Role of α2-adrenoceptors in the lateral parabrachial nucleus in the control of body fluid homeostasis

Central α2-adrenoceptors and the pontine lateral parabrachial nucleus (LPBN) are involved in the control of sodium and water intake. Bilateral injections of moxonidine (α2-adrenergic/imidazoline receptor agonist) or noradrenaline into the LPBN strongly increases 0.3 M NaCl intake induced by a combined treatment of furosemide plus captopril. Injection of moxonidine into the LPBN also increases hypertonic NaCl and water intake and reduces oxytocin secretion, urinary sodium, and water excreted by cell-dehydrated rats, causing a positive sodium and water balance, which suggests that moxonidine injected into the LPBN deactivates mechanisms that restrain body fluid volume expansion. Pretreatment with specific α2-adrenoceptor antagonists injected into the LPBN abolishes the behavioral and renal effects of moxonidine or noradrenaline injected into the same area, suggesting that these effects depend on activation of LPBN α2-adrenoceptors. In fluid-depleted rats, the palatability of sodium is reduced by ingestion of hypertonic NaCl, limiting intake. However, in rats treated with moxonidine injected into the LPBN, the NaCl palatability remains high, even after ingestion of significant amounts of 0.3 M NaCl. The changes in behavioral and renal responses produced by activation of α2-adrenoceptors in the LPBN are probably a consequence of reduction of oxytocin secretion and blockade of inhibitory signals that affect sodium palatability. In this review, a model is proposed to show how activation of α2-adrenoceptors in the LPBN may affect palatability and, consequently, ingestion of sodium as well as renal sodium excretion.

Mutations in the HFE gene and sporadic amyotrophic lateral sclerosis risk: a meta-analysis of observational studies

Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegenerative diseases. The H63D and C282Y polymorphisms in theHFE gene may be involved in the development of sporadic amyotrophic lateral sclerosis (ALS) through the disruption of iron homeostasis. However, studies investigating the relationship between ALS and these two polymorphisms have yielded contradictory outcomes. We performed a meta-analysis to assess the roles of the H63D and C282Y polymorphisms of HFEin ALS susceptibility. PubMed, MEDLINE, EMBASE, and Cochrane Library databases were systematically searched to identify relevant studies. Strict selection criteria and exclusion criteria were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed- or random-effect model was selected, depending on the results of the heterogeneity test. Fourteen studies were included in the meta-analysis (six studies with 1692 cases and 8359 controls for C282Y; 14 studies with 5849 cases and 13,710 controls for H63D). For the C282Y polymorphism, significant associations were observed in the allele model (Y vs C: OR=0.76, 95%CI=0.62-0.92, P=0.005) and the dominant model (YY+CYvs CC: OR=0.75, 95%CI=0.61-0.92, P=0.006). No associations were found for any genetic model for the H63D polymorphism. The C282Y polymorphism in HFE could be a potential protective factor for ALS in Caucasians. However, the H63D polymorphism does not appear to be associated with ALS.

Cyclin D1 expression in prostate carcinoma

The purpose of this study was to investigate the relationship between cyclin D1 expression and clinicopathological parameters in patients with prostate carcinoma. We assessed cyclin D1 expression by conventional immunohistochemistry in 85 patients who underwent radical prostatectomy for prostate carcinoma and 10 normal prostate tissue samples retrieved from autopsies. We measured nuclear immunostaining in the entire tumor area and based the results on the percentage of positive tumor cells. The preoperative prostate-specific antigen (PSA) level was 8.68±5.16 ng/mL (mean±SD). Cyclin D1 staining was positive (cyclin D1 expression in >5% of tumor cells) in 64 cases (75.4%) and negative (cyclin D1 expression in ≤5% of tumor cells) in 21 cases (including 15 cases with no immunostaining). Normal prostate tissues were negative for cyclin D1. Among patients with a high-grade Gleason score (≥7), 86% of patients demonstrated cyclin D1 immunostaining of >5% (P<0.05). In the crude analysis of cyclin D1 expression, the high-grade Gleason score group showed a mean expression of 39.6%, compared to 26.9% in the low-grade Gleason score group (P<0.05). Perineural invasion tended to be associated with cyclin D1 expression (P=0.07), whereas cyclin D1 expression was not associated with PSA levels or other parameters. Our results suggest that high cyclin D1 expression could be a potential marker for tumor aggressiveness.

Accuracy of dose planning for prostate radiotherapy in the presence of metallic implants evaluated by electron spin resonance dosimetry

Radiotherapy is one of the main approaches to cure prostate cancer, and its success depends on the accuracy of dose planning. A complicating factor is the presence of a metallic prosthesis in the femur and pelvis, which is becoming more common in elderly populations. The goal of this work was to perform dose measurements to check the accuracy of radiotherapy treatment planning under these complicated conditions. To accomplish this, a scale phantom of an adult pelvic region was used with alanine dosimeters inserted in the prostate region. This phantom was irradiated according to the planned treatment under the following three conditions: with two metallic prostheses in the region of the femur head, with only one prosthesis, and without any prostheses. The combined relative standard uncertainty of dose measurement by electron spin resonance (ESR)/alanine was 5.05%, whereas the combined relative standard uncertainty of the applied dose was 3.35%, resulting in a combined relative standard uncertainty of the whole process of 6.06%. The ESR dosimetry indicated that there was no difference (P>0.05, ANOVA) in dosage between the planned dose and treatments. The results are in the range of the planned dose, within the combined relative uncertainty, demonstrating that the treatment-planning system compensates for the effects caused by the presence of femur and hip metal prostheses.

