pinecone/core-2020-05-10-deduplication huggingface dataset:
A novel canine model for prostate cancer

BACKGROUND  No existing animal model fully recapitulates all features of human prostate cancer. The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer. Canine prostate cancer features many similarities with its human counterpart. We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models.    METHODS  The Ace‐1 canine prostate cancer cell line was injected transabdominally under transrectal ultrasound (TRUS) guidance into the prostates of immunosuppressed, intact, adult male dogs. Tumor progression was monitored by TRUS imaging. Some dogs were subjected to positron emission tomography (PET) for tumor detection. Time of euthanasia was determined based on tumor size, impingement on urethra, and general well‐being. Euthanasia was followed by necropsy and histopathology.    RESULTS  Ace‐1 tumor cells grew robustly in every dog injected. Tumors grew in subcapsular and parenchymal regions of the prostate. Tumor tissue could be identified using PET. Histological findings were similar to those observed in human prostate cancer. Metastases to lungs and lymph nodes were detected, predominantly in dogs with intraprostatic tumors.    CONCLUSIONS  We have established a minimally invasive dog model of prostate cancer. This model may be valuable for studying prostate cancer progression and distant metastasis. Prostate 73: 952–959, 2013. © 2013 Wiley Periodicals, Inc
Obesity‐induced diabetes and lower urinary tract fibrosis promote urinary voiding dysfunction in a mouse model

BACKGROUND  Progressive aging‐ and inflammation‐associated fibrosis effectively remodels the extracellular matrix (ECM) to increase prostate tissue stiffness and reduce urethral flexibility, resulting in urinary flow obstruction and lower urinary tract symptoms (LUTS). In the current study, we sought to test whether senescence‐accelerated mouse prone (SAMP)6 mice, which were reported to develop prostatic fibrosis, would also develop LUTS, and whether these symptoms would be exacerbated by diet‐induced obesity and concurrent Type 2 Diabetes Mellitus (T2DM).    METHODS  To accomplish this, SAMP6 and AKR/J background strain mice were fed regular mouse chow, low fat diet chow, or high fat diet chow for 8 months, then subjected to glucose tolerance tests, assessed for plasma insulin levels, evaluated for urinary voiding function, and assessed for lower urinary tract fibrosis.    RESULTS  The results of these studies show that SAMP6 mice and AKR/J background strain mice develop diet‐induced obesity and T2DM concurrent with urinary voiding dysfunction. Moreover, urinary voiding dysfunction was more severe in SAMP6 than AKR/J mice and was associated with pronounced prostatic and urethral tissue fibrosis.    CONCLUSIONS  Taken together, these studies suggest that obesity, T2DM, lower urinary tract fibrosis, and urinary voiding dysfunction are inextricably and biologically linked. Prostate 73: 1123–1133, 2013. © 2013 Wiley Periodicals, Inc
Exogenous  SPARC  Suppresses Proliferation and Migration of Prostate Cancer by Interacting With Integrin β1

BACKGROUND  The matricellular protein secreted protein acidic and rich in cysteine (SPARC) plays an important role on tumor metastasis and progression in several cancers. However, the roles of SPARC in prostate cancer (PCa) remain unclear.    METHODS  To identify SPARC protein in prostate tissue, immunohistochemical analysis of SPARC was conducted using human prostate tissue microarray. To detect SPARC expression in prostate cancer (LNCaP, DU145, and PC‐3) and stromal cells, RT‐PCR, western blot analysis, and ELISA was conducted. To reveal the function of exogenous SPARC in PCa cells, AKT phosphorylation was confirmed by western blot analysis after coculture with stromal cells. Proliferation and migration of PCa cells were examined by addition of SPARC. The interaction between SPARC and integrin β1 was confirmed by western blot analysis after immunoprecipitation.    RESULTS  SPARC protein was expressed well in normal tissue compared with PCa tissue. ELISA showed high secreted SPARC protein in normal prostate‐derived stromal cell (PrSC) compared with PCa‐derived stromal cell (PCaSC) and PCa. PCa cells cocultured with PrSC showed reduced AKT phosphorylation more than with PCaSC. PCa cells cocultured with PrSC whose SPARC was knocked‐down restored AKT phosphorylation. Moreover, PCa cells treated with SPARC led to reduced AKT phosphorylation. Immunoprecipitation with SPARC revealed interaction of SPARC and integrin β1 in PCa cells. Inhibited proliferation and migration of PCa cells by SPARC was restored by integrin β1 neutralizing antibody.    CONCLUSIONS  Reduced SPARC secretion from stromal cells might affect PCa progression mediating through limiting AKT phosphorylation after interaction with integrin β1. Prostate 73: 1159–1170, 2013. © 2013 Wiley Periodicals, Inc
The E2F1/DNMT1 axis is associated with the development of AR negative castration resistant prostate cancer

