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1.
BJU Int ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38961742

ABSTRACT

OBJECTIVES: To evaluate a cancer detecting artificial intelligence (AI) algorithm on serial biopsies in patients with prostate cancer on active surveillance (AS). PATIENTS AND METHODS: A total of 180 patients in the Prostate Cancer Research International Active Surveillance (PRIAS) cohort were prospectively monitored using pre-defined criteria. Diagnostic and re-biopsy slides from 2011 to 2020 (n = 4744) were scanned and analysed by an in-house AI-based cancer detection algorithm. The algorithm was analysed for sensitivity, specificity, and for accuracy to predict need for active treatment. Prognostic properties of cancer size, prostate-specific antigen (PSA) level and PSA density at diagnosis were evaluated. RESULTS: The sensitivity and specificity of the AI algorithm was 0.96 and 0.73, respectively, for correct detection of cancer areas. Original pathology report diagnosis was used as the reference method. The area of cancer estimated by the pathologists correlated highly with the AI detected cancer size (r = 0.83). By using the AI algorithm, 63% of the slides would not need to be read by a pathologist as they were classed as benign, at the risk of missing 0.55% slides containing cancer. Biopsy cancer content and PSA density at diagnosis were found to be prognostic of whether the patient stayed on AS or was discontinued for active treatment. CONCLUSION: The AI-based biopsy cancer detection algorithm could be used to reduce the pathologists' workload in an AS cohort. The detected cancer amount correlated well with the cancer length measured by the pathologist and the algorithm performed well in finding even small areas of cancer. To our knowledge, this is the first report on an AI-based algorithm in digital pathology used to detect cancer in a cohort of patients on AS.

2.
Eur Urol Focus ; 9(6): 983-991, 2023 11.
Article in English | MEDLINE | ID: mdl-37105783

ABSTRACT

BACKGROUND: Molecular signatures in prostate cancer (PCa) tissue can provide useful prognostic information to improve the understanding of a patient's risk of harbouring aggressive disease. OBJECTIVE: To develop and validate a gene signature that adds independent prognostic information to clinical parameters for better treatment decisions and patient management. DESIGN, SETTING, AND PARTICIPANTS: Expression of 14 genes was evaluated in radical prostatectomy (RP) tissue from an Irish cohort of PCa patients (n = 426). A six-gene molecular risk score (MRS) was identified with strong prognostic performance to predict adverse pathology (AP) at RP or biochemical recurrence (BCR). The MRS was combined with the Cancer of the Prostate Risk Assessment (CAPRA) score, to create a molecular and clinical risk score (MCRS), and validated in a Swedish cohort (n = 203). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary AP outcome was assessed by the likelihood ratio statistics and area under the receiver operating characteristics curves (AUC) from logistic regression models. The secondary time to BCR outcome was assessed by likelihood ratio statistics and C-indexes from Cox proportional hazard regression models. RESULTS AND LIMITATIONS: The six-gene signature was significantly (p < 0.0001) prognostic and added significant prognostic value to clinicopathological features for AP and BCR outcomes. For both outcomes, both the MRS and the MCRS increased the AUC/C-index when added to European Association of Urology (EAU) and CAPRA scores. Limitations include the retrospective nature of this study. CONCLUSIONS: The six-gene signature has strong performance for the prediction of AP and BCR in an independent clinical validation study. MCRS improves prognostic evaluation and can optimise patient management after RP. PATIENT SUMMARY: We found that the expression panel of six genes can help predict whether a patient is likely to have a disease recurrence after radical prostatectomy surgery.


