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Biochimica Et Biophysica Acta. Reviews... Mar 2024Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in male population worldwide. Since the growth... (Review)
Review
Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in male population worldwide. Since the growth and progression of PC highly depend on the androgen pathway, androgen deprivation therapy (ADT) is the mainstay of systemic treatment. Enzalutamide is a second-generation antiandrogen, which is widely used for the treatment of advanced and metastatic PC. However, treatment failure and disease progression, caused by the emergence of enzalutamide resistant phenotypes, remains an important clinical challenge. MicroRNAs (miRNAs) are key regulators of gene expression and have recently emerged as potential biomarkers for being stable and easily analysed in several biological fluids. Several miRNAs that exhibit dysregulated expression patterns in enzalutamide-resistant PC have recently been identified, including miRNAs that modulate critical signalling pathways and genes involved in PC growth, survival and in the acquisition of enzalutamide phenotype. The understanding of molecular mechanisms by which miRNAs promote the development of enzalutamide resistance can provide valuable insights into the complex interplay between miRNAs, gene regulation, and treatment response in PC. Moreover, these miRNAs could serve as valuable tools for monitoring treatment response and disease progression during enzalutamide administration. This review summarises the miRNAs associated with enzalutamide resistance in PC already described in the literature, focusing on their biological roles and on their potential as biomarkers.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgen Antagonists; MicroRNAs; Androgens; Biomarkers; Disease Progression; Benzamides; Nitriles; Phenylthiohydantoin
PubMed: 38160898
DOI: 10.1016/j.bbcan.2023.189067 -
The Prostate Apr 2024Prostate-specific membrane antigen (PSMA) is a US Food and Drug Administration-approved theranostic target for prostate cancer (PCa). Although PSMA is known to be...
INTRODUCTION
Prostate-specific membrane antigen (PSMA) is a US Food and Drug Administration-approved theranostic target for prostate cancer (PCa). Although PSMA is known to be glycosylated, the composition and functional roles of its N-linked glycoforms have not been fully characterized.
METHODS
PSMA was isolated from pooled seminal plasma from low-risk grade Groups 1 and 2 PCa patients. Intact glycopeptides were analyzed by mass spectrometry to identify site-specific glycoforms.
RESULTS
We observed a rich distribution of PSMA glycoforms in seminal plasma from low and low-intermediate-risk PCa patients. Some interesting generalities can be drawn based on the predicted topology of PSMA on the plasma membrane. The glycoforms at ASN-459, ASN-476, and ASN-638 residues that are located at the basal domain facing the plasma membrane in cells, are predominantly high mannose glycans. ASN-76 which is located in the interdomain region adjacent to the apical domain of the protein shows a mixture of high mannose glycans and complex glycans, whereas ASN-121, ASN-195 and ASN-336 that are located and are exposed at the apical domain of the protein predominantly possess complex sialylated and fucosylated N-linked glycans. These highly accessible glycosites display the greatest diversity in isoforms across the patient samples.
CONCLUSIONS
Our study provides novel qualitative insights into PSMA glycoforms that are present in the seminal fluid of PCa patients. The presence of a rich diversity of glycoforms in seminal plasma provides untapped potential for glycoprotein biomarker discovery and as a clinical sample for noninvasive diagnostics of male urological disorders and diseases including PCa. Specifically, our glycomics approach will be critical in uncovering PSMA glycoforms with utility in staging and risk stratification of PCa.
Topics: Humans; Male; Mannose; Polysaccharides; Prostate; Prostatic Neoplasms; Semen
PubMed: 38151791
DOI: 10.1002/pros.24666 -
Theriogenology Feb 2024Boar fertility is a key determinant of the production efficiency of the whole pig breeding industry and boar sperm motility is the seminal parameter with the greatest...
