layers. In dysplastic lesions with 12 weeks of carcinogen exposure, cytoplasmic survivin was evidenced in the superficial layer of epithelium only. In well-differetiated squamous cell carcinoma induced after 20 weeks of treatment with 4NQO, cytoplasmic survivin was expressed in some cells adjacent to keratin pearls. No immunoreativity was detected in the negative control group. Taken together, our results suggest that expression of cytoplasmic/nuclear survivin is an early event during 4NQO-induced rat tongue carcinogenesis and may provide a useful toll for the identification of lesions at higher risk of progression into oral squamous cell carcinoma.
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The MEN 1 Pancreas : Tumor Development and HaploinsufficiencyHalin Lejonklou, Margareta January 2012 (has links)
Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization. We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas. Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets. Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals. It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.
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The role of inhibitor of apoptosis (IAP) family member survivin in prostatic diseaseMcIlwain, David W. 23 June 2017 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Continual and recalcitrant inflammation is an extremely common condition
in the human prostate and has been found to be associated with a number of
prostatic diseases including prostate cancer and benign prostatic hyperplasia
(BPH). While much has been described regarding prostate disease resulting from
oxygen and nitrogen radicals during inflammation, proliferative mechanisms
associated with repair and regeneration are less understood. The Inhibitor of
Apoptosis (IAP) family member survivin has been found to be overexpressed
during inflammation and associated with prostate cancer progression.
Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a
multifunctional protein that is essential in activating inflammatory transcription
factors. Because APE1/Ref-1 is expressed and elevated in prostate cancer, we
sought to characterize APE1/Ref-1 expression and activity in human prostate
cancer cell lines and determine the effect of selective reduction-oxidation (redox)
function inhibition on prostate cancer cells in vitro and in vivo. Due to the role of
inflammatory transcriptional activators NFĸB and STAT3 in survivin protein
expression, and APE1/Ref-1 redox activity regulating their transcriptional activity,
we assessed selective inhibition of APE1/Ref-1’s redox function as a novel method to halt prostate cancer cell growth and survival. Our study demonstrates
that survivin and APE1/Ref-1 are significantly higher in human prostate cancer
specimens compared to noncancerous controls and that APE1/Ref-1 redox
specific inhibition with small molecule inhibitors APX3330 and APX2009
decreases prostate cancer cell proliferation and induces cell cycle arrest.
Inhibition of APE1/Ref-1 redox function significantly reduced NFĸB transcriptional
activity, survivin mRNA and survivin protein levels. These data indicate that
APE1/Ref-1 is a key regulator of survivin and a potentially viable target in
prostate cancer.
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Optimization of Survivin Dimerization Inhibitors for the Treatment of Docetaxel-Resistant Prostate CancerPeery, Robert Craig 01 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Despite therapeutic advancements, prostate cancer remains the second
most common cause of cancer-related mortality in men. Docetaxel is the first
cytotoxic agent to show modest improvements in overall survival rate in patients
with metastatic prostate cancer. Unfortunately, over half of these patients do not
respond to treatment and ultimately all develop resistance. The mechanism
mediating docetaxel resistance remains unknown. Survivin has a classical
biological role in cancer, in fact survivin has been shown to be overexpressed in
almost every solid tumor and is associated with drug resistance and clinically
aggressive disease. In these studies I demonstrate that docetaxel resistant cells
have overexpression of survivin compared to sensitive parental cells, knockdown
of survivin decreases docetaxel resistance, and stable overexpression of survivin
increases resistance to docetaxel. The data in these studies suggest that survivin
is likely implicated in docetaxel resistance and treatment with a direct survivin
inhibitor may sensitize resistant cells to docetaxel. To this end the evaluation and
optimization of two different backbones of survivin inhibitors was performed. One
such inhibitor identified is LQZ-7-3 which decreases survivin level via
proteasome degradation, leads to apoptosis of cells, and showed efficacy in a
prostate cancer xenograft model in vivo when given in an oral formulation. LQZ-
7-3 showed strong specificity to survivin versus other IAP family members at the
protein level. Another inhibitor, LQZ-7F-1, demonstrated nanomolar inhibition of cancer cell growth and similar effects on survivin. Both compounds synergized
with docetaxel in vitro warranting future in vivo efficacy studies as a combinatorial
therapy. Overall, our findings indicate survivin is a significant contributor to
docetaxel resistance in metastatic prostate cancer at the molecular level and
survivin inhibitors may prove efficacious as a new therapy to sensitize cancer
cells to chemotherapies.
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Small Molecule Inhibitors asAnticancer AgentsBhasin, Deepak 21 July 2011 (has links)
No description available.
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Le rôle des protéines apoptotiques dans la physiophathologie de la sclérose systémique chez l'humainParadis, Martin January 2003 (has links)
Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.