Subject(s)
Neoplasm Recurrence, Local , Prostatic Neoplasms , Male , Humans , Retrospective Studies , Risk Assessment/methods , Neoplasm Recurrence, Local/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Prostate/pathology
3.
Pathol Res Pract ; 232: 153811, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35259550

ABSTRACT

BACKGROUND: The signal transducer and activator of transcription 3 (STAT3) is involved in the progression of different tumors including prostate cancer (PCa). The expression of STAT3 in benign and malignant epithelium has been described previously but it has not been described in the stromal compartment. The aim of the present study was to evaluate the nuclear expression and prognostic value of different forms of phosphorylated STAT3 in the stromal compartment of non-cancer and cancer areas of prostatic tissue. MATERIAL AND METHODS: Tissue microarray cores from radical prostatectomy of 225 patients with hormone-naïve localized PCa were immunostained for two phosphorylated forms of STAT3, pSTAT3Tyr705 and pSTAT3Ser727. The prognostic value of the expression levels was studied by Cox regression analysis and biochemical recurrence (BCR)-free survival illustrated by Kaplan-Meier curves. RESULTS: Expression of pSTAT3Tyr705 and pSTAT3Ser727 in the stromal compartment of cancer tissue was lower compared with non-cancer areas. In univariable and multivariable Cox regression analysis, expression levels of pSTAT3Tyr705 and STAT3Ser727 showed similar prognostic value as pathological T-stage, Gleason score and surgical margin status. Kaplan-Meier survival analysis showed that low nuclear expression levels of pSTAT3Tyr705 and pSTAT3Ser727 in stromal cells in cancer compartment and in non-cancer areas were related to BCR-free survival. CONCLUSIONS: Nuclear expression of pSTAT3Tyr705 and pSTAT3Ser727 in the stromal cells mirrors previous findings in the epithelial component in that it displays prognostic value in men undergoing radical prostatectomy for localized hormone-naïve PCa.


Subject(s)
Prostatic Neoplasms , STAT3 Transcription Factor , Hormones/metabolism , Humans , Male , Phosphorylation , Prognosis , Prostate/pathology , Prostatectomy , Prostatic Neoplasms/pathology , STAT3 Transcription Factor/metabolism
4.
EBioMedicine ; 65: 103269, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33706249

ABSTRACT

BACKGROUND: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed. METHODS: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns. FINDINGS: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR(95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59(1.49-8.62)) associations of the tumour stroma fraction with survival. INTERPRETATION: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance. FUNDING: The Swedish Cancer Society, The Lions Cancer Foundation Uppsala, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P.O.Zetterling Foundation, and The Sjöberg Foundation, Sweden.


Subject(s)
Machine Learning , Neoplasms/pathology , Humans , Neoplasms/mortality , Prognosis , Proportional Hazards Models , Retrospective Studies , Stromal Cells/pathology , Survival Analysis
5.
Eur Urol Focus ; 7(5): 995-1001, 2021 Sep.
Article in English | MEDLINE | ID: mdl-33303404

ABSTRACT

BACKGROUND: Gleason grading is the standard diagnostic method for prostate cancer and is essential for determining prognosis and treatment. The dearth of expert pathologists, the inter- and intraobserver variability, as well as the labour intensity of Gleason grading all necessitate the development of a user-friendly tool for robust standardisation. OBJECTIVE: To develop an artificial intelligence (AI) algorithm, based on machine learning and convolutional neural networks, as a tool for improved standardisation in Gleason grading in prostate cancer biopsies. DESIGN, SETTING, AND PARTICIPANTS: A total of 698 prostate biopsy sections from 174 patients were used for training. The training sections were annotated by two senior consultant pathologists. The final algorithm was tested on 37 biopsy sections from 21 patients, with digitised slide images from two different scanners. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Correlation, sensitivity, and specificity parameters were calculated. RESULTS AND LIMITATIONS: The algorithm shows high accuracy in detecting cancer areas (sensitivity: 100%, specificity: 68%). Compared with the pathologists, the algorithm also performed well in detecting cancer areas (intraclass correlation coefficient [ICC]: 0.99) and assigning the Gleason patterns correctly: Gleason patterns 3 and 4 (ICC: 0.96 and 0.94, respectively), and to a lesser extent, Gleason pattern 5 (ICC: 0.82). Similar results were obtained using two different scanners. CONCLUSIONS: Our AI-based algorithm can reliably detect prostate cancer and quantify the Gleason patterns in core needle biopsies, with similar accuracy as pathologists. The results are reproducible on images from different scanners with a proven low level of intraobserver variability. We believe that this AI tool could be regarded as an efficient and interactive tool for pathologists. PATIENT SUMMARY: We developed a sensitive artificial intelligence tool for prostate biopsies, which detects and grades cancer with similar accuracy to pathologists. This tool holds promise to improve the diagnosis of prostate cancer.


