Normal Prostate Tissue Research Articles

Introduction to matrix-based method for analyzing hybrid multidimensional prostate MRI data.

A new approach to analysis of prostate hybrid multidimensional MRI (HM-MRI) data was introduced in this study. HM-MRI data were acquired for a combination of a few echo times (TEs) and a few b-values. Naturally, there is a matrix associated with HM-MRI data for each image pixel. To process the data, we first linearized HM-MRI data by taking the natural logarithm of the imaging signal intensity. Subsequently, a hybrid symmetric matrix was constructed by multiplying the matrix for each pixel by its own transpose. The eigenvalues for each pixel could then be calculated from the hybrid symmetric matrix. In order to compare eigenvalues between patients, three b-values and three TEs were used, because this was smallest number of b-values and TEs among all patients. The results of eigenvalues were displayed as qualitative color maps for easier visualization. For quantitative analysis, the ratio (λr) of eigenvalues (λ1, λ2, λ3) was defined as λr=(λ1/λ2)/λ3 to compare region of interest (ROI) between prostate cancer (PCa) and normal tissue. The results show that the combined eigenvalue maps show PCas clearly and these maps are quite different from apparent diffusion coefficient (ADC) and T2 maps of the same prostate. The PCa has significant larger λr, smaller ADC and smaller T2 values than normal prostate tissue (p<0.001). This suggests that the matrix-based method for analyzing HM-MRI data provides new information that may be clinically useful. The method is easy to use and could be easily implemented in clinical practice. The eigenvalues are associated with combination of ADC and T2 values, and could aid in the identification and staging of PCa.

Highly sensitive deep panel sequencing of 27 HPV genotypes in prostate cancer biopsies results in very low detection rates and indicates that HPV is not a major etiological driver of this malignancy

BackgroundHuman papillomavirus (HPV) has been proposed to contribute to the carcinogenesis of prostate cancer. However, previous studies have yielded conflicting results. This study aims to add useful information to the ongoing discussion concerning the association between HPV infection and prostate cancer.MethodsWe used two high-throughput next-generation sequencing (NGS) approaches to detect HPV RNA in malignant and adjacent normal (AN) prostate tissue (cohorts 1 and 2) and HPV DNA from carcinogenic and probably/possibly carcinogenic-classified HPV types (cohort 3) in malignant prostate, AN prostate, and benign prostatic hyperplasia (BPH) tissues.ResultsIn total, 0% (cohort 1: 0/83, cohort 2: 0/16) of the malignant prostate tissue samples and 0% (cohort 1: 0/23, cohort 2: 0/8) of the AN prostate tissue samples were positive for HPV RNA. A total of 8.3% (1/12) of the BPH samples, 0% (0/28) of the AN samples, and 0.8% (1/132) of the malignant prostate samples were positive for HPV16 DNA. However, the normalized read count of the HPV16-positive malignant sample was close to the cut-off. In addition, no other carcinogenic-classified HPV types were detected in any of the BPH, AN, or malignant prostate tissue samples.ConclusionOur study does not support HPV infection as a major contributor to the etiology of prostate cancer.

A Polyvinyl Alcohol (PVA)-Based Phantom for Prostate Cancer Detection Using Multiparametric Ultrasound: A Validation Study.

Four PVA samples, varying in Mw with constant concertation, were mixed with glycerol, silicon carbide (SiC), and aluminium oxide (Al2O3). Phantoms with varying depth and inclusion sizes were created and tested using shear-wave elastography (SWE). An mpUS phantom was developed to mimic prostate tissue, including isoechoic and hypoechoic inclusions and vessels. The phantom was scanned using supersonic ultrasound, strain elastography, and Doppler ultrasound. Validation was performed using radical prostatectomy data and shear-wave elastography. The acoustic properties varied with enhancers like glycerol and Al2O3. Low Mw PVA samples had a speed of sound ranging from 1547.50 ± 2 to 1553.70 ± 2.2 m/s and attenuation of 0.61 ± 0.062 to 0.63 ± 0.05 dB/cm/MHz. High Mw PVA samples ranged from 1555 ± 2.82 to 1566 ± 4.5 m/s and 0.71 ± 0.02 to 0.73 ± 0.046 dB/cm/MHz. Young's modulus ranged from 11 ± 2 to 82.3 ± 0.5 kPa across 1 to 10 freeze-thaw cycles. Inclusion size, depth, and interaction statistically affect the SWE measurements with p-value = 0.056327, p-value = 8.0039 × 10-8, and p-value = 0.057089, respectively. SWE showed isoechoic inclusions, prostate tissue, and surrounding tissue only. The Doppler velocity was measured in three different inner diameters. PVA mixed with enhancer materials creates an mpUS phantom with properties that mimic normal and abnormal prostate tissue, blood vessels, and soft tissue, facilitating advanced diagnostic training and validation.

