Prostatic Acid Phosphatase Research Articles

IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC)

BackgroundSipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that...

Developmental validation of a multiplex proteomic assay for the identification of forensically relevant biological fluids

The aim of this study was to validate a multiplex proteomic assay for the identification of high-specificity protein biomarkers by multiple reaction monitoring mass spectrometry on a triple quadrupole mass spectrometer for the accurate, reliable, and confirmatory identification of bodily fluids commonly encountered in a forensic context. This includes the identification of peripheral blood, semen, saliva, urine, and vaginal/menstrual fluid. The assay is able to efficiently identify pure or mixed stains through the identification of target peptide fragments originating from tissue-specific proteins including: uromodulin from urine; prostatic acid phosphatase, prostate specific antigen and semenogelin-II for semen; statherin, submaxillary gland androgen-regulated protein 3B and amylase for saliva; cornulin, martrigel-induced gene C4 protein, suprabasin and neutrophil gelatinase-associated lipocalin for vaginal/menstrual fluid; and alpha-1 antitrypsin, hemopexin, and hemoglobin subunit beta for peripheral blood. Based on the results of the developmental validation studies which included an assessment of reproducibility and repeatability, sensitivity, species specificity, carryover, mixtures, as well as a series of casework type samples. Only a small selection of case samples was unable to unambiguously identify the target fluid including urine recovered from substrates as well as semen when mixed with personal lubricants. Overall, the mass spectrometry-based workflow offers significant advantages compared to existing serological methods.

Yohimbine hydrochloride inhibits benign prostatic hyperplasia by downregulating steroid 5α-reductase type 2

Benign prostatic hyperplasia (BPH) is a frequently encountered disease in older men that affects sexual function and is capable of causing lower urinary tract dysfunction. Unfortunately, current treatment options for BPH primarily seek to address the lower urinary tract dysfunction aspect of the disease and do not improve sexual function. Yohimbine has been effectively used for decades to treat erectile dysfunction. Therefore, the objective of this study was to evaluate the inhibitory effect of yohimbine on BPH and explore the associated underlying mechanisms. Thirty-six rats were randomly divided into the control, BPH, finasteride (1 mg/kg), and yohimbine (2, 4, and 8 mg/kg) groups. Except for the rats in the control group, those in the other groups were subcutaneously injected testosterone propionate (5 mg/kg/day) daily for a period of 4 weeks to establish BPH models. They were also administration the corresponding drug daily for a period of 6 weeks. After the treatments, in addition to determining prostate wet weight and index, the histopathological status of the prostate was observed, and the levels of testosterone, dihydrotestosterone, prostatic acid phosphatase, the prostate-specific antigen, proliferating cell nuclear antigen, and steroid 5α-reductase were determined. Specifically, the administration of 2, 4, and 8 mg/kg yohimbine inhibited prostatic index increase by 46.7, 55.1, and 69.3%, respectively, in BHP rats. Further, yohimbine significantly reduced the levels of dihydrotestosterone, prostatic acid phosphatase, prostate-specific antigen, proliferating cell nuclear antigen, and steroid 5α-reductase, suggesting that it exerts beneficial effects against BPH by modulating the steroid 5α-reductase pathway.

Comparative effects of combined use of alcohol with cannabis and tobacco on testicular function in rats.

Alcoholism has been linked to problems with male reproductive function. The combined effects of alcohol, cannabis, and tobacco were compared in this study. A total of 35 rats were assigned randomly into seven groups A-G: animals in A were administered distilled water. Animals in B-G were either administered alcohol orally (30ml 40% alcohol) or exposed to smoke from ignited tobacco (exposure to smoke from 0.7g tobacco for 5 min) or cannabis (exposure to smoke from 0.7g tobacco and cannabis for 5 min): B (orally administered alcohol), C (exposed to the smoke from tobacco), D (exposed to smoke from cannabis), E (treated with alcohol and exposed to smoke from tobacco), F (treated with alcohol and exposed to smoke from cannabis), G (treated with alcohol and exposed to smokes from tobacco and cannabis). Assays were carried on the testicular homogenate after a 14-day treatment. There was a significant increase in activity of alkaline phosphatase (P≤0.05), concentrations of cholesterol, glutathione reductase, and malondialdehyde in treated rats by the co-administration of alcohol with cannabis and tobacco compared with the control group. The combined treatment also caused degeneration and morphological distortions of testicular cells. The biochemical and histoarchitectural change was due to oxidative damage attributable to the synergistic effects. The high binding energy of tetrahydrocannabinol ligand to prostate acid phosphatase may be a prediction that the ligand can have an inhibitory effect on the function of enzymes in the prostate.