Subject(s)
Prostate , Prostatic Neoplasms , Artificial Intelligence , Automation , Biopsy , Humans , Image Interpretation, Computer-Assisted , Male , Neoplasm Grading , Prostate/pathology , Prostatic Neoplasms/pathology
6.
Cell Rep ; 32(12): 108181, 2020 09 22.
Article in English | MEDLINE | ID: mdl-32966797

ABSTRACT

Hemopexin (Hx) is a scavenger of labile heme. Herein, we present data defining the role of tumor stroma-expressed Hx in suppressing cancer progression. Labile heme and Hx levels are inversely correlated in the plasma of patients with prostate cancer (PCa). Further, low expression of Hx in PCa biopsies characterizes poorly differentiated tumors and correlates with earlier time to relapse. Significantly, heme promotes tumor growth and metastases in an orthotopic murine model of PCa, with the most aggressive phenotype detected in mice lacking Hx. Mechanistically, labile heme accumulates in the nucleus and modulates specific gene expression via interacting with guanine quadruplex (G4) DNA structures to promote PCa growth. We identify c-MYC as a heme:G4-regulated gene and a major player in heme-driven cancer progression. Collectively, these results reveal that sequestration of labile heme by Hx may block heme-driven tumor growth and metastases, suggesting a potential strategy to prevent and/or arrest cancer dissemination.


Subject(s)
Heme/metabolism , Hemopexin/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Cell Cycle , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation , DNA/genetics , Disease Progression , G-Quadruplexes , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasm Metastasis , Phenotype , Promoter Regions, Genetic/genetics , Prostatic Neoplasms/blood , Prostatic Neoplasms/genetics , Proto-Oncogene Proteins c-myc/metabolism , Treatment Outcome , Urokinase-Type Plasminogen Activator/metabolism
7.
Sci Rep ; 10(1): 9391, 2020 06 10.
Article in English | MEDLINE | ID: mdl-32523019

ABSTRACT

In Alzheimer's disease (AD) amyloid-ß (Aß) deposits may cause impairments in choroid plexus, a specialised brain structure which forms the blood-cerebrospinal fluid (CSF) barrier. We previously carried out a mass proteomic-based study in choroid plexus from AD patients and we found several differentially regulated proteins compared with healthy subjects. One of these proteins, annexin A5, was previously demonstrated implicated in blocking Aß-induced cytotoxicity in neuronal cell cultures. Here, we investigated the effects of annexin A5 on Aß toxicity in choroid plexus. We used choroid plexus tissue samples and CSF from mild cognitive impairment (MCI) and AD patients to analyse Aß accumulation, cell death and annexin A5 levels compared with control subjects. Choroid plexus cell cultures from rats were used to analyse annexin A5 effects on Aß-induced cytotoxicity. AD choroid plexus exhibited progressive reduction of annexin A5 levels along with progressive increased Aß accumulation and cell death as disease stage was higher. On the other hand, annexin A5 levels in CSF from patients were found progressively increased as the disease stage increased in severity. In choroid plexus primary cultures, Aß administration reduced endogenous annexin A5 levels in a time-course dependent manner and simultaneously increased annexin A5 levels in extracellular medium. Annexin A5 addition to choroid plexus cell cultures restored the Aß-induced impairments on autophagy flux and apoptosis in a calcium-dependent manner. We propose that annexin A5 would exert a protective role in choroid plexus and this protection is lost as Aß accumulates with the disease progression. Then, brain protection against further toxic insults would be jeopardised.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Annexin A5/metabolism , Blood-Brain Barrier/pathology , Choroid Plexus/physiology , Cognitive Dysfunction/metabolism , Neurons/pathology , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Animals , Apoptosis , Autophagy , Calcium/metabolism , Cells, Cultured , Cognitive Dysfunction/genetics , Female , Humans , Male , Middle Aged , Proteomics , Rats , Rats, Wistar
8.
Prostate ; 79(7): 784-797, 2019 05.
Article in English | MEDLINE | ID: mdl-30905090