Boar fertility is a key determinant of the production efficiency of the whole pig breeding industry and boar sperm motility is the seminal parameter with the greatest impact on the fecundity of a sow. Exosomes are small, extracellular vesicles found in many body fluids. Seminal plasma exosomes, which are secreted by the epididymis, prostate, seminal vesicles, and testes, contain a large number of miRNAs, the types and levels of which can reflect the physiological state of source cells. It has been shown that the expression profile of seminal plasma exosomal miRNA differs between low-motility semen and normal semen. The aim of this study was to investigate the relationship between semen motility and exosomal miRNA profiles to obtain information that would allow to predict boar fertility, as well as contribute to the understanding of the mechanisms by which exosomal miRNAs regulate semen motility. Three high-motility (semen motility >90 %) and three low-motility (semen motility <80 %) semen samples were collected from Landrace and Yorkshire boars, respectively, and seminal plasma exosomes were extracted by ultracentrifugation. Exosome characterization was performed using transmission electron microscopy, NTA, and Western blot. The expression profiles of exosomal miRNAs associated with semen motility in the two boar breeds were subsequently determined by small RNA sequencing. The results showed that 297 known miRNAs and 295 novel RNAs were co-expressed in the four groups. Notably, six miRNAs (ssc-miR-122-5p, ssc-miR-486, ssc-miR-451, ssc-miR-345-3p, ssc-miR-362, and ssc-miR-500-5p) were found to be differentially expressed in both boar breeds. Enrichment analysis of the target genes of the differentially expressed miRNAs showed that they were mainly involved in biological processes such as regulation of transcription from RNA polymerase II promoter, regulation of gene expression, and intracellular signal transduction and signaling pathways such as the PI3K-Akt, MAPK, and Ras signaling pathways. The six differentially expressed miRNAs identified in this study have significant potential as noninvasive markers of boar semen motility. Meanwhile, the results of the enrichment analysis provide novel insights into the mechanisms underlying the regulation of semen motility.
Topics: Swine; Male; Animals; Female; Semen; MicroRNAs; Exosomes; Phosphatidylinositol 3-Kinases; Sperm Motility; Sequence Analysis, RNA
PubMed: 38150851
DOI: 10.1016/j.theriogenology.2023.11.028 -
Cancer Apr 2024Androgen deprivation therapy for prostate cancer was pioneered by Charles Huggins, laureate of the Nobel Prize in Medicine in 1966. The authors tried to understand the...
Androgen deprivation therapy for prostate cancer was pioneered by Charles Huggins, laureate of the Nobel Prize in Medicine in 1966. The authors tried to understand the scientific context and how previous findings paved Huggins way to his discoveries. With the help of summary or review articles on androgen deprivation therapy, the authors identified key publications and used his Nobel Prize speech as a basis to understand his discoveries. Furthermore, they used a recording of the laboratory-talk interview he gave about his findings to guide them to relevant publications. The authors found that the basis for Huggins' discoveries was the isolation of testosterone in 1935, not long before Huggins' 1941 hallmark publication. Huggins' work follows major experiments in the 19th century in orchiectomy done as a treatment for prostate hypertrophy. Researching the etiology of idiopathic hydrocele, Huggins analyzed the composition of prostate fluid. Further research led to the discovery of the influence of castration, testosterone, and estrogen on acid phosphatase. Recently developed methods facilitated the measurement of the phosphatases. He, therefore, had a biomarker for metastatic prostate cancer to measure treatment response. Very early on, he reported clinical improvements after castration in metastatic patients. Although the effect of orchiectomy on prostate hypertrophy was already known, Huggins was the first to show that testosterone stimulated and estrogen decreased the activity of prostate cancer. Huggins also established phosphatases as a tumor marker to measure disease response.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Testosterone; Estrogens; Phosphoric Monoester Hydrolases; Hypertrophy
PubMed: 38146679
DOI: 10.1002/cncr.35173 -
Pharmaceutics Dec 2023Nanomedicines engineered to deliver molecules with therapeutic potentials, overcoming drawbacks such as poor solubility, toxicity or a short half-life, are targeted...
Nanomedicines engineered to deliver molecules with therapeutic potentials, overcoming drawbacks such as poor solubility, toxicity or a short half-life, are targeted towards their cellular destination either passively or through various elements of cell membranes. The differences in the physicochemical properties of the cell membrane between tumor and nontumor cells have been reported, but they are not systematically used for drug delivery purposes. Thus, in this study, a new approach based on a match between the liposome compositions, i.e., membrane fluidity, to selectively interact with the targeted cell membrane was used. Lipid-based carriers of two different fluidities were designed and used to deliver 4()-4-F-Neuroprostane (F-NeuroP), a potential antitumor molecule derived from docosahexaenoic acid (DHA). Based on its hydrophobic character, F-NeuroP was added to the lipid mixture prior to liposome formation, a protocol that yielded over 80% encapsulation efficiency in both rigid and fluid liposomes. The presence of the active molecule did not modify the liposome size but increased the liposome negative charge and the liposome membrane fluidity, which suggested that the active molecule was accommodated in the lipid membrane. F-NeuroP integration in liposomes with a fluid character allowed for the selective targeting of the metastatic prostate cell line PC-3 vs. fibroblast controls. A significant decrease in viability (40%) was observed for the PC-3 cancer line in the presence of F-NeuroP fluid liposomes, whereas rigid F-NeuroP liposomes did not alter the PC-3 cell viability. These findings demonstrate that liposomes encapsulating F-NeuroP or other related molecules may be an interesting model of drug carriers based on membrane fluidity.