Integrating Multi-Omics Data to Uncover Prostate Tissue DNA Methylation Biomarkers and Target Genes for Prostate Cancer Risk.

Previous studies have indicated that specific CpG sites may be linked to the risk of prostate cancer (PCa) by regulating the expression of PCa target genes. However, most existing studies aim to identify DNA methylation (DNAm) biomarkers through blood tissue genetic instruments, which impedes the identification of relevant biomarkers in prostate tissue. To identify PCa risk-associated CpG sites in prostate tissue, we established genetic prediction models of DNAm levels using data from normal prostate samples in the GTEx (N = 108) and assessed associations between genetically predicted DNAm in prostate and PCa risk by studying 122,188 cases and 604,640 controls. We observed significant associations for 3879 CpG sites, including 926 at novel genomic loci. Among them, DNAm levels of 80 CpG sites located at novel loci are significantly associated with expression levels of 45 neighboring genes in normal prostate tissue. Of these genes, 11 further exhibit significant associations with PCa risk for their predicted expression levels in prostate tissue. Intriguingly, a total of 31 CpG sites demonstrate consistent association patterns across the methylation-gene expression-PCa risk pathway. Our findings suggest that specific CpG sites may be related to PCa risk by modulating the expression of nearby target genes.

Therapeutic potential of targeting AKR1C2 in the treatment of prostate cancer.

Prostate cancer development and progression are driven by androgens, and changes in androgen metabolic pathways can lead to prostate cancer progression or remission. AKR1C2 is a member of the aldo-keto reductase superfamily and plays an important role in the metabolism of steroids and prostaglandins.Alterations in the expression and activity of AKR1C2 affect the homeostasis of active androgens, which in turn affects the progression of prostate cancer. AKR1C2 reduces the highly active dihydrotestosterone to the less active 3α-diol in the prostate, resulting in lower androgen levels. Whereas the expression of AKR1C2 is significantly reduced in prostate cancer tissues relative to normal prostate tissues, this results in a weakening of the dihydrotestosterone metabolic inactivation pathway, leading to the retention of dihydrotestosterone in the prostate cancer cells, which promotes the progress of prostate cancer. Given the critical role of AKR1C2 in prostate cancer cells, targeting AKR1C2 for the treatment of prostate cancer may be an effective strategy. It has been demonstrated that curcumin and neem leaf extract effectively inhibit prostate cancer in vitro and in vivo by modulating AKR1C2.

Extrachromosomal circular DNAs in prostate adenocarcinoma: global characterizations and a novel prediction model.

The role of focal amplifications and extrachromosomal circular DNA (eccDNA) is still uncertain in prostate adenocarcinoma (PRAD). Here, we first mapped the global characterizations of eccDNA and then investigate the characterization of eccDNA-amplified key differentially expressed encoded genes (eKDEGs) in the progression, immune response and immunotherapy of PRAD. Circular_seq was used in conjunction with the TCGA-PRAD transcriptome dataset to sequence, annotate, and filter for eccDNA-amplified differentially expressed coding genes (eDEGs) in PRAD and para-cancerous normal prostate tissues. Afterwards, risk models were created and eKDEGs linked to the PRAD prognosis were identified using Cox and Lasso regression analysis. The immune microenvironment of the risk model was quantified using a variety of immunological algorithms, which also identified its characteristics with regard to immunotherapy, immune response, and immune infiltration. In this research, there was no significant difference in the size, type, and chromosomal distribution of eccDNA in PRAD and para-cancerous normal prostate tissues. However, 4,290 differentially expressed eccDNAs were identified and 1,981 coding genes were amplified. Following that, 499 eDEGs were tested in conjunction with the transcriptome dataset from TCGA-PRAD. By using Cox and Lasso regression techniques, ZNF330 and PITPNM3 were identified as eKDEGs of PRAD, and a new PRAD risk model was conducted based on this. Survival analysis showed that the high-risk group of this model was associated with poor prognosis and validated in external data. Immune infiltration analysis showed that the model risks affected immune cell infiltration in PRAD, not only mediating changes in immune cell function, but also correlating with immunophenotyping. Furthermore, the high-risk group was negatively associated with anti-CTLA-4/anti-PD-1 response and mutational burden. In addition, Tumor Immune Dysfunction and Exclusion analyses showed that high-risk group was more prone to immune escape. Drug sensitivity analyses identified 10 drugs, which were instructive for PRAD treatment. ZNF330 and PITPNM are the eKDEGs for PRAD, which can be used as potential new prognostic markers. The two-factor combined risk model can effectively assess the survival and prognosis of PRAD patients, but also can predict the different responses of immunotherapy to PRAD patients, which may provide new ideas for PRAD immunotherapy.