Plasma level of prostate related-antigen peptide-reactive IgG is a prognostic factor of patients with breast cancer treated with personalized peptide vaccines.

The present study assessed plasma IgG in patients with metastatic recurrent breast cancer (mrBC) that is reactive to various T-cell epitope peptides of prostate-related antigens (PRAs), such as prostate-specific antigen, prostate-specific membrane antigen and prostate acid phosphatase. Patients were treated with personalized peptide vaccines (PPVs) which were selected and administered from a panel of candidate peptides based on human leukocyte antigen-types and prevaccination IgG levels to each peptide. The peptide panel consisted of 27 cytotoxic T-lymphocyte-epitope peptides derived from tumor-associated antigens, not including PRA. PRA peptides and peptide panels were retrospectively analyzed in 77 PPV-treated patients. The results revealed that PRA reactive IgG levels were increased after vaccination in 31 of the 97 patients included in the present study. Although there was no significant association between anti-PRA peptide levels and progression-free survival (PFS) or overall survival, anti-PRA peptide levels were significantly associated with PFS (P=0.009) in estrogen-receptor positive (ER+) patients with cancer. The results suggested that plasma anti-PRA IgG levels may be a useful prognostic marker for monitoring PPVs, particularly for ER+ patients with mrBC (trial registration no. from the UMIN Clinical Trials Registry, UMIN000001844).

Development of Parallel Reaction Monitoring Assays for the Detection of Aggressive Prostate Cancer Using Urinary Glycoproteins.

Recently, we have found that two urinary glycoproteins, prostatic acid phosphatase (ACPP) and clusterin (CLU), combined with serum prostate-specific antigen (PSA) can serve as a three-signature panel for detecting aggressive prostate cancer (PCa) based on a quantitative glycoproteomic study. To facilitate the translation of candidates into clinically applicable tests, robust and accurate targeted parallel reaction monitoring (PRM) assays that can be widely adopted in multiple labs were developed in this study. The developed PRM assays for the urinary glycopeptides, FLN*ESYK from ACPP and EDALN*ETR from CLU, demonstrated good repeatability and a sufficient working range covering three to four orders of magnitude, and their performance in differentiating aggressive PCa was assessed by the quantitative analysis of urine specimens collected from 69 nonaggressive (Gleason score = 6) and 73 aggressive (Gleason ≥ 8) PCa patients. When ACPP combined with CLU, the discrimination power was improved from an area under a curve (AUC) of 0.66 to 0.78. By combining ACPP, CLU, and serum PSA to form a three-signature panel, the AUC was further improved to 0.83 (sensitivity: 84.9%, specificity: 66.7%). Since the serum PSA test alone had an AUC of 0.68, our results demonstrated that the new urinary glycopeptide PRM assays can serve as an adjunct to the serum PSA test to achieve better predictive power toward aggressive PCa. In summary, our developed PRM assays for urinary glycopeptides were successfully applied to clinical PCa urine samples with a promising performance in aggressive PCa detection.

TGM4: an immunogenic prostate-restricted antigen

BackgroundProstate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the...

The impact of prior radiation therapy on outcome in a phase 2 trial combining sipuleucel-T (SipT) and ipilimumab (Ipi) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).

