Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

BACKGROUND: Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. METHODS: AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. RESULTS: AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. CONCLUSIONS: AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance.

Presence of task-1 channel in the laryngeal mucosa in the newborn lamb.

Nearly 40 potassium channels have been described in respiratory epithelial cells. Of these are found several members of the 4-transmembrane domain, 2-pore K(+) channel family (K2P family), namely Twik-1 and -2, Trek-1 and -2, Task-2, -3, and -4, Thik-1, and KCNK7. The aim of this study was to verify whether the Twik-related acid-sensitive K(+) channel, subtype 1 (Task-1) (also known as KCNK3), is present in the laryngeal mucosa in the newborn lamb. Through the use of immunohistochemistry and nested polymerase chain reaction (PCR) amplification, results indicate that Task-1 protein and mRNA are present in the laryngeal mucosa, in both the ciliated, pseudostratified columnar (respiratory) epithelium and the nonkeratinized, stratified squamous epithelium. The complete ovine Task-1 protein sequence showed high homology levels with previously reported mouse, bovine, and human Task-1 sequences. This includes a complete homology for the C-terminal amino acid sequence, which is mandatory for protein trafficking to the cell membrane. These results represent the first demonstration that Task-1, a pH-sensitive channel responsible for setting membrane potential, is present in the laryngeal mucosa of a newborn mammal.

Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer.

BACKGROUND: Seladin-1 belongs to a subgroup of androgen-dependent genes associated with anti-proliferative, pro-differentiation, and pro-apoptotic functions and plays a protective role against oncogenic stress. The present study aims to investigate the localization and expression of Seladin-1 protein in normal and tumoral human prostatic tissues as well as to explore its role in proliferation and steroid secretion in androgen-dependent (LnCaP) and androgen-independent (DU145) cell lines and in human prostate primary cell culture. METHODS: Seladin-1 protein localization and expression were assessed on whole tissue sections by tissue array/immunohistochemistry and following immunofluorescence and Western blotting. Proliferation (Ki67 fluorescence labeling and cell counts) and steroid secretion (ELISA) were assessed in cell lines and primary epithelial cell cultures. RESULTS: In human prostatic tissue and cells, Seladin-1 was mostly localized within epithelial and rarely within stromal cells and primarily present in secretory luminal cells of normal and tumoral prostate cells. Its expression was increased in low-risk prostate cancer but reduced in advanced prostate cancers when compared to normal tissues. Seladin-1 was highly expressed in LnCaP, whereas its expression level was lower in DU145 cells. Seladin-1 inhibition by treatment with its specific inhibitor, U18666A (75 nM), increased proliferation in LnCaP and primary cell culture, as well as testosterone and dihydrotestosterone levels in both LnCaP and DU145 cell lines. CONCLUSIONS: Seladin-1 involvement in proliferation and secretion suggests that its downregulation may be a major mechanism causing prostate cancer evolution. Seladin-1 may thus potentially decrease cell growth and steroid dependency in low-grade prostate cancer.

Effects of reflux laryngitis on non-nutritive swallowing in newborn lambs.

Reflux laryngitis in infants may be involved not only in laryngeal disorders, but also in disorders of cardiorespiratory control through its impact on laryngeal function. Our objective was to study the effect of reflux laryngitis on non-nutritive swallowing (NNS) and NNS-breathing coordination. Two groups of six newborn lambs, randomized into laryngitis and control groups, were surgically instrumented for recording states of alertness, swallowing and cardiorespiratory variables without sedation. A mild to moderate reflux laryngitis was induced in lambs from the experimental group. A significant decrease in the number of NNS bursts and apneas was observed in the laryngitis group in active sleep (p=0.03). In addition, lower heart and respiratory rates, as well as prolonged apnea duration (p<0.0001) were observed. No physiologically significant alterations in NNS-breathing coordination were observed in the laryngitis group. We conclude that a mild to moderate reflux laryngitis alters NNS burst frequency and autonomous control of cardiac activity and respiration in lambs.

Malignant peripheral nerve sheath tumour of the renal parenchyma presenting as a fast growing atypical renal cyst.