Establishing and Characterizing the Molecular Profiles, Cellular Features, and Clinical Utility of a Patient-Derived Xenograft Model Using Benign Prostatic Tissues

Benign prostatic hyperplasia (BPH) is a common condition marked by the enlargement of the prostate gland, which often leads to significant urinary symptoms and a decreased quality of life. The development of clinically relevant animal models is crucial for understanding the pathophysiology of BPH and improving treatment options. This study aims to establish a patient-derived xenograft (PDX) model using benign prostatic tissues to explore the molecular and cellular mechanisms of BPH. PDXs were generated by implanting fresh BPH (transition zone) and paired normal (peripheral zone) prostate tissue from 8 patients under the renal capsule of immunodeficient male mice. Tissue weight, architecture, cellular proliferation, apoptosis, prostate-specific marker expression, and molecular profiles of PDXs were assessed after 1 week and 1, 2, or 3 months of implantation by immunohistochemistry, enzyme-linked immunosorbent assay, transcriptomics, and proteomics. Responses to finasteride, a standard-of-care therapy, were evaluated. PDXs maintained histologic and molecular characteristics of the parental human tissues. BPH, but not normal PDXs, demonstrated significant increases in weight and cellular proliferation, particularly at 1 month. Molecular profiling revealed specific gene and protein expression patterns correlating with BPH pathophysiology. Specifically, an increased immune and stress response was observed at 1 week, followed by increased expression of proliferation markers and BPH-specific stromal signaling molecules, such as BMP5 and CXCL13, at 1 month. Graft stabilization to preimplant characteristics was apparent between 2 and 3 months. Treatment with finasteride reduced proliferation, increased apoptosis, and induced morphologic changes consistent with therapeutic responses observed in human BPH. Our PDX model recapitulates the morphologic, histologic, and molecular features of human BPH, offering a significant advancement in modeling the complex interactions of cell types in BPH microenvironments. These PDXs respond to therapeutic intervention as expected, providing a valuable tool for preclinical testing of new therapeutics that will improve the well-being of BPH patients.

Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development

Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12–24 h, with approximate levels of 1200 μg/mL, 0.14 μg/mL, and 0.2–0.3 μg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 μg/mg) is 10-fold higher than that in normal prostate tissues (0.14 μg/mg). The analysis also reveals that C6-STA has t1/2 of 12.8 h and Tmax of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Androgen receptor deficiency-induced TUG1 in suppressing ferroptosis to promote benign prostatic hyperplasia through the miR-188-3p/GPX4 signal pathway

Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1β, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia in vivo. Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.

Promoter Hypermethylation of the BRCA1 Gene as a Novel Biomarker for Prostate Cancer.

