Hormone concentration, metabolic disorders and immunoexpression of androgen and estrogen-alpha receptors in men with benign prostatic hyperplasia and testosterone deficiency syndrome

Introduction. A slight decrease in blood testosterone level in men is a physiological state associated with the aging. The aim of our study was to evaluate the occurrence of hormone and metabolic disorders, as well as the immunolocalization and immunoexpression of androgen receptors (AR) and estrogen-alpha receptors (ERa) in the prostates of men with benign prostatic hyperplasia (BPH) and coexisting testosterone deficiency syndrome (TDS). Material and methods. The study involved 150 men, diagnosed with and receiving pharmacological treatment for BPH. Concentrations of glucose, total cholesterol (TCh), high-density lipoproteins (HDL), low-density lipoproteins (LDL), and triglycerides (TG) were determined in blood serum. Serum concentrations of total testosterone (TT), free testosterone (FT), estradiol (E2), luteinizing hormone (LH), insulin (I), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor 1 (IGF-1) were measured by ELISA. The number of AR-positive cells and ERa-positive cells were measured in prostate sections of men with BPH. Results. Patients eligible for transurethral resection of the prostate and TDS were significantly more likely to have higher abdominal circumference and higher serum levels of insulin and IGF-1 as well as lower levels of FT and SHBG than control subjects with BPH and no TDS. Quantitative analysis revealed 35.8% AR-positive colum­nar epithelial cells and 24.3% AR-positive stromal cells in prostates of BPH patients with TDS and 30.5% and 23.0%, respectively, in BPH patients without TDS. However, the differences between the study and the control groups were statistically not significant. In prostates of BPH patients with TDS the immunoexpression of ERa was observed in 2.88% of the columnar epithelial cells and 0.39% of stromal cells. In BPH patients without TDS ERa-positive cells were only found in 0.04% of columnar epithelial cells and 0.62% of prostatic stromal cells. Conclusions. Considering the statistically significantly higher levels of I and IGF-1 and larger abdominal circumference of men with BPH and TT deficiency, it can be supposed that visceral obesity and carbohydrate disorders may contribute to the reduction of testosterone concentration. The results of our study indicate a relationship between TT concentration in the plasma of patients with BPH and the percentage of AR-positive cells in the prostate.

An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer

Various experimental studies indicate potential involvement of bone marrow (BM)-derived stem cells (SCs) in malignancy development and progression. In this study, we comprehensively analysed systemic trafficking of various populations of BM-derived SCs (BMSCs), i.e., mesenchymal, haematopoietic, endothelial stem/progenitor cells (MSCs, HSCs, EPCs respectively), and of recently discovered population of very small embryonic/epiblast-like SCs (VSELs) in pancreatic cancer patients. Circulating CD133^+/Lin^−/CD45^−/CD34^+ cells enriched for HSCs, CD105^+/STRO^-1^+/CD45− cells enriched for MSCs, CD34^+/KDR^+/CD31^+/CD45− cells enriched for EPCs and small CXCR4^+CD34^+CD133^+ subsets of Lin^−CD45^− cells that correspond to VSELs were enumerated and sorted from blood samples derived from 29 patients with pancreatic cancer, and 19 healthy controls. In addition, plasma levels of stromal-derived factor-1 (SDF-1), growth/inhibitory factors and sphingosine-1-phosphate (S1P; chemoattractants for SCs), as well as, of complement cascade (CC) molecules (C3a, C5a and C5b-9/membrane attack complex – MAC) were measured. Higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (P < 0.05 and 0.01 respectively). This trafficking of BMSCs was associated with significantly elevated C5a (P < 0.05) and C5b-9/MAC (P < 0.005) levels together with S1P concentrations detected in plasma of cancer patients, and seemed to be executed in a SDF-1 independent manner. In conclusion, we demonstrated that in patients with pancreatic cancer, intensified peripheral trafficking of selected populations of BMSCs occurs. This phenomenon seems to correlate with systemic activation of the CC, hepatocyte growth factor and S1P levels. In contrast to previous studies, we demonstrate herein that systemic SDF-1 levels do not seem to be linked with increased mobilization of stem cells in patients with pancreatic cancer

Association between the Perioperative Antioxidative Ability of Platelets and Early Post-Transplant Function of Kidney Allografts: A Pilot Study

BACKGROUND: Recent studies have demonstrated that the actions of platelets may unfavorably influence post-transplant function of organ allografts. In this study, the association between post-transplant graft function and the perioperative activity of platelet antioxidants was examined among kidney recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups. METHODOLOGY/PRINCIPAL FINDINGS: Activities of superoxide dismutase, catalase, glutathione transferase (GST), glutathione peroxidase, and glucose-6-phosphate dehydrogenase (G6P) were determined and levels of glutathione, oxidized glutathione, and isoprostane were measured in blood samples collected immediately before and during the first and fifth minutes of renal allograft reperfusion. Our results demonstrated a significant increase in isoprostane levels in all groups. Interestingly, in DGF patients, significantly lower levels of perioperative activity of catalase (p<0.02) and GST (p<0.02) were observed. Moreover, in our study, the activity of platelet antioxidants was associated with intensity of perioperative oxidative stress. For discriminating SGF/DGF from EGF, sensitivity, specificity, and positive and negative predictive values of platelet antioxidants were 81-91%, 50-58%, 32-37%, and 90-90.5%, respectively. CONCLUSIONS: During renal transplantation, significant changes occur in the activity of platelet antioxidants. These changes seem to be associated with post-transplant graft function and can be potentially used to differentiate between EGF and SGF/DGF. To the best of our knowledge, this is the first study to reveal the potential protective role of platelets in the human transplantation setting

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Designing of Biodegradable and Biocompatible Release and Delivery Systems of Selected Antioxidants Used in Cosmetology

Conjugates of antioxidants p-anisic (p-AA) and vanillic (VA) acids with nontoxic, biocompatible, and biodegradedable oligo-<i>(R,S)</i>-(3-hydoxybutyrate) carrier were synthesized, and their structural and biological characterization was performed. The molecular structure of the bioconjugates, in which antioxidants are covalently bonded with oligo­(3-hydroxybutyrate) (OHB) chains, has been proven by mass spectrometry supported by NMR. The bioconjugate hydrolytic degradation studies allowed gaining thorough insight into the hydrolysis process and confirmed the release of p-AA and VA. In vitro studies demonstrated that all of the conjugates studied were well tolerated by KB and HaCaT cell lines, as they had no marked cytotoxicity, while conjugates with a relatively short OHB carrier are optimal to support keratinocyte function. The preliminary study of the biological activity confirmed the protective effect of VA–OHB conjugates against H₂O₂-induced lipid peroxidation in human keratinocytes (HaCaT). It was also demonstrated that the selected bioconjugates can penetrate all layers of the skin, which shows their functionality and opens up their potential application in cosmetology