5045 Background: SipT is an FDA-approved autologous cellular immunotherapy targeting Prostatic Acid Phosphatase (PAP) that improves survival in patients with mCRPC. Combining immunotherapies could provide opportunities to enhance efficacy. We performed a randomized phase II trial adding CTLA-4 blockade with Ipi following SipT treatment and assessed whether timing of this sequence could modify immune and/or clinical responses to this treatment. Methods: Fifty chemotherapy-naïve mCRPC pts were randomized to receive ipi (4 doses of 3mg/kg every 3 weeks) either immediately (n = 24) or 3 weeks (n = 26) following completion of sipT. Blood was collected at various time points of the study. Immune-related adverse events (irAE) were recorded. The primary endpoint was to determine the proportion of pts who achieved an antibody titer of ³1:400 to PA2024, the targeting cassette in SipT and/or PAP. Clinical response was defined as ³30% reduction in serum prostate specific antigen (PSA) compared to pre-treatment levels. Radiographic progression-free survival (rPFS) and overall survival (OS) were defined as from the date of randomization to the date of radiographic progression and the date of death, respectively, or last follow-up date. Luminex assays for anti-PAP and anti-PA2024 specific serum IgG and ELISpot for IFN-g production against PAP and PA2024 were used to assess antigen-specific B and T cells responses, respectively. Modulation of circulating immune cells was evaluated by CyTOF. Results: SipT + Ipi did not induce any unexpected irAEs. The timing of Ipi did not significantly alter the rates of clinical response, rPFS, OS, toxicity, nor antigen-specific B and T cell responses. Clinical responses were observed in 6 of 50 (12%) pts and were often durable (median 140 days, range 55-689 days). Pts experiencing irAEs were more likely to have a PSA response (P = 0.001). The median rPFS was 5.7 months (mos). The median OS was 31.9 mos. This treatment induced antibody and T cell immune responses irrespective of treatment arm. Single cell assessment bt CyTOF demonstrated that treatment induced CD4 and CD8 T cell activation that was more pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells were associated with better clinical outcomes even at baseline. Lower frequencies of CTLA-4 positive T cells was associated with prior radiation therapy. Prior radiation treatment was associated with improved rPFS (6.5 vs. 3.9 mos, P = 0.004). Conclusions: These findings suggest that pre-existing immunity may help dictate responsiveness to Ipi and SipT combination immunotherapy in mCRPC pts. Prior radiation therapy seems to leave not only a lasting impression on the T cell compartment, but also can associate with improved clinical outcomes with subsequent immunotherapy. Clinical trial information: NCT01804465.

ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Prostatic Acid Phosphatase Is a Progenitor Cell Marker That Persists After Androgen Ablation

Introduction: Prostatic Acid Phosphatase (PAP), a protein phosphatase and 5’ecto-nucleotidase, is expressed in prostate cancer (PCa) bone metastases and correlates with poor survival. Growing evidence suggests that PAP is not regulated by androgens, but rather by factors in the tumor microenvironment.Hypothesis: We hypothesized that PAP is a marker for a more progenitor type PCa cell and its expression is androgen-independent, persisting in castration-resistant disease.Methods: Protein expression of PAP and three androgen-regulated proteins, the Androgen Receptor (AR), Prostate-Specific Antigen (PSA), and ETS-related gene (ERG) protein, was assessed with immunohistochemistry in human fetal prostate (9.5 - 20 weeks of gestational age), archival human PCa bone metastases, and human PCa cell lines. VCaP cells were treated in vitro with dihydrotestosterone (DHT) and the effects on AR and PAP protein expression determined with Western Blotting. PAP-expressing PCa cell lines (LNCaP, C42B, and VCaP) were inoculated subcutaneously (s.c.) into SCID mice. To model tumor-bone interaction, LNCaP and MC3T3 osteoblast cells were co-inoculated s.c. into SCID mice. A VCaP castration study with surgical or sham castration was performed after tumors were palpable and effects of castration on tumor growth and protein expression determined.Results: PAP expression was observed in the fetal prostate as early as 11.5 weeks of gestational age prior to PSA and AR expression. Strong PAP expression was noted in all human PCa bone metastases examined, both treatment-naive and castrate-resistant (n=10). In vitro, VCaP cells expressed high levels of AR and PAP protein and DHT treatment increased AR and decreased PAP protein expression. In vivo, PAP expression was observed in all tumor models; LNCaP (low PAP expression), C42B (moderate PAP expression) and VCaP (high PAP expression). Castrated VCaP tumors underwent tumor stasis, were significantly smaller compared to intact mice, had decreased AR, PSA and ERG expression but persistent expression of PAP. Double staining of tumors for PAP and AR demonstrated a population of cells that were positive for PAP but negative for AR expression in hypoxic areas near necrosis. Inoculation of LNCaP cells with MC3T3 osteoblastic cells increased PAP expression in vivo.Conclusions: PAP is expressed early in human fetal prostate development prior to the secretion of significant androgens or expression of AR. In mouse xenograft tumors and human PCa bone metastases, androgens did not significantly regulate PAP expression. Both hypoxia and stroma increased PAP expression. These data demonstrate that PAP is a marker of early progenitor cells, is persistently expressed after castration and is upregulated by tumor microenvironmental factors. PAP may be a suitable target for the treatment of castration-resistant metastatic disease.