ABSTRACT

BACKGROUND: The signal transducer and activator of transcription 3 (STAT3) pathway is observed to be constitutively activated in several malignancies including prostate cancer (PCa). In the present study, we investigated the expression of total STAT3 (tSTAT3) and two forms of activated phosphorylated STAT3 (pSTAT3727 and pSTAT3705 ) in tissue microarrays (TMA) of two cohorts of localized hormone-naïve PCa patients and analyzed associations between the expression and disease outcome. METHODS: The expression of tSTAT3, pSTAT3727 , and pSTAT3705 was scored in the nuclei and cytoplasm of prostatic gland epithelial cells in two TMAs of paraffin-embedded prostatic tissue. The TMAs consisted of tissue originated from hormone-naïve radical prostatectomy patients from two different sites: Malmö, Sweden (n = 300) and Dublin, Ireland (n = 99). RESULTS: The nuclear expression levels of tSTAT3, pSTAT3727 , and pSTAT3705 in the epithelial cells of benign glands were significantly higher than in the cancerous glands. Cytoplasmic tSTAT3 levels were also higher in benign glands. Patients with low pSTAT3727 and pSTAT3705 levels in the cancerous glands showed reduced times to biochemical recurrence, compared with those with higher levels. No significant trends in nuclear nor in cytoplasmic tSTAT3 were observed in relation to biochemical recurrence in the Malmö cohort. Higher cytoplasmic tSTAT3 was associated with reduced time to biochemical recurrence in the Dublin cohort. Adding the tSTAT3 and pSTAT3 expression data to Gleason score or pathological T stage did not improve their prognostic values. CONCLUSIONS: Low pSTAT3727 and pSTAT3705 expression in epithelial cells of cancerous prostatic glands in hormone-naïve PCa was associated with faster disease progression. However, pSTAT3 and tSTAT3 expression did not improve the prognostic value of Gleason score or pathological T stage and may not be a good biomarker in the early hormone naïve stages of PCa.


Subject(s)
Epithelial Cells/metabolism , Prostate/metabolism , Prostatic Neoplasms/metabolism , STAT3 Transcription Factor/biosynthesis , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/metabolism , Humans , Male , Middle Aged , Phosphorylation , Prostate/chemistry , Prostate/surgery , Prostatectomy , Prostatic Neoplasms/chemistry , Prostatic Neoplasms/surgery , STAT3 Transcription Factor/analysis , STAT3 Transcription Factor/metabolism , Tissue Array Analysis
9.
Front Neuroanat ; 13: 102, 2019.
Article in English | MEDLINE | ID: mdl-31969808

ABSTRACT

Reelin is a large extracellular matrix (ECM) glycoprotein secreted by several neuronal populations in a specific manner in both the developing and the adult central nervous system. The extent of Reelin protein distribution and its functional role in the adult neocortex is well documented in different mammal models. However, its role in the adult spinal cord has not been well characterized and its distribution in the rodent spinal cord is fragmentary and has not been investigated in carnivores or primates as of yet. To gain insight into which neuronal populations and specific circuits may be influenced by Reelin in the adult spinal cord, we have conducted light and confocal microscopy study analysis of Reelin-immunoreactive cell types in the adult spinal cord. Here, we describe and compare Reelin immunoreactive cell type and distribution in the spinal cord of adult non-human primate (macaque monkeys, Macaca mulatta), carnivore (ferret, Mustela putorius) and rodent (rat, Rattus norvegicus). Our results show that in all three species studied, Reelin-immunoreactive neurons are present in the intermediate gray matter, ventricular zone and superficial dorsal horn and intermedio-lateral nucleus, while positive cells in the Clarke nucleus are only found in rats and primates. In addition, Reelin intermediolateral neurons colocalize with choline acetyltransferase (ChAT) only in macaque whilst motor neurons also colocalize Reelin and ChAT in macaque, ferret and rat spinal cord. The different expression patterns might reflect a differential role for Reelin in the pathways involved in the coordination of locomotor activity in the fore- and hind limbs.