Prostate cancer (PCa) is recognized as one of the most common malignancies that greatly affects the male population globally. Breast cancer gene 1 (BRCA1) is an important tumor suppressor gene that plays a central role in the maintenance of genomic integrity by promoting the repair of double-strand breaks of DNA. Here, we present a pilot study to examine the promoter methylation and gene expression of the BRCA1 gene in patients with PCa in Erbil governorate, Iraq. The collection of samples took place in Erbil City, Iraq, specifically at Rizgary Hospital, PAR Hospital, and Al-Mufti's private laboratory. A total of 40 tissue samples were collected from age-matched individuals, comprising 30 pathologically confirmed PCa cases and 10 normal prostatic tissue taken from individuals who, during diagnosis, were found to be negative for PCa. Data on demographic and clinical information, such as pathological stage, age, and prostate-specific antigen (PSA) level, were gathered from the medical records. The impact of the promoter methylation was forecasted using the DNA bisulfite conversion technique and methyl-specific PCR (MSP) with specific primers for the BRCA1 promoter region. The assessment of BRCA1 expression was conducted using quantitative real-time PCR (qPCR). Among the 30 patients examined, 76.6% (23 cases) were found to have BRCA1 promoter methylation, and none of the normal tissues appeared to have DNA methylation. BRCA1 promoter methylation was positively associated with the advanced stage of disease (p=0.01) and Gleason score (p=0.007). The analysis revealed a significant downregulation of the BRCA1 gene expression in methylated tumor samples as compared to non-methylated tumors and normal tissues, suggesting the role of epigenetic silencing. To the best of our knowledge, this is the first study investigating methylation status and level of BRCA1 mRNA transcripts among PCa patients in Iraq. Our findings suggest that promoter hypermethylation of the BRCA1 gene could serve as a viable biomarker for PCa, marking a significant discovery.

Feasibility study of ADCs targeting TROP-2, HER2, and CD46 in Ductal Adenocarcinoma and Intraductal Carcinoma of the prostate.

Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P.

Physiological biodistribution on Ga68-PSMA PET/CT and the factors effecting biodistribution

AimThe study aims to determine the physiological and pathophysiological distribution of the radiopharmaceutical (Ga68-PSMA-617) and investigate whether there are differences in distribution according to the laboratory, histopathological and clinical findings that can affect image evaluation. Also, we aimed to determine cut-off values to distinguish physiological and pathological uptake in prostate, bone, and lymph nodes.Materials and Methods229 prostate cancer patients who underwent Ga68-PSMA PET/CT at our department were retrospectively analyzed. The patients were grouped according to PET/CT results, Gleason scores, PSA values, received treatments, metastatic status and other laboratory values. The SUV values of the organs, tissues, and pathological lesions of the patients in these subgroups were compared among themselves.ResultsNo significant difference was detected in the physiological uptake of lymph nodes and bone between the groups. In the group with patients that received androgen deprivation therapy (ADT), the bone metastasis SUV values were found to be higher and the SUV values of the submandibular gland and renal cortex were found to be lower (Mann–Whitney U, p = 0.043; 0.004; 0.01, respectively). In the group with patients who received radiotherapy, the normal prostate tissue SUV values were determined to be higher (Mann–Whitney U, p = 0.009). The SUV values of the submandibular gland, muscle, liver, and blood pool were found to be lower in the group of patients with high serum LDH values. The cut-off SUVmax value was determined to be 6.945 (sensitivity 89.6%, specificity 98.1%) for primary prostate lesion; 4.72 for lymph node metastasis; 4.25 for bone metastasis. The serum PSA cut-off value to distinguish the negative/positive groups was found to be 1,505 (sensitivity 79.7%, specificity 77.3%).ConclusionIn conclusion, PSMA-617 demonstrates a similar biodistribution with other PSMA ligands. The physiological uptake of lymph nodes and bone which are mostly metastasized in prostate cancer, are not affected by the factors we examined. It should be kept in mind that the normal prostate tissue uptake may increase in patients receiving radiotherapy, and the physiological/pathological uptake of the organs may differ due to the changes in PSMA expression in patients receiving ADT, tumor burden, and kidney function may affect the biodistribution.

Characteristics, clinical significance, and cancer immune interactions of lipid metabolism in prostate cancer.