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Investigations of equine sarcoids and bovine papillomavirus in Western CanadaWobeser, Bruce 25 February 2011
Equine sarcoids are the most common skin tumors of horses. Despite being such a common entity, relatively little is known about many features of sarcoid epidemiology or growth. In addition, due to the detection of Bovine Papillomavirus (BPV) DNA of 2 different types, BPV type 1 (BPV1) and BPV type 2 (BPV2), in equine sarcoids BPV has been suggested as the causative agent of sarcoid development. Recently, however, BPV DNA has also been detected in other skin conditions of horses; the significance of this is unclear. Multiple studies to learn more about sarcoids were undertaken.<p>
To investigate the epidemiology of sarcoids in horses in Western Canada the records of five veterinary diagnostic laboratories were searched to identify submissions of sarcoids from horses. The submission record and diagnostic reports of 802 separate submissions of equine sarcoids were reviewed for age, breed, and gender of the horse and the number, location and clinical type of sarcoid. Based on these submissions, horses of a wide variety of ages and 23 different equine breeds were affected, within these breeds, Donkeys were overrepresented.<p>
The presence of BPV was determined by Polymerase Chain Reaction (PCR). BPV was found in 74 of 96 (77.1%) samples, and using Restriction Fragment Length Polymorphism, BPV1 and BPV2 were identified in these samples. BPV2 was present in 59 (79.7%) of these. Unlike other areas in the world, in Western Canada, equine sarcoids are most commonly associated with BPV2.<p>
A second study examined different clinical types of sarcoids to determine if there was differential expression of immunohistochemical markers associated with apoptosis, Cleaved Caspase 3(ClC3), and antiapoptotic factors, B-Cell Lymphoma 2 (Bcl-2) and Survivin. No differences in the expression of any of these markers regardless of BPV type were noted. Survivin was expressed in equine sarcoids of all types and increased levels of expression are associated with more aggressive clinical behaviour.<p>
Finally, the location of BPV DNA was determined in both sarcoids and a variety of non-sarcoid inflammatory skin conditions of horses, as well as, normal skin. PCR for BPV DNA was performed on 86 skin biopsies from horses with non-sarcoid skin conditions, as well as, normal skin. BPV DNA was present in 41 of 86 biopsies. These positive samples, in addition to BPV positive sarcoid samples from the earlier study, were dissected into tissue compartments using laser microdissection followed by 2 forms of BPV DNA amplification, PCR and isothermal loop mediated amplification. BPV DNA was more often located in the epidermis of non-sarcoid skin conditions than in sarcoids. In addition, areas of inflammation within the dermis and epidermis were more likely to contain BPV DNA than non-inflamed areas. These results suggest that while BPV is commonly found in equine skin, the location where it is found differs between sarcoids and non-sarcoid samples. When BPV DNA was found in non-sarcoid samples, it was commonly associated with inflammation suggesting that microscopic damage to the epidermal barrier of the skin maybe an adequate predisposing factor to the development of sarcoids.
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Investigations of equine sarcoids and bovine papillomavirus in Western CanadaWobeser, Bruce 25 February 2011 (has links)
Equine sarcoids are the most common skin tumors of horses. Despite being such a common entity, relatively little is known about many features of sarcoid epidemiology or growth. In addition, due to the detection of Bovine Papillomavirus (BPV) DNA of 2 different types, BPV type 1 (BPV1) and BPV type 2 (BPV2), in equine sarcoids BPV has been suggested as the causative agent of sarcoid development. Recently, however, BPV DNA has also been detected in other skin conditions of horses; the significance of this is unclear. Multiple studies to learn more about sarcoids were undertaken.<p>
To investigate the epidemiology of sarcoids in horses in Western Canada the records of five veterinary diagnostic laboratories were searched to identify submissions of sarcoids from horses. The submission record and diagnostic reports of 802 separate submissions of equine sarcoids were reviewed for age, breed, and gender of the horse and the number, location and clinical type of sarcoid. Based on these submissions, horses of a wide variety of ages and 23 different equine breeds were affected, within these breeds, Donkeys were overrepresented.<p>
The presence of BPV was determined by Polymerase Chain Reaction (PCR). BPV was found in 74 of 96 (77.1%) samples, and using Restriction Fragment Length Polymorphism, BPV1 and BPV2 were identified in these samples. BPV2 was present in 59 (79.7%) of these. Unlike other areas in the world, in Western Canada, equine sarcoids are most commonly associated with BPV2.<p>
A second study examined different clinical types of sarcoids to determine if there was differential expression of immunohistochemical markers associated with apoptosis, Cleaved Caspase 3(ClC3), and antiapoptotic factors, B-Cell Lymphoma 2 (Bcl-2) and Survivin. No differences in the expression of any of these markers regardless of BPV type were noted. Survivin was expressed in equine sarcoids of all types and increased levels of expression are associated with more aggressive clinical behaviour.<p>
Finally, the location of BPV DNA was determined in both sarcoids and a variety of non-sarcoid inflammatory skin conditions of horses, as well as, normal skin. PCR for BPV DNA was performed on 86 skin biopsies from horses with non-sarcoid skin conditions, as well as, normal skin. BPV DNA was present in 41 of 86 biopsies. These positive samples, in addition to BPV positive sarcoid samples from the earlier study, were dissected into tissue compartments using laser microdissection followed by 2 forms of BPV DNA amplification, PCR and isothermal loop mediated amplification. BPV DNA was more often located in the epidermis of non-sarcoid skin conditions than in sarcoids. In addition, areas of inflammation within the dermis and epidermis were more likely to contain BPV DNA than non-inflamed areas. These results suggest that while BPV is commonly found in equine skin, the location where it is found differs between sarcoids and non-sarcoid samples. When BPV DNA was found in non-sarcoid samples, it was commonly associated with inflammation suggesting that microscopic damage to the epidermal barrier of the skin maybe an adequate predisposing factor to the development of sarcoids.
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