10.
Clin Cancer Res ; 25(2): 595-608, 2019 01 15.
Article in English | MEDLINE | ID: mdl-30274982

ABSTRACT

PURPOSE: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.Experimental Design: We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. RESULTS: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. CONCLUSIONS: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.


Subject(s)
Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Proteogenomics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Animals , Carcinoma, Neuroendocrine/pathology , Cell Cycle/genetics , Cell Line, Tumor , Computational Biology/methods , Disease Models, Animal , Disease Susceptibility , Gene Expression Profiling , Heterografts , Humans , Male , Mice , Proportional Hazards Models , Prostatectomy , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/surgery , Proteogenomics/methods
11.
PLoS One ; 12(9): e0184418, 2017.
Article in English | MEDLINE | ID: mdl-28886116

ABSTRACT

Prostate cancer patients with high WNT5A expression in their tumors have been shown to have more favorable prognosis than those with low WNT5A expression. This suggests that reconstitution of Wnt5a in low WNT5A-expressing tumors might be an attractive therapeutic approach. To explore this idea, we have in the present study used Foxy-5, a WNT5A mimicking peptide, to investigate its impact on primary tumor and metastasis in vivo and on prostate cancer cell viability, apoptosis and invasion in vitro. We used an in vivo orthotopic xenograft mouse model with metastatic luciferase-labeled WNT5A-low DU145 cells and metastatic luciferase-labeled WNT5A-high PC3prostate cancer cells. We provide here the first evidence that Foxy-5 significantly inhibits the initial metastatic dissemination of tumor cells to regional and distal lymph nodes by 90% and 75%, respectively. Importantly, this effect was seen only with the WNT5A-low DU145 cells and not with the WNT5A-high PC3 cells. The inhibiting effect in the DU145-based model occurred despite the fact that no effects were observed on primary tumor growth, apoptosis or proliferation. These findings are consistent with and supported by the in vitro data, where Foxy-5 specifically targets invasion without affecting apoptosis or viability of WNT5A-low prostate cancer cells. To conclude, our data indicate that the WNT5A-mimicking peptide Foxy-5, which has been recently used in a phase 1 clinical trial, is an attractive candidate for complimentary anti-metastatic treatment of prostate cancer patients with tumors exhibiting absent or low WNT5A expression.


Subject(s)
Molecular Mimicry , Oligopeptides/pharmacology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Wnt-5a Protein/chemistry , Wnt-5a Protein/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Humans , Male , Mice , Neoplasm Metastasis , Prostatic Neoplasms/drug therapy , Xenograft Model Antitumor Assays
12.
Eur Urol ; 71(3): 313-316, 2017 03.
Article in English | MEDLINE | ID: mdl-27344294

ABSTRACT

STAT3 and its upstream activator IL6R have been implicated in the progression of prostate cancer and are possible future therapeutic targets. We analyzed 223 metastatic samples from rapid autopsies of 71 patients who had died of castration-resistant prostate cancer (CRPC) to study protein and gene expression of pSTAT3 and IL6R. Immunohistochemical analysis revealed that 95% of metastases were positive for pSTAT3 and IL6R, with varying expression levels. Bone metastases showed significantly higher expression of both pSTAT3 and IL6R in comparison to lymph node and visceral metastases. STAT3 mRNA levels were significantly higher in bone than in lymph node and visceral metastases, whereas no significant difference in IL6R mRNA expression was observed. Our study strongly supports the suggested view of targeting STAT3 as a therapeutic option in patients with metastatic CRPC. PATIENT SUMMARY: We studied the levels of two proteins (pSTAT3 and IL6R) in metastases from patients who died from castration-resistant prostate cancer. We found high levels of pSTAT3and IL6R in bone metastases, suggesting that these proteins could be used as targets for new anticancer drugs.