The relationship between lipid metabolism, immune response, and immunotherapy in prostate cancer (PCa) is closely intertwined, and targeted intervention in lipid metabolism may facilitate the success of anticancer immunotherapy. This research attempted to explore effective immunotherapy for PCa. We obtained RNA sequencing (RNA-seq) data for PCa patients from the UCSC Xena platform. Data analysis of differentially expressed genes (DEGs) was performed using package limma in R. Then, DEGs were subjected to enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The Human Protein Atlas (HPA) database was conducted to validate the protein expression of the up-regulated lipid metabolism related genes (LMRGs) between PCa tissues and normal prostate tissues. And then we identified critical transcription factors (TFs), LMRGs and miRNA by constructing a regulatory network of TF-gene-miRNA. Furthermore, we determined the high and low groups based on the score of lipid metabolism enrichment. The hallmark gene sets were derived from gene expression profiles using the gene set variation analysis (GSVA) R package. Finally, we conducted immune infiltration analysis and drug sensitivity analysis. Immune response and lipid metabolism have undergone significant changes in PCa and paracancerous tissues compared to normal tissues. A total of 21 LMRGs were differentially up-regulated in PCa. The TF-gene-miRNA network showed that PLA2G7, TWIST1, and TRIB3 may be the key genes that elevated lipid metabolism in PCa. The high group had more infiltration of B cell memory, macrophage M0, macrophage M1, and myeloid dendritic cell resting, and the low group had more infiltration of B cell plasma, monocyte, myeloid dendritic cell activated, and mast cell resting. The majority of checkpoint genes exhibited high expression levels in the low group. Lipid metabolism was remarkedly correlated with drug sensitivity. The analysis of lipid metabolism and related genes has revealed a complex regulatory mechanism that has a significant influence on immune response, immunotherapy, and medication guidance for patients with PCa. Prostate cancer (PCa); lipid metabolism; cancer immune; RNA sequencing (RNA-seq).

To Establish a Nomogram Prediction of Prostate Cancer Based on Pyroptosis-Related Genes that Affect the Immune Microenvironment.

Prostate cancer is the most common tumor in men worldwide with a poor prognosis. In recent years, studies have revealed that pyroptosis can affect the tumor immune microenvironment. However, the relationship between the immune microenvironment regulated by pyroptosis-related genes and the prognosis of prostate cancer is still unclear. Thirty-three cell death-associated genes were selected from a literature review. The "DESeq2" R package was used to identify differentially expressed cell death-associated genes between normal prostate tissue (GTEx) and prostate cancer tissue (TCGA) samples. Biological functional enrichment analysis of differentially expressed cell death genes was performed using R statistical software packages, such as "clusterProfiler," "org.Hs.eg.db," "enrichplot," "ggplot2," and "GOplot." Univariate Cox and LASSO Cox regression analyses were conducted to identify prognostic genes associated with the immune microenvironment using the "survival" package. Finally, a predictive model was established based on Gleason score, T stage, and cell death-associated genes.odel was established based on Gleason score, T stage, and cell death-associated genes. Seventeen differentially expressed genes related to pyroptosis were screened out. Based on these differentially expressed genes, biological function enrichment analysis showed that they were related to pyroptosis of prostate cells. Based on univariate Cox and (LASSO) Cox regression analysis, four pyroptosis-related genes (CASP3, PLCG1, GSDMB, GPX4) were determined to be related to the prognosis of prostate cancer, and the immune correlation analysis of the four pyroptosis-related genes was performed. The expression of CASP3, PLCG1 and GSDMB was positively correlated with the proportion of immune cells, and the expression of GPX4 was negatively correlated with the proportion of immune cells. A predictive nomogram was established by combining Gleason score, T and pyroptosis genes. The nomogram was accompanied by a calibration curve and used to predict 1 -, 2 -, and 5-year survival in PAAD patients. Cell death-associated genes (CASP3, PLCG1, GSDMB, GPX4) play crucial roles in modulating the immune microenvironment and can be used to predict the prognosis of prostate cancer.

A Comparison of Arterial Input Function Interpolation Methods for Patlak Plot Analysis of 68Ga-PSMA-11 PET Prostate Cancer Studies.

Positron emission tomography (PET) imaging enables quantitative assessment of tissue physiology. Dynamic pharmacokinetic analysis of PET images requires accurate estimation of the radiotracer plasma input function to derive meaningful parameter estimates, and small discrepancies in parameter estimation can mimic subtle physiologic tissue variation. This study evaluates the impact of input function interpolation method on the accuracy of Patlak kinetic parameter estimation through simulations modeling the pharmacokinetic properties of [68Ga]-PSMA-11. This study evaluated both trained and untrained methods. Although the mean kinetic parameter accuracy was similar across all interpolation models, the trained node weighting interpolation model estimated accurate kinetic parameters with reduced overall variability relative to standard linear interpolation. Trained node weighting interpolation reduced kinetic parameter estimation variance by a magnitude approximating the underlying physiologic differences between normal and diseased prostatic tissue. Overall, this analysis suggests that trained node weighting improves the reliability of Patlak kinetic parameter estimation for [68Ga]-PSMA-11 PET.