BACKGROUND  Research on castration resistant prostate cancer (CRPC) has focused primarily on functional alterations of the androgen receptor (AR). However, little is known about the loss of AR gene expression itself and the possible contribution of AR negative cells to CRPC.    METHODS  Human and murine prostate cancer tissue microarrays (TMAs) were evaluated with antibodies specific for E2F1, DNA methyltransferase 1 or AR. The human prostate cancer TMA consisted of clinical samples ranging from normal tissue to samples of metastatic disease. The murine TMA was comprised of benign, localized or metastatic prostate cancer acquired from TRAMP mice treated with castration and/or 5′‐Aza‐2′‐deoxycytidine (5Aza).    RESULTS  Immunohistochemical analysis revealed increased nuclear DNMT1 staining in localized PCa ( P  < 0.0001) and metastatic PCa ( P  < 0.0001) compared to normal tissue. Examination of specific diagnoses revealed that Gleason seven tumors exhibited greater nuclear DNMT1 staining than Gleason six tumors ( P  < 0.05) and that metastatic tissue exhibited greater levels of nuclear DNMT1 than Gleason seven tumors ( P  < 0.01). Evaluation of the murine tissue cores revealed that 8.2% and 8.1% of benign tissue cores stained positive for E2F1 and DNMT1 respectively, while 97.0% were AR positive. Conversely, 81% and 100% of tumors were positive for E2F1and DNMT1 respectively. This was in stark contrast to only 18% of tumors positive for AR. Treatment of mice with 5Aza reduced DNMT1 staining by 30%, while AR increased by 27%.    CONCLUSIONS  These findings demonstrate that the E2F1/DNMT1 inhibitory axis of AR transcription is activated during the emergence of CRPC.  Prostate 73:1776–1785, 2013 . © 2013 Wiley Periodicals, Inc
p62/SQSTM1 is required for cell survival of apoptosis-resistant bone metastatic prostate cancer cell lines

BACKGROUND: Bone marrow stromal cell (BMSC) paracrine factor(s) can induce apoptosis in bone metastatic prostate cancer (PCa) cell lines. However, the PCa cells that escape BMSC-induced apoptosis can upregulate cytoprotective autophagy. METHODS: C4-2, C4-2B, MDA PCa 2a, MDA PCa 2b, VCaP, PC3, or DU145 PCa cell lines were grown in BMSC conditioned medium and analyzed for mRNA and/or protein accumulation of p62 (also known as sequestome-1/SQSTM1), Microtubule-associated protein 1 light chain 3B (LC3B), or lysosomal-associated membrane protein 1 (LAMP1) using quantitative polymerase chain reaction (QPCR), Western blot, or immunofluorescence. Small interfering RNA (siRNA) was used to determine if p62 is necessary PCa cell survival. RESULTS: BMSC paracrine signaling upregulated p62 mRNA and protein in a subset of the PCa cell lines. The PCa cell lines that were insensitive to BMSC-induced apoptosis and autophagy induction had elevated basal p62 mRNA and protein. In the BMSC-insensitive PCa cell lines, siRNA knockdown of p62 was cytotoxic and immunostaining showed peri-nuclear clustering of autolysosomes. However, in the BMSC-sensitive PCa cell lines, p62 siRNA knockdown was not appreciably cytotoxic and did not affect autolysosome subcellular localization. CONCLUSIONS: A pattern emerges wherein the BMSC-sensitive PCa cell lines are known to be osteoblastic and express the androgen receptor, while the BMSC-insensitive PCa cell lines are characteristically osteolytic and do not express the androgen receptor. Furthermore, BMSC-insensitive PCa may have evolved a dependency on p62 for cell survival that could be exploited to target and kill these apoptosis-resistant PCa cells in the bone
Clinical presentation of prostate cancer in Black South Africans