Mining The Cancer Genome Atlas gene expression data for lineage markers in distinguishing bladder urothelial carcinoma and prostate adenocarcinoma

Distinguishing bladder urothelial carcinomas from prostate adenocarcinomas for poorly differentiated carcinomas derived from the bladder neck entails the use of a panel of lineage markers to help make this distinction. Publicly available The Cancer Genome Atlas (TCGA) gene expression data provides an avenue to examine utilities of these markers. This study aimed to verify expressions of urothelial and prostate lineage markers in the respective carcinomas and to seek the relative importance of these markers in making this distinction. Gene expressions of these markers were downloaded from TCGA Pan-Cancer database for bladder and prostate carcinomas. Differential gene expressions of these markers were analyzed. Standard linear discriminant analyses were applied to establish the relative importance of these markers in lineage determination and to construct the model best in making the distinction. This study shows that all urothelial lineage genes except for the gene for uroplakin III were significantly expressed in bladder urothelial carcinomas (p < 0.001). In descending order of importance to distinguish from prostate adenocarcinomas, genes for uroplakin II, S100P, GATA3 and thrombomodulin had high discriminant loadings (> 0.3). All prostate lineage genes were significantly expressed in prostate adenocarcinomas(p < 0.001). In descending order of importance to distinguish from bladder urothelial carcinomas, genes for NKX3.1, prostate specific antigen (PSA), prostate-specific acid phosphatase, prostein, and prostate-specific membrane antigen had high discriminant loadings (> 0.3). Combination of gene expressions for uroplakin II, S100P, NKX3.1 and PSA approached 100% accuracy in tumor classification both in the training and validation sets. Mining gene expression data, a combination of four lineage markers helps distinguish between bladder urothelial carcinomas and prostate adenocarcinomas.

Electroacupuncture Relieves Neuropathic Pain by Inhibiting Degradation of the Ecto-Nucleotidase PAP in the Dorsal Root Ganglions of CCI Mice

Electroacupuncture (EA) is an effective treatment for relieving neuropathic pain, however, its underlying effect mechanisms remain unclear. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs). To test this, we applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5′-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase–polymerase chain reaction, western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation. EA treatment alleviated CCI surgery induced mechanical allodynia. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4–L6 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP. In summary, EA treatment alleviated peripheral nerve injury-induced tactile allodynia in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs. Our findings provide new insights into the underlying mechanisms of pain relief provided by acupuncture. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China 414 (Nos. 81874371, 81803853, 81771133, 81970995), Shanghai Shenkang Hospital Development Center Founding (SHDC12017X11), and Shanghai municipal Education Commission-Gaofeng Clinical Medicine Support [20191903], Shanghai Municipal Key Clinical Specialty (shslczdzk03601)，State Key Laboratoy of Neuroscience(SKLN-201803). Declaration of Interests: The authors have declared that no competing interests exist regarding the publication of this paper. Ethics Approval Statement: All of the experiments were approved by the Animal Care and Use Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine, and all protocols followed the policies issued by the National Institutes of Health and the International Association for the Study of Pain.

LC-MS/MS-Based Quantitative Proteomics Analysis of Different Stages of Non-Small-Cell Lung Cancer.