Interaction of pRb and beta-catenin in cancer and normal tissue in the human prostate

Prostate cancer (PCa) is one of the most common oncological diseases, which goes through two stages in its development. The first stage, localized prostate cancer, can proceed indefinitely in a dormant form that does not require active medical intervention, or suddenly turn into an aggressive metastatic form with lethal outcome. The pathogenesis of the transition of the dormant form of PCa to the metastatic form remains not fully understood. The signaling pathways of the tumor suppressor pRb and the proto-oncogene β-catenin are probably the most involved in the pathogenesis of PCa but the role of their interaction in the pathogenesis of prostate cancer has not been studied. The publication on the pathogenesis of tumors in other tissues suggests that pRb may lose some properties of a tumor suppressor at the initial stage of PCa development due to its interaction with β-catenin that enables tumor cells to gain competitive advantages for reproduction. In this work, we have shown that the RB and β-catenin (CTNNB1) genes are well expressed in tumor and normal prostate tissue. Unlike β-catenin, pRb is not detected by immunoblotting in tumor and normal prostate tissue, but is easily determined in this way in extracts of control T98G cells. Co-immunoprecipitation with antibodies to pRb from extracts of tumor and normal prostate tissue makes it possible to detect this protein and β-catenin by subsequent immunoblotting, which indicates the physical interaction of these proteins in prostate tissue. On the other hand, immunoprecipitation of β-catenin with antibodies to its C-terminal fragment does not detect this protein in prostate extracts by subsequent immunoblotting using the same antibody. In contrast to prostate tissue, β-catenin is readily detected by immunoprecipitation combined with immunoblotting in T98G control cell extracts. The obtained data suggest that pRb and β-catenin physically interact with each other in cells of different tissue specificity. In T98G cells, this interaction probably occurs through the C-terminal fragment of β-catenin, but in prostate cells it occurs in a different way, since the C-fragment of β-catenin is shielded from such interaction, possibly due to its physical association with pRb.

Differential modulation of cell morphology, migration, and Neuropilin-1 expression in cancer and non-cancer cell lines by substrate stiffness.

Physical changes in the tumor microenvironment, such as increased stiffness, regulate cancer hallmarks and play an essential role in gene expression, cell morphology, migration, and malignancy. However, the response of cancer cells to stiffness is not homogeneous and varies depending on the cell type and its mechanosensitivity. In this study, we investigated the differential responses of cervical (HeLa) and prostate (PC-3) cancer cell lines, as well as non-tumoral cell lines (HEK293 and HPrEC), to stiffness using polyacrylamide hydrogels mimicking normal and tumoral tissues. We analyzed cell morphology, migration, and the expression of neuropilin 1 (NRP1), a receptor involved in angiogenesis, cell migration, and extracellular matrix remodeling, known to be associated with cancer progression and poor prognosis. Our findings reveal that NRP1 expression increases on substrates mimicking the high stiffness characteristic of tumoral tissue in the non-tumoral cell lines HPrEC and HEK293. Conversely, in tumoral PC-3 cells, stiffness resembling normal prostate tissue induces an earlier and more sustained expression of NRP1. Furthermore, we observed that stiffness influences cell spreading, pseudopodia formation, and the mode of cell protrusion during migration. Soft substrates predominantly trigger bleb cell protrusion, while pseudopodia protrusions increase on substrates mimicking normal and tumor-like stiffnesses in HPrEC cells compared to PC-3 cells. Stiffer substrates also enhance the percentage of migratory cells, as well as their velocity and total displacement, in both non-tumoral and tumoral prostate cells. However, they only improve the persistence of migration in tumoral PC-3 cells. Moreover, we found that NRP1 co-localizes with actin, and its suppression impairs tumoral PC-3 spreading while decreasing pseudopodia protrusion mode. Our results suggest that the modulation of NRP1 expression by the stiffness can be a feedback loop to promote malignancy in non-tumoral and cancer cells, contingent upon the mechanosensitivity of the cells.