BACKGROUND : Compared with White Americans, Black American men are at a significant increased risk of presenting with prostate cancer (PCa) and associated mortality, suggesting a link to African-ancestry. However, PCa status within Africa is largely unknown. We address the clinical presentation of PCa within Black South African men. METHODS : Over 1,000 participants with or without PCa have enrolled in the Southern African Prostate Cancer Study (SAPCS). Using genome-wide profiling we establish a unique within Africa population substructure. Adjusting for age, clinical variables were assessed,compared against Black Americans and between rural and urban localities while addressing potential socio-demographic confounders.
RESULTS. We report a significant difference in the distribution of prostate specific antigen
(PSA) levels skewed towards higher PSA levels in the PCa cases (83.0% present with a
PSA 20mg/L; median PSA¼98.8mg/L) relative to men with no detectable PCa (18.5%
present with a PSA 20mg/L; median PSA¼9.1mg/L). Compared with Black Americans,
Black South Africans presented with significantly more aggressive disease defined by Gleason score >7 (17% and 36%, respectively) and PSA 20mg/L (17.2% and 83.2%, respectively). We report exasperated disease aggression defined by Gleason score >7 (P¼0.0042) and poorly differentiated tumor grade (P<0.0001) within rural versus urban localities. CONCLUSION : Black South African men present with higher PSA levels and histopathological tumor grade compared with Black Americans, which is further escalated in men from rural localities. Our data suggests that lack of PSA testing may be contributing to an aggressive PCa disease phenotype within South African men.Medical Research Council (MRC) of South Africa, Unistel Medical Laboratories, South Africa, Cancer Institute of New South Wales, Australia, National Health and Medical Research Council of Australia, National Institute of Health,#CA170081, Venter Family Fund, CA, U.S.A, Petre Foundation Australia.http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-0045hb201
Up-regulation of miR-582-5p regulates cellular proliferation of prostate cancer cells under androgen-deprived conditions.

[BACKGROUND]MicroRNAs are noncoding small RNA that negatively regulate target gene expression by binding to the 3′-UTR of mRNA. Previous studies have shown that several microRNAs play a pivotal role in prostate cancer by acting as oncogenes or tumor suppressors. This study was aimed at identifying microRNAs that contribute to the progression to castration resistant prostate cancer. [METHODS]MicroRNAs expression profiles of a xenograft model and cell lines were examined by microarray analysis and real-time PCR. Functional analysis of miR-582-5p in cellular proliferation was examined by cell counting. Furthermore, in order to investigate a candidate target of miR-582-5p, microarray analysis and analysis in silico were utilized. [RESULTS]MiR-582-5p was identified to be up-regulated at the castration resistant stage of a xenograft model, KUCaP2 and in castration resistant cell line, AILNCaP#1. Overexpression of miR-582-5p increased the number and the percentage of S phase of LNCaP cells under androgen deprived condition. Moreover, suppression of miR-582-5p decreased the number and the percentage of S phase of AILNCaP#1 cells. Furthermore, we identified that miR-582-5p down-regulates EFNB2 expression, which is down-regulated at the castration resistant stage of a xenograft model, KUCaP2 and in castration resistant cell line, AILNCaP#1. [CONCLUSIONS]Our results suggest that up-regulation of miR-582-5p contributes to an increase in the proliferation of prostate cancer cells under androgen deprived conditions
Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells.