Subject(s)
Adenocarcinoma/genetics , Benzamides/metabolism , Bone Neoplasms/genetics , Liver Neoplasms/genetics , Piperidines/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Interleukin-6/genetics , STAT3 Transcription Factor/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/secondary , Autopsy , Bone Neoplasms/metabolism , Bone Neoplasms/secondary , Humans , Immunohistochemistry , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Lymph Nodes/metabolism , Lymphatic Metastasis , Male , Neoplasm Metastasis , Phosphoproteins/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Interleukin-6/metabolism , STAT3 Transcription Factor/metabolism , Transcriptome
13.
PLoS One ; 11(6): e0156497, 2016.
Article in English | MEDLINE | ID: mdl-27275582

ABSTRACT

BACKGROUND: Natural killer (NK) cells and NK T cells (NKT) are vital parts of tumour immunosurveillance. However, their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, has not yet been described. METHODS: Immune cell-specific expression of CD56, CD3, CD68 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (I-type) morphology. Kaplan-Meier and Cox regression analysis were applied to determine the impact of CD56+ NK/NKT cells on 5-year overall survival (OS). RESULTS: High density of CD56+ NK/NKT cells correlated with low N-stage and lack of perineural, lymphatic vessel and peripancreatic fat invasion. High density of CD56+ NK/NKT cells was associated with prolonged OS in Kaplan-Meier analysis (p = 0.003), and in adjusted Cox regression analysis (HR = 0.49; 95% CI 0.29-0.86). The prognostic effect of high CD56+ NK/NKT cell infiltration was only evident in cases not receiving adjuvant chemotherapy in PB-type tumours (p for interaction = 0.014). CONCLUSION: This study demonstrates that abundant infiltration of CD56+ NK/NKT cells is associated with a prolonged survival in periampullary adenocarcinoma. However, the negative interaction with adjuvant treatment is noteworthy. NK cell enhancing strategies may prove to be successful in the management of these cancers.


Subject(s)
Adenocarcinoma , Intestinal Neoplasms , Killer Cells, Natural , Natural Killer T-Cells , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Antigens, CD/immunology , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Intestinal Neoplasms/drug therapy , Intestinal Neoplasms/immunology , Intestinal Neoplasms/mortality , Intestinal Neoplasms/pathology , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Male , Natural Killer T-Cells/immunology , Natural Killer T-Cells/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Survival Rate
14.
J Histochem Cytochem ; 64(5): 311-22, 2016 05.
Article in English | MEDLINE | ID: mdl-27026295

ABSTRACT

Androgen receptor (AR) and prostate-specific antigen (PSA) are expressed in the prostate and are involved in prostate cancer (PCa). The aim of this study was to develop reliable protocols for reproducible quantification of AR and PSA in benign and malignant prostate tissue using time-resolved fluorescence (TRF) imaging techniques. AR and PSA were detected with TRF in tissue microarrays from 91 PCa patients. p63/ alpha-methylacyl-CoA racemase (AMACR) staining on consecutive sections was used to categorize tissue areas as benign or cancerous. Automated image analysis was used to quantify staining intensity. AR intensity was significantly higher in AMACR+ and lower in AMACR- cancer areas as compared with benign epithelium. The PSA intensity was significantly lower in cancer areas, particularly in AMACR- glands. The AR/PSA ratio varied significantly in the AMACR+ tumor cells as compared with benign glands. There was a trend of more rapid disease progression in patients with higher AR/PSA ratios in the AMACR- areas. This study demonstrates the feasibility of developing reproducible protocols for TRF imaging and automated image analysis to study the expression of AR and PSA in benign and malignant prostate. It also highlighted the differences in AR and PSA protein expression within AMACR- and AMACR+ cancer regions.