Lung cancer has a higher incidence rate and mortality rate than all other cancers. Early diagnosis and treatment of lung cancer remain a major challenge, and the 5-year survival rate of its patients is only 15%. Basic and clinical research, especially the discovery of biomarkers, is crucial for improving the diagnosis and treatment of lung cancer patients. To identify novel biomarkers for lung cancer, we used the iTRAQ8-plex labeling technology combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the serum and urine of patients with different stages of lung adenocarcinoma and healthy individuals. A total of 441 proteins were identified in the serum, and 1,161 proteins were identified in the urine. The levels of elongation factor 1-alpha 2, proteasome subunit alpha type, and spermatogenesis-associated protein increased significantly in the serum of patients with lung cancer compared with those in healthy controls. The levels of transmembrane protein 143, cadherin 5, fibronectin 1, and collectin-11 decreased significantly in the serum of patients with metastases compared with those of nonmetastatic lung cancer patients. In the urine of stage III and IV lung cancer patients, the prostate-specific antigen and prostatic acid phosphatase decreased significantly, whereas neutrophil defensin 1 increased significantly. The results of LC-MS/MS were confirmed by enzyme-linked immunosorbent assay (ELISA) for transmembrane protein 143, cadherin 5, fibronectin 1, and collectin-11 in the serum. These proteins may be a potential early diagnosis and metastasis biomarkers for lung adenocarcinoma. Furthermore, the relative content of these markers in the serum and urine could be used to determine the progression of lung adenocarcinoma and achieve accurate staging and diagnosis.

Potential therapeutic effects of Ulva lactuca water fraction on monosodium glutamate-induced testicular and prostatic tissue damage in rats.

Male infertility is considered one of the most critical health problems that are expected to expand worldwide. Ulva lactuca is a species of green seaweeds which is known to be a rich source of many important nutrients. Accordingly, this study is designated to investigate the therapeutic role of Ulva lactuca water fraction (UL) against monosodium glutamate (MSG)-induced male reproductive system disorders in male rats. Ulva lactuca methanolic crude extract was prepared firstly, and then water-dissolved compounds of this crude methanolic extract were separated. Ulva lactuca water fraction active phenolic compounds were determined using high-performance liquid chromatography (HPLC). Thirty-two male rats were divided equally into four groups; male infertility was induced in sixteen experimental animals by MSG at dose of 15mg/Kg for 45days. Eight infertile animals were treated with 100mg/Kg of Ulva lactuca water fraction for 30days. The rest of the animals were divided into two control groups; one control group (eight animals) was used to study the effect of UL on healthy rats at dose of 100mg/Kg for 30days and healthy control group (eight animals). Semen quality parameters (concentration and motility ratio), serum testosterone, prostate-specific antigen (PSA), and phosphatases were estimated by using standard protocols. Moreover, prooxidants and endogenous antioxidant enzymes were measured in prostate and testis homogenates. In addition, relative expression of pro-inflammatory genes (inducible nitric oxide synthase (i-NOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α alpha (TNF-α), and tumor protein (P53)) were assessed in testicular and prostatic tissues. Finally, histological alterations were measured by hematoxylin and eosin (H&E) stain. Results revealed that Ulva lactuca water fraction contains active phenolic constituents responsible for its antioxidant bioactivity. Oral administration of MSG significantly induced histological alterations. Oxidative stress was observed with elevated levels of nitric oxide (NO), thiobarbituric acid reactive substances (TBARS), and xanthine oxidase (XO) activity in both testis and prostate tissues. MSG adversely affected prostate function via elevation of PSA, prostatic acid phosphatases (PAPs), and total acid phosphatases (TAPs). In addition, it upregulated pro-inflammatory genes in testis and prostate tissues. Meanwhile, MSG reduced serum testosterone, semen quality, and antioxidant enzyme activities (glutathione peroxidase (GPx), glutathione-s-transferase (GST), and superoxide dismutase (SOD)). Treatment with UL notably ameliorated the state of oxidative stress and downregulated the expression of pro-inflammatory gene markers. This study highlighted the potential efficacy of Ulva lactuca water fraction on MSG-induced male infertility in rats. Therapeutic effect of UL on oxidative stress and inflammation induced by MSG in testicular and prostatic tissues.