This is the peer reviewed version of the following article: Yacqub-Usman, K., Pickard, M. R., & Williams, G. T. (2015). Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate, 75(7), 693-705. DOI: 10.1002/pros.22952, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/pros.22952/abstract;jsessionid=B9892067CCD9082275B1EFFFC59926F6.f02t02. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingBACKGROUND:\ud
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New therapies are required for castrate-resistant prostate cancer (CRPC), and growth-arrest specific 5 (GAS5) lncRNA, which riborepresses androgen receptor action, may offer novel opportunities in this regard. This lncRNA promotes the apoptosis of prostate cancer cells and its levels decline as prostate cancer cells acquire castrate-resistance, so that enhancing GAS5 expression may improve the effectiveness of chemotherapies. Since GAS5 is a member of the 5' terminal oligopyrimidine gene family, we have examined mTOR inhibition as a strategy to increase GAS5 expression. Furthermore, we have determined if GAS5 itself mediates the action of mTOR inhibitors, as demonstrated for other chemotherapeutic agents in prostate cancer cells.\ud
METHODS:\ud
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The effects of mTOR inhibitors on GAS5 lncRNA levels and cell growth were determined in a range of prostate cancer cell lines. Transfection of cells with GAS5 siRNAs and plasmid constructs was performed to determine the involvement of GAS5 lncRNA in mTOR inhibitor action.\ud
RESULTS:\ud
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First generation mTORC1, combined mTORC1/mTORC2 and dual PI3K/mTOR inhibitors all increased cellular GAS5 levels and inhibited culture growth in androgen-dependent (LNCaP) and androgen-sensitive (22Rv1) cell lines, but not in androgen-independent (PC-3 and DU 145) cell lines. The latter exhibited low endogenous GAS5 expression, and GAS5 silencing in LNCaP and 22Rv1 cells decreased the sensitivity to mTOR inhibitors, whereas transfection of GAS5 lncRNA sensitized PC-3 and DU 145 cells to these agents.\ud
CONCLUSION:\ud
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mTOR inhibition enhances GAS5 transcript levels in certain prostate cancer cell lines. This selectivity is likely to be related to endogenous GAS5 expression levels, since GAS5 lncRNA is itself required for mTOR inhibitor action in prostate cancer cells
Circulating total testosterone and PSA concentrations in a nationally representative sample of men without a diagnosis of prostate cancer

BACKGROUND  The association between serum sex steroid hormones and PSA in a general population has not been described.  METHODS  Included were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/ml per hormone quintile using logistic regression.  RESULTS  Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/ml was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment.  CONCLUSIONS  In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment
Decreased expression of lysophosphatidylcholine (16:0/OH) in high resolution imaging mass spectrometry independently predicts biochemical recurrence after surgical treatment for prostate cancer.

Article first published online: 1 SEP 2015[Background]Human prostate cancers are highly heterogeneous, indicating a need for various novel biomarkers to predict their prognosis. Lipid metabolism affects numerous cellular processes, including cell growth, proliferation, differentiation, and motility. Direct profiling of lipids in tissue using high-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry (HR-MALDI-IMS) may provide molecular details that supplement tissue morphology. [Methods]Prostate tissue samples were obtained from 31 patients, with localized prostate cancer who underwent radical prostatectomy. The samples were assessed by HR-MALDI-IMS in positive mode, with the molecules identified by tandem mass spectrometry (MS/MS). The effect of identified molecules on prostate specific antigen recurrence free survival after radical prostatectomy was determined by Cox regression analysis and by the Kaplan–Meier method. [Results]Thirteen molecules were found to be highly expressed in prostate tissue, with five being significantly lower in cancer tissue than in benign epithelium. MS/MS showed that these molecules were [lysophosphatidylcholine (LPC)(16:0/OH)+H]+, [LPC(16:0/OH)+Na]+, [LPC(16:0/OH)+K]+, [LPC(16:0/OH)+matrix+H]+, and [sphingomyelin (SM)(d18:1/16:0)+H]+. Reduced expression of LPC(16:0/OH) in cancer tissue was an independent predictor of biochemical recurrence after radical prostatectomy. [Conclusions]HR-MALDI-IMS showed that the expression of LPC(16:0/OH) and SM(d18:1/16:0) was lower in prostate cancer than in benign prostate epithelium. These differences in expression of phospholipids may predict prostate cancer aggressiveness, and provide new insights into lipid metabolism in prostate cancer
Spectrum of mitochondrial genomic variation and associated clinical presentation of prostate cancer in South African men