PubMed: 38140081
DOI: 10.3390/pharmaceutics15122739 -
Life (Basel, Switzerland) Dec 2023Resistin is an adipokine with metabolic and inflammatory functions. Epidemiological and translational studies report that an increase in plasma levels and tissue...
Resistin is an adipokine with metabolic and inflammatory functions. Epidemiological and translational studies report that an increase in plasma levels and tissue expression of resistin increases the aggressiveness of prostate tumor cells. Extracellular vesicles (EVs) are secreted constitutively and induced by cytokines, growth factors, and calcium and are found in multiple biological fluids such as saliva, serum, semen, and urine. In particular, EVs have been shown to promote tumor progression through the induction of proliferation, growth, angiogenesis, resistance to chemotherapy, and metastasis. However, the role of resistin in the migration, invasion, and secretion of EVs in invasive prostate tumor cells remains to be studied. In the present study, we demonstrate that resistin induces increased migration and invasion in PC3 cells. In addition, these phenomena are accompanied by increased p-FAK levels and increased secretion of MMP-2 and MMP-9 in resistin-treated PC3 cells. Interestingly, EVs isolated from supernatants of PC3 cells treated with resistin induce an increase in migration and invasion accompanied by high MMP-2 and MMP-9 secretion in an autocrine stimulation model. In summary, our data for the first time demonstrate that resistin induces migration and invasion, partly through the secretion of EVs with pro-invasive characteristics in PC3 cells.
PubMed: 38137922
DOI: 10.3390/life13122321 -
JCI Insight Dec 2023Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and...
Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-β1-treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue deposition. Single-cell RNA-Seq data obtained from human tissues and flow cytometric and histological evaluation of mouse tissues demonstrated increased presence of PDGFRα+ cells in lymphedema; human tissue analysis verified these cells have the capacity for adipogenic and fibrogenic differentiation. Upon treatment with rosiglitazone, we noted a reduction in the overall quantity of PDGFRα+ cells and LipidTOX+ cells. Our findings provide a framework for treating secondary lymphedema as a condition of fibrosis and adipose tissue deposition, both of which, paradoxically, can be prevented with a pro-adipogenic agent.
Topics: Male; Female; Humans; Mice; Animals; Receptor, Platelet-Derived Growth Factor alpha; PPAR gamma; Rosiglitazone; Lymphedema; Fibrosis
PubMed: 38131378
DOI: 10.1172/jci.insight.165324 -
Biochemia Medica Feb 2024Antidiuretic hormone (ADH) is secreted by the posterior pituitary gland. Unsuppressed release of ADH leads to hyponatremia. This condition is referred to as syndrome of... (Review)
Review
Antidiuretic hormone (ADH) is secreted by the posterior pituitary gland. Unsuppressed release of ADH leads to hyponatremia. This condition is referred to as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hereby, a case report is presented on ciprofloxacin-induced SIADH. A 67-year-old male patient was examined in the emergency room with symptoms of lethargy, headache, lack of attention, and a generally depressed mood lasting for three days. One week prior, empirical antimicrobial therapy involving ciprofloxacin for prostatitis was initiated. Laboratory analysis showed no relevant abnormalities except for hyponatremia (Na = 129 mmol/L). Chronic hyponatremia, thyroid dysfunction, and adrenal dysfunction were ruled out. Serum osmolality was 263 mOsmol/kg, urine osmolality was 206 mOsmol/kg, and urine sodium was 39 mmol/L. Given that all criteria for SIADH were met, ciprofloxacin was discontinued, and fluid restriction was advised. Four days later, the patient's serum sodium concentrations nearly normalized (Na = 135 mmol/L), and all symptoms resolved. The Naranjo Scale yielded a score of 8, supporting the likelihood of a probable adverse reaction to ciprofloxacin. This case is presented to raise awareness among clinicians about the potential of ciprofloxacin to cause even mild hyponatremia.