A study of serum levels of prostate specific antigen, prostate acid phosphatase in prostate cancer patients and its complications on liver

Background: The prostate cancer (PC) is most leading disorders in human beings particularly in males. Prostate specific antigen (PSA) and prostate acid phosphatase (PAP) are tumor markers useful for early detection and diagnosis of PC. In prostate cancer patients more prone to liver and bone cancer metastasis because in these patients elevated levels of serum liver function tests (LFT) and these liver enzymes more specific for early detection of pathological changes in liver and bones.Methods: This is the case control study was carried out the association of serum levels of PSA/PAP inpatients with prostate cancer and healthy controls. Total 120 subjects included in this study in that 60 PC patients and 60 controls was included and blood was collected. The serum PSA levels are estimated by ELISA, PAP estimated by Kinetic method and LFT Was analyzed by commercial kits. Results: The present study evaluates the serum levels of LFT, PSA and PAP in patients with prostate cancer and compared with the healthy controls. The statistically significant difference between the PSA, PAP and LFT levels in patients with PC when compared to controls. The positive correlation in between PSA, PAP with LFT (p=0.001).Conclusions: This study suggesting that the serum PSA, PAP levels sensitive parameters for early detection of prostatic cancer and also for these patients’ frequent measurements of serum liver function tests, useful for early detection of significant pathological changes occurs in the liver and bone cancers metastasis from prostate.

Dual concentration-dependent effect of ascorbic acid on PAP(248–286) amyloid formation and SEVI-mediated HIV infection

Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid peptide PAP(248–286), which forms amyloid fibrils termed SEVI (semen-derived enhancer of viral infection) that increase the infectivity of HIV-1 by orders of magnitude. Inhibiting amyloid formation by PAP(248–286) may mitigate the sexual transmission of HIV-1. Several vitamins have been shown to reduce the aggregation of amyloids such as Aβ, α-Synuclein, and Tau, which are associated with neurodegenerative diseases. Since ascorbic acid (AA, vitamin C) is the most abundant vitamin in semen with average concentrations of 0.4 mM, we here examined how AA affects PAP(248–286) aggregation in vitro. Using ThT binding assays, transmission electron microscopy, and circular dichroism spectroscopy, a dual and concentration-dependent behavior of AA in modulating PAP(248–286) fibril formation was observed. We found that low molar ratios of AA:PAP(248–286) promoted whereas high molar ratios inhibited PAP(248–286) fibril formation. Accordingly, PAP(248–286) aggregated in the presence of low amounts of AA enhanced HIV-1 infection, whereas excess amounts of AA during aggregation reduced the infectivity enhancing effect in cell culture. Collectively, this work provides a biophysical insight into the effect of AA, an important seminal component, on SEVI fibrillation which might impact amyloid formation kinetics, thereby modulating the biological activity of semen amyloids.

Therapeutic metastatic prostate cancer vaccines: lessons learnt from urologic oncology

IntroductionTherapeutic cancer vaccines have been recognized as a promising treatment option in clinical oncology for nearly three decades. However, despite many efforts, only one cancer vaccine – sipuleucel-T, activating the anti-PAP (prostatic acid phosphatase) immune response, has obtained Food and Drug Administration (FDA) approval.Material and methodsThis review describes the most advanced research on the use of therapeutic cancer vaccines in the treatment of prostate cancer.ResultsIn addition to sipuleucel-T, which was approved in urologic oncology in 2010, four cancer vaccines were and have been tested in phase III clinical trials in patients with metastatic castration resistant prostate cancer (mCRPC): GVAX (prostate cancer variant) containing irradiated prostate cancer cell, PPV peptide vaccine, PCVAC/PCa dendritic cell-based vaccine and PROSTVAC anti PSA (prostate-specific antigen) vaccine. This review compares the most promising and best-studied cancer vaccines: sipuleucel-T and PROSTVAC. Currently, both vaccines have been tested in combination with other therapeutic approaches, including check point inhibitors.ConclusionsIt seems possible that the efficacy of sipuleucel-T and PROSTVAC could be increased in combination therapy with other medications.