BACKGROUND : Prostate cancer incidence and mortality rates are significantly increased in
African–American men, but limited studies have been performed within Sub–Saharan
African populations. As mitochondria control energy metabolism and apoptosis we speculate
that somatic mutations within mitochondrial genomes are candidate drivers of aggressive
prostate carcinogenesis.
METHODS : We used matched blood and prostate tissue samples from 87 South African men
(77 with African ancestry) to perform deep sequencing of complete mitochondrial genomes.
Clinical presentation was biased toward aggressive disease (Gleason score >7, 64%), and
compared with men without prostate cancer either with or without benign prostatic hyperplasia.
RESULTS : We identified 144 somatic mtDNA single nucleotide variants (SNVs), of which 80
were observed in 39 men presenting with aggressive disease. Both the number and frequency
of somatic mtDNA SNVs were associated with higher pathological stage.
CONCLUSIONS : Besides doubling the total number of somatic PCa-associated mitochondrial
genome mutations identified to date, we associate mutational load with aggressive
prostate cancer status in men of African ancestry.NIH R21- CA170081, Australian Prostate Cancer Research Centre NSW, the J. Craig Venter Institute, the Garvan Institute, the Petre Foundation, Australia, the Cancer Association of South Africa (CANSA).http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-0045hb201
Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients

Background: Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. 
Methods: In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. 
Results: The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n=47) were higher than in controls (n=30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values <0.02) and did not reach the median survival point. The survival distributions for the groups were statistically significant for the cfDNA concentration, GSTP1 and APC copies, as well as PSA combined with GSTP1+APC (P-values <0.03). Furthermore, there were strong positive correlations between PSA and marker response after starting treatment (P-values <0.04). 
Conclusions: In conclusion, this study showed the kinetics of methylated cfDNA (GSTP1 and APC) in plasma of CRPC patients after starting treatment. Furthermore, the value of the markers before treatment is prognostic for overall survival. These results are promising for developing a test to guide treatment-decision-making for CRPC patients
Effect of culture conditions on androgen sensitivity of the human prostatic cancer cell line LNCaP

Several effects of androgens on LNCaP-FGC prostate tumor cells showed a biphasic pattern. Stimulation of growth and inhibition of secretion of prostatic acid phosphatase (PAP) was observed at low androgen concentrations (below 1 nM of the synthetic androgen R1881), and inhibition of growth and stimulation of PAP secretion was observed at higher concentrations. In contrast, prostate specific antigen (PSA) secretion did not show this biphasic response pattern. Comparable effects were found for two sublines of the LNCaP-FGC cells: an early (passage 20, androgen-dependent) and relatively late (passage 70, androgen-sensitive) passage of the cells. Culturing of both sublines in the presence of a high concentration of androgens (10 nM R1881) resulted initially in a decrease in growth rate, but the cells started to proliferate within 3 weeks. These cells became less sensitive to androgens, lost their biphasic response pattern, and showed reduced androgen receptor levels. Three weeks after removal of the excess of androgens, the passage 70 cells regained a biphasic growth response to androgens. Culture in medium without steroids but with EGF resulted in a decrease of both androgen sensitivity and androgen receptor level.\ud
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In conclusion, rapid changes of the androgen sensitivity and receptor level of the LNCaP cells occurred under the influence of culture conditions. These changes were partly reversible and, therefore, were most likely due to adaptation of the cells