Interaction of pRb and β-Catenin in Cancer and Normal Human Prostate Tissue

Interaction of pRb and β-Catenin in Cancer and Normal Human Prostate Tissue

The Association Between Immune-Histochemical Expressions of Program Death Ligand with some Aggressive Features of Prostate Cancer

Prostate cancer (PC), accounts for more than one-fourth of all cancer diagnoses, and the most frequently diagnosed cancer among men in 2022. The immunoglobulin (IG) Program death ligand-1(PD-1) cell surface receptor is predominantly expressed on the surface of many cells. The purpose of this study was to demonstrate the relationship between Program death ligand expression and some aggressive features of prostate cancer including perineural invasion, vascular invasion and necrosis. Thirty cases of prostate cancer with age range from 60 to 80 year old and 30 cases of normal prostate tissue with age under 25 year old were separated into two groups in a retrospective case-control research that encompassed 60 cases. All malignant cases were examined by consultant pathologists for the diagnosis of prostate carcinoma, and each block of tissue was divided into two slides, one for hematoxylin and eosin (H&amp;E) staining and the other for immunoglobulin (IHC) staining of PDL-1. The expression pattern of Program Death Ligand was investigated in these samples and its relationship to particular clinic-pathological characteristics. Despite it was not expressed in healthy prostatic tissue, program death ligand demonstrated to be positive in prostate cancer with vascular invasion, perineural invasion, and necrosis, while it was negative in healthy prostatic tissue. High expression of Program death ligand was correlated with poor differentiation, neural invasion, and vascular invasion; these criteria indicate that the expression of Program death ligand is associated with high grade and aggressive tumors. The current study confirms that perineural invasion, vascular invasion, and necrosis are all accompanied by a rise in Program death ligand expression regardless their grade and stage

Identification and validation of the TRHDE-AS1/hsa-miR-449a/ADAMTS5 axis as a novel prognostic biomarker in prostate cancer.

Despite advancements in cancer research, the prognostic implications of competing endogenous RNA (ceRNA) networks in prostate cancer (PCa) remain incompletely understood. This study aimed to elucidate the prognostic relevance of ceRNA networks in PCa, utilizing a comprehensive bioinformatics approach alongside experimental validation. After searching The Cancer Genome Atlas (TCGA) database, RNA sequencing (RNA-Seq) data were extracted to identify differentially expressed RNAs (DERs) between 491 PCa samples and 51 normal prostate tissues, following which a comprehensive bioinformatics strategy was implemented to construct a ceRNA network. An optimal prognostic signature comprising these DERs was then established and validated using TCGA data. In addition, functional validation was performed through RNA pull-down, dual-luciferase reporter assays, quantitative real-time PCR, and western blot analysis conducted in PC-3 and DU145 cell lines, thereby complementing the bioinformatics analysis. A total of 613 DERs, comprising 103 long noncoding RNAs (lncRNAs), 60 microRNAs (miRNAs), and 450 messenger RNAs (mRNAs), were identified and utilized in constructing a ceRNA network, which encompassed 23 lncRNAs, 9 miRNAs, and 52 mRNAs. An optimal prognostic signature was established, including VPS9D1 antisense RNA 1 (VPS9D1-AS1), miR-449a, cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1), targeting protein for Xklp2 (TPX2), solute carrier family 7 member 11 (SLC7A11), copine7 (CPNE7), and maternal embryonic leucine zipper kinase (MELK), yielding area under the curve (AUC) values exceeding 0.8 across training, validation, and entire datasets. Our experiments results revealed an interaction between lncRNA TRHDE antisense RNA 1 (TRHDE-AS1) and miR-449a and that miR-449a could target the ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) mRNA. Knockdown of miR-449a significantly impeded cell proliferation, G1/S transition, migration and invasion, and promoted apoptosis in PC-3 and DU145 cells. Furthermore, knockdown of miR-449a notably downregulated protein expression of CDK4, cyclin D1, N-cadherin and vimentin, while upregulating protein expression of cleaved caspase-3 and E-cadherin. This study contributes to a deeper understanding of the prognostic-linked ceRNA network in PCa, providing fundamental insights that could improve diagnostic and therapeutic approaches for PCa management.