Subject(s)
Prostate-Specific Antigen/metabolism , Prostate/metabolism , Prostatic Neoplasms/metabolism , Receptors, Androgen/metabolism , Aged , Feasibility Studies , Fluorescent Antibody Technique, Direct , Humans , Male , Middle Aged , Neoplasm Grading , Prostate/pathology , Prostatic Neoplasms/pathology , Tissue Array Analysis
15.
Eur Urol ; 69(3): 400-4, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26144873

ABSTRACT

UNLABELLED: Signal transducer and activator of transcription 3 (STAT3) is known to be involved in the progression of prostate cancer (PCa) and is a key factor in drug resistance and tumor immunoescape. As a result, it represents a promising target for PCa therapy. We studied the effects of the STAT3 inhibitor galiellalactone (GL) on tumor growth and metastatic spread in vitro and in vivo. The effect of GL on cell viability, apoptosis, and invasion was studied in vitro using androgen-independent DU145 and DU145-Luc cell lines. For in vivo studies, mice were injected orthotopically with DU145-Luc cells and treated with daily intraperitoneal injections of GL for 6 wk. GL significantly reduced the growth of the primary tumor and the metastatic spread of PCa cells to regional and distal lymph nodes in vivo. Treatment with GL also resulted in decreased cell proliferation and increased apoptosis compared with controls. In vitro, GL reduces the viability and invasive abilities of DU145-Luc cells and induces apoptosis. Our results showed that tumor growth and early metastatic dissemination of PCa can be significantly reduced by GL, indicating its potential use as a therapeutic compound in advanced metastatic PCa. PATIENT SUMMARY: In this study, we tested the STAT3 inhibitor galiellalactone (GL) in an animal model of PCa. We found that mice treated with GL had smaller primary tumors and decreased lymph node metastases compared with mice treated with vehicle. GL has potential for treating advanced metastatic PCa.


Subject(s)
Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Lactones/pharmacology , Prostatic Neoplasms/drug therapy , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Lymphatic Metastasis , Male , Mice, Nude , Neoplasm Invasiveness , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Time Factors , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
16.
J Neuropathol Exp Neurol ; 74(4): 359-69, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25756589

ABSTRACT

Recent studies indicate that the choroid plexus has important physiologic and pathologic roles in Alzheimer disease (AD). To obtain additional insight on choroid plexus function, we performed a proteomic analysis of choroid plexus samples from patients with AD stages I to II (n = 16), III to IV (n = 16), and V to VI (n = 11) and 7 age-matched control subjects. We used 2-dimensional differential gel electrophoresis coupled with mass spectrometry to generate a complete picture of changes in choroid plexus protein expression occurring in AD patients. We identified 6 proteins: 14-3-3 ß/α, 14-3-3 ε, moesin, proteasome activator complex subunit 1, annexin V, and aldehyde dehydrogenase, which were significantly regulated in AD patient samples (p < 0.05, >1.5-fold variation in expression vs control samples). These proteins are implicated in major physiologic functions including mitochondrial dysfunction and apoptosis regulation. These findings contribute additional significance to the emerging importance of molecular and functional changes of choroid plexus function in the pathophysiology of AD.


Subject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , Alzheimer Disease/metabolism , Choroid Plexus/metabolism , Gene Expression Regulation , 14-3-3 Proteins/biosynthesis , Aged , Aged, 80 and over , Aldehyde Dehydrogenase/biosynthesis , Alzheimer Disease/pathology , Annexin A5/biosynthesis , Choroid Plexus/pathology , Early Diagnosis , Humans , Male , Microfilament Proteins/biosynthesis
17.
Neurobiol Aging ; 34(9): 2133-45, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23582662

ABSTRACT

Elevated levels of amyloid beta (Aß) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aß deposition; (3) enhanced astrocyte-mediated Aß degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.