Topics: Male; Humans; Aged; Inappropriate ADH Syndrome; Hyponatremia; Ciprofloxacin; Sodium
PubMed: 38125612
DOI: 10.11613/BM.2024.010803 -
Translational Andrology and Urology Nov 2023Lymphoceles, lymph fluid-filled collections within the body lacking epithelial lining, are a common complication after pelvic lymph node dissection (PLND) during...
BACKGROUND
Lymphoceles, lymph fluid-filled collections within the body lacking epithelial lining, are a common complication after pelvic lymph node dissection (PLND) during robot-assisted radical prostatectomy (RARP). In this study, we investigate the incidence of imaging confirmed symptomatic lymphoceles (SLC) in a centralized high-volume operating centre and assess predictive factors and treatment.
METHODS
We retrospectively analysed the incidence, risk factors and treatment of a consecutive series of patients who underwent PLND during RARP between September 2018 and January 2021 in a specialised operation clinic. We compared baseline patients' characteristics and pathological data between men who developed an SLC and those who did not. A multivariable model for the occurrence of an SLC was created using predetermined, clinically relevant variables to investigate predictive factors.
RESULTS
We analysed the records of 404 patients. The median follow-up length was 29 months. A total of 30 (7.4%) patients with an SLC were identified. The median time until SLC presentation was 12 weeks [interquartile range (IQR), 4-31 weeks], one-third of SLCs presented after 180 days. Percutaneous drainage was performed in 17 patients (57%). On multivariable analysis, only body mass index (BMI) significantly increased the odds of an SLC [per 5 odds ratio (OR) =1.7; 95% confidence interval (CI): 1.0-3.0, P=0.04].
CONCLUSIONS
SLCs present significant consequences, as more than half of patients with an SLC were treated with percutaneous drainage. Many patients presented later than the centralized surgeons' postoperative follow-up, a drawback of centralized care. An increased BMI was a significant predictor for SLC.
PubMed: 38106676
DOI: 10.21037/tau-23-416 -
Frontiers in Molecular Biosciences 2023Prostate cancer (PCa), one of the most prevalent malignancies affecting men worldwide, presents significant challenges in terms of early detection, risk stratification,...
Prostate cancer (PCa), one of the most prevalent malignancies affecting men worldwide, presents significant challenges in terms of early detection, risk stratification, and active surveillance. In recent years, liquid biopsies have emerged as a promising non-invasive approach to complement or even replace traditional tissue biopsies. Extracellular vesicles (EVs), nanosized membranous structures released by various cells into body fluids, have gained substantial attention as a source of cancer biomarkers due to their ability to encapsulate and transport a wide range of biological molecules, including RNA. In this study, we aimed to validate 15 potential RNA biomarkers, identified in a previous EV RNA sequencing study, using droplet digital PCR. The candidate biomarkers were tested in plasma and urinary EVs collected before and after radical prostatectomy from 30 PCa patients and their diagnostic potential was evaluated in a test cohort consisting of 20 benign prostate hyperplasia (BPH) and 20 PCa patients' plasma and urinary EVs. Next, the results were validated in an independent cohort of plasma EVs from 31 PCa and 31 BPH patients. We found that the levels of NKX3-1 ( = 0.0008) in plasma EVs, and tRF-Phe-GAA-3b ( < 0.0001) tRF-Lys-CTT-5c ( < 0.0327), piR-28004 ( = 0.0081) and miR-375-3p ( < 0.0001) in urinary EVs significantly decreased after radical prostatectomy suggesting that the main tissue source of these RNAs is prostate and/or PCa. Two mRNA biomarkers-GLO1 and NKX3-1 showed promising diagnostic potential in distinguishing between PCa and BPH with AUC of 0.68 and 0.82, respectively, in the test cohort and AUC of 0.73 and 0.65, respectively, in the validation cohort, when tested in plasma EVs. Combining these markers in a biomarker model yielded AUC of 0.85 and 0.71 in the test and validation cohorts, respectively. Although the PSA levels in the blood could not distinguish PCa from BPH in our cohort, adding PSA to the mRNA biomarker model increased AUC from 0.71 to 0.76. This study identified two novel EV-enclosed RNA biomarkers-NKX3-1 and GLO1-for the detection of PCa, and highlights the complementary nature of GLO1, NKX3-1 and PSA as combined biomarkers in liquid biopsies of PCa.
PubMed: 38099195
DOI: 10.3389/fmolb.2023.1279854