Transient receptor potential vanilloid subtype 1 depletion mediates mechanical allodynia through cellular signal alterations in small-fiber neuropathy

Transient receptor potential vanilloid subtype 1 (TRPV1) is a polymodal nociceptor that monitors noxious thermal sensations. Few studies have addressed the role of TRPV1 in mechanical allodynia in small-fiber neuropathy (SFN) caused by sensory nerve damage. Accordingly, this article reviews the putative mechanisms of TRPV1 depletion that mediates mechanical allodynia in SFN. The intraepidermal nerve fibers (IENFs) degeneration and sensory neuronal injury are the primary characteristics of SFN. Intraepidermal nerve fibers are mainly C-polymodal nociceptors and Aδ-fibers, which mediated allodynic pain after neuronal sensitization. TRPV1 depletion by highly potent neurotoxins induces the upregulation of activating transcription factor 3 and IENFs degeneration which mimics SFN. TRPV1 is predominately expressed by the peptidergic than nonpeptidergic nociceptors, and these neurochemical discrepancies provided the basis of the distinct pathways of thermal analgesia and mechanical allodynia. The depletion of peptidergic nociceptors and their IENFs cause thermal analgesia and sensitized nonpeptidergic nociceptors respond to mechanical allodynia. These distinct pathways of noxious stimuli suggested determined by the neurochemical-dependent neurotrophin cognate receptors such as TrkA and Ret receptors. The neurogenic inflammation after TRPV1 depletion also sensitized Ret receptors which results in mechanical allodynia. The activation of spinal TRPV1(+) neurons may contribute to mechanical allodynia. Also, an imbalance in adenosinergic analgesic signaling in sensory neurons such as the downregulation of prostatic acid phosphatase and adenosine A1 receptors, which colocalized with TRPV1 as a membrane microdomain also correlated with the development of mechanical allodynia. Collectively, TRPV1 depletion-induced mechanical allodynia involves a complicated cascade of cellular signaling alterations.

Direct seminal fluid identification by protease-free high-resolution mass spectrometry.

Serological screening of sexual assault evidence has traditionally focused on enzyme activity and immunochromatographic assays that provide only a presumptive indication of seminal fluid and have limited sensitivity relative to DNA testing. Seminal fluid detection based on protein mass spectrometry represents a "Next Gen" serological technology that overcomes the specificity and sensitivity limitations of traditional serological screening but requires time-consuming sample preparation protocols. This paper describes a novel "peptidomics" approach to seminal fluid detection that eliminates the need for lengthy trypsin digestion. This streamlines sample preparation to a one-step process followed by high-resolution mass spectrometry to identify naturally occurring seminal fluid peptides and low-molecular weight proteins. Multiple protein biomarkers of seminal fluid were consistently and confidently identified based on the multiplexed detection of numerous endogenous peptides. These included Semenogelin I and II (90% and 86% sequence coverage, respectively); Prostate Specific Antigen/p30 (29% sequence coverage); and Prostatic Acid Phosphatase (24% sequence coverage). The performance of this streamlined peptidomics approach to seminal fluid identification in a forensic context was also assessed using simulated casework samples of the type typically collected as part of a sexual assault examination (e.g., oral and vaginal swabs stained with semen). The resulting data demonstrate that sub-microliter quantities of seminal fluid on cotton swabs can be recovered and reliably detected. This supports the forensic applicability of a peptidomic assay for seminal fluid identification with same-day sample preparation and analysis. Future development and streamlined multiplex peptidomic assays for additional biological stains can easily be envisaged.

Prostate Specific Antigen (PSA): The Historical Perspective

In 1970, shortly after joining Roswell Park Memorial Institute, the New York State institute for the study of malignant diseases, the author initiated investigations on the use of tumor cell products for diagnosis and therapy of cancer. Immunochemical approaches were used primarily to differentiate quantitatively or qualitatively normal cells from tumor cells. Prostate cancer was a major area of endeavor, with the goal to identify and characterize prostate tumor specific and associated antigens, and eventually to develop a simple but reliable blood test for prostate cancer. Prostate cancer research had not received much attention at the time this work was begun. The early studies focused upon, among others, prostatic acid phosphatase, alkaline phosphatase, and new prostate tumor markers. By the mid 1970s, three able investigators--Dr. Ching-Li Lee, Dr. Carl S. Killian, and Dr. Ming C. Wang--had joined the prostate cancer research team, and were invited to take charge of these three research projects, respectively.