Comparative antiproliferation of human prostate cancer cells by ethanolic extracts of two groups of Brazilian propolis

Two groups of propolis, group 12, which was collected in the southeastern Brazil and group 13, which was collected in the northeastern Brazil, were examined for antiproliferation of primary malignant tumor (RC-58T/h/SA#4)-derived human prostate cancer cells and human prostate epithelial cells. The strongest inhibition of RC-58T/h/SA#4 cells was observed in propolis group 13 extracts, whereas moderate growth inhibition was observed in human prostate epithelial cells in comparison with group 12. It can be said that the Brazilian propolis of group 13 contains important chemical ingredients.

Identification and validation of novel prostate cancer biomarkers

Prostate cancer (PCa) has emerged as the most commonly diagnosed lethal cancer in European men. PCa is a heterogeneous cancer that in the majority of the cases is slow growing: consequently, these patients would not need any medical treatment. Currently, the measurement of prostate-specific antigen (PSA) from blood by immunoassay followed by digital rectal examination and a pathological examination of prostate tissue biopsies are the most widely used methods in the diagnosis of PCa. These methods suffer from a lack of sensitivity and specificity that may cause either missed cancers or overtreatment as a consequence of over-diagnosis. Therefore, more reliable biomarkers are needed for a better discrimination between indolent and potentially aggressive cancers. The aim of this thesis was the identification and validation of novel biomarkers for PCa. The mRNA expression level of 14 genes including AMACR, AR, PCA3, SPINK1, TMPRSS2-ERG, KLK3, ACSM1, CACNA1D, DLX1, LMNB1, PLA2G7, RHOU, SPON2, and TDRD1 was measured by a truly quantitative reverse transcription PCR in different prostate tissue samples from men with and without PCa. For the last eight genes the function of the genes in PCa progression was studied by a specific siRNA knockdown in PC-3 and VCaP cells. The results from radical prostatectomy and cystoprostatectomy samples showed statistically significant overexpression for all the target genes, except for KLK3 in men with PCa compared with men without PCa. Statistically significant difference was also observed in low versus high Gleason grade tumors (for PLA2G7), PSA relapse versus no relapse (for SPON2), and low versus high TNM stages (for CACNA1D and DLX1). Functional studies and siRNA silencing results revealed a cytotoxicity effect for the knock-down of DLX1, PLA2G7, and RHOU, and altered tumor cell invasion for PLA2G7, RHOU, ACSM1, and CACNA1D knock-down in 3D conditions. In addition, effects on tumor cell motility were observed after silencing PLA2G7 and RHOU in 2D monolayer cultures. Altogether, these findings indicate the possibility of utilizing these new markers as diagnostic and prognostic markers, and they may also represent therapeutic targets for PCa.

Collagen binding integrins and cancer testis antigens in prostate cancer and melanoma

Camilla Pelo Collagen Binding Integrins and Cancer Testis Antigens in Prostate Cancer and Melanoma Department of Biochemistry, MediCity Research Laboratory, University of Turku, Finland Annales Universitatis Turkuensis, Painosalama Oy, Turku, Finland 2016 ABSTRACT Prostate cancer is the second most common cancer in men worldwide. The incidence of melanoma, in turn, is increasing faster than any other cancer incidences. In Finland, more than 5000 prostate cancer and 1200 new melanoma cases are diagnosed each year. One approach to further understand the cellular processes involved in prostate cancer and melanoma is to gain better knowledge about alterations in gene expression and their potential impact on the progression of the diseases. This thesis is focused on expression studies in two gene families; integrins and cancer testis antigens (CT antigens), in human prostate adenocarcinoma and advanced human melanoma. Integrins are heterodimeric transmembrane receptors which regulate many important cellular processes such as cell proliferation, migration and survival. CT antigens are frequently expressed in different types of cancers, but are only expressed in testis in healthy individuals. CT antigens are also highly immunogenic proteins. Due to the properties mentioned above, integrins and CT antigens can function as target molecules for the development of cancer diagnostics and drugs. One of the main purposes of this thesis was to study the expression of the four collagen binding integrins α1β1, α2β1, α10β1, α11β1 and the cancer testis antigen 16 (CT16) in cancer cell lines and human tissues of prostate cancer and metastatic melanoma. Additional aims included studies on the biological role of CT16 and the abundance of CT16 in sera of advanced melanoma patients. The prognostic and diagnostic significance of CT16 and the collagen binding integrins were also evaluated. Expression studies on collagen binding integrins and the CT antigen CT16 in melanoma and prostate cancer were limited and the biological role of CT16 was unknown. In this thesis, the expression levels of α2β1 and α11β1 were found to be significantly altered in prostate cancer tissues. Integrin α2β1 decreased gradually during disease progression while α11 was elevated in prostate carcinoma compared to healthy tissues. In advanced melanoma, enhanced levels of α2 were associated with a significant shorter overall survival in advanced melanoma. In this thesis, CT16 was identified as a frequently expressed melanoma CT antigen with an anti-apoptotic function. To conclude, this thesis presents α2β1 and CT16, as potential and promising biomarkers for advanced melanoma. This thesis reports also the first functional study of CT16. Keywords: Collagen binding integrins, α1β1, α2β1, α10β1, α11β1, Cancer Testis antigens, CT16, melanoma, prostate cancer, expression