Subject(s)
Alzheimer Disease , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Quinazolines/pharmacology , Quinazolines/therapeutic use , Alzheimer Disease/drug therapy , Alzheimer Disease/etiology , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Animals , Astrocytes/metabolism , Behavior/drug effects , Cells, Cultured , Cognition/drug effects , Cyclic AMP/physiology , Cyclic AMP Response Element-Binding Protein/physiology , Cyclic Nucleotide Phosphodiesterases, Type 7/physiology , Disease Models, Animal , Glycogen Synthase Kinase 3/metabolism , Male , Mice , Mice, Transgenic , Molecular Targeted Therapy , Phosphorylation/drug effects , Rats , Rats, Wistar , Signal Transduction/physiology , tau Proteins/metabolism
18.
Brain Behav ; 2(5): 678-97, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23139912

ABSTRACT

Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods. Here we present a comprehensive review of the currently used rodent models of inflammatory and neuropathic pain adapted to the orofacial areas, taking into account the difficulties and drawbacks of the existing approaches. We examine the available testing methods and procedures used for assessing the behavioral responses in the face in both mice and rats and provide a summary of some pharmacological agents used in these paradigms to date. The use of these agents in animal models is also compared with outcomes observed in the clinic.

19.
Front Pharmacol ; 3: 75, 2012.
Article in English | MEDLINE | ID: mdl-22563316

ABSTRACT

Morphological alterations of choroid plexus in Alzheimer's disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover. Recent studies discuss the potential impacts of these changes, including the possibility of reduced resistance to stress insults and slow clearance of toxic compounds from CSF with specific reference to the amyloid peptide. Here, we review new evidences for AD-related changes in the choroid plexus. The data suggest that the significantly altered functions of the choroid plexus contribute to the multiparametric pathogenesis of late-onset AD.

20.
J Neurosci Methods ; 201(1): 46-54, 2011 Sep 30.
Article in English | MEDLINE | ID: mdl-21782847

ABSTRACT

Chronic orofacial pain encompasses a range of debilitating conditions, however in contrast to other body regions, few animal models are available to investigate mechanisms and treatments in the trigeminal area. Particularly, there is a lack of reliable models and testing methods in mice. We have behaviourally tested C57BL/6 mice subjected to unilateral chronic constriction injury (CCI) of the infraorbital nerve (IoN) or unilateral injections of Complete Freunds Adjuvant (CFA) into the vibrissal pad region with the aid of von Frey filaments and air-puffs and the use of a newly designed restraining device. These models were validated by suppressing the pain responses with appropriate drugs. The IoN-CCI group showed significant hyperalgesia on the ipsilateral side in comparison to baseline values for up to 20 days post-CCI following von Frey and air-puff stimulation. Gabapentin (60mg/kg), but not saline, temporarily reversed the hyperalgesia. Animals that received a CFA injection showed hyperresponsivity to both von Frey and air-puff stimulation for up to 4 days post injection. These effects were transiently reversed with 3mg/kg i.p. morphine but not saline. Our study proposes a new restraining device for mice, and validates a behavioural testing procedure of several facial pain models in mice, allowing for reproducible and robust assessment of the effects of pain-related agents and treatments, or phenotyping of genetically modified animals.


Subject(s)
Disease Models, Animal , Pain Measurement/methods , Trigeminal Neuralgia/physiopathology , Animals , Inflammation/diagnosis , Inflammation/drug therapy , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , Morphine/pharmacology , Morphine/therapeutic use , Pain Measurement/drug effects , Pain Measurement/instrumentation , Pain Threshold/drug effects , Pain Threshold/physiology , Random Allocation , Trigeminal Neuralgia/diagnosis , Trigeminal Neuralgia/drug therapy
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