Malignant peripheral nerve sheath tumours (MPNST) of the kidney are very rare, with only 3 cases reported in the English and French literature. However, we report the first case of fast growing atypical renal cyst where a magnetic resonance imaging was an interesting adjunct to the computed tomography scan in imaging this rare tumour.

A 17 year old male with a testicular fibrothecoma: a case report.

We herein report the case of a right-sided testicular fibrothecoma in a 17 year old male and review the pertinent literature relatable to this rare, benign lesion. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7738283021019280.

Effects of postnatal environmental tobacco smoke on non-nutritive swallowing-breathing coordination in newborn lambs.

While prenatal environmental tobacco smoke (ETS) exposure is a well-known risk factor for sudden infant death syndrome, the effect of postnatal ETS exposure is less clear. The objective of this study was to investigate the effect of postnatal ETS exposure on non-nutritive swallowing (NNS) and NNS-breathing coordination, which are crucial to prevent aspiration related-cardiorespiratory events. Eighteen newborn lambs (6 per group) were randomly exposed to either 10 cigarettes/day, 20 cigarettes/day or room air for 15 days. Lambs were instrumented for recording states of alertness, swallowing, electrocardiogram and breathing; recordings were performed in non-sedated lambs at the end of ETS exposure. Urinary cotinine/creatinine ratio confirmed relevant real-life exposure. Postnatal ETS exposure had no effect on NNS frequency but tended to decrease inspiratory NNS (p=0.07) during quiet sleep. No effect on respiratory or heart rate (p>0.6), apnea index (p=0.2) or sleep states (p=0.3) was observed. In conclusion, postnatal ETS exposure in lambs had only mild effects on NNS-breathing coordination.

Strategies for biochemical and pathologic quality assurance in a large multi-institutional biorepository; The experience of the PROCURE Quebec Prostate Cancer Biobank.

Well-characterized, high-quality fresh-frozen prostate tissue is required for prostate cancer research. As part of the PROCURE Prostate Cancer Biobank launched in 2007, four University Hospitals in Quebec joined to bank fresh frozen prostate tissues from radical prostatectomies (RP). As the biobank progressed towards allocation, the nature and quality of the tissues were determined. RP tissues were collected by standardized alternate mirror-image or biopsy-based targeted methods, and frozen for banking. Clinical/pathological parameters were captured. For quality control, two presumed benign and two presumed cancerous frozen, biobanked tissue blocks per case (10/site) were randomly selected during the five years of collection. In a consensus meeting, 4 pathologists blindly evaluated slides (n=160) and graded quality, Gleason score (GS), and size of cancer foci. The quality of tissue RNA (37/40 cases) was assessed using the RNA Integrity Number. The biobank included 1819 patients of mean age: 62.1 years; serum PSA: 8 ng/ml; prostate weight: 47.8 g; GS: 7; and pathological stage: T2 in 64.5%, T3A in 25.5% and T3B in 10% of cases. Of the 157 evaluable slides, 79 and 78 had benign and cancer tissue, respectively. GS for the 37 cancer-positive cases were: 6 in 9, 7 in 18 and >7 in 10 and, in most instances, in concordance with final GS. In 40% of slides containing cancer, foci occupied ≥50% of block surface and 42% had a diameter ≥1 cm. Tissue was well preserved and consistently yielded RNA of very good quality with RNA Integrity Number (RIN) >7 for 97% of cases (mean=8.7 ± 0.7) during the five-year collection period. This study confirms the high quality of randomly selected benign and cancerous fresh-frozen prostate tissues of the PROCURE Quebec Prostate Cancer Biobank. These results strengthen the uniqueness of this large prospective resource for prostate cancer research.

Effects of simulated reflux laryngitis on laryngeal chemoreflexes in newborn lambs.

It has been suggested that reflux laryngitis (RL) is involved in apneas-bradycardias of the newborn. The aim of the present study was to develop a unique RL model in newborn lambs to test the hypothesis that RL enhances the cardiorespiratory components of the laryngeal chemoreflexes (LCR) in the neonatal period. Gastric juice surrogate (2 ml of normal saline solution with HCl pH 2 + pepsin 300 U/ml) (RL group, n = 6) or normal saline (control group, n = 6) was repeatedly injected onto the posterior aspect of the larynx, 3 times a day for 6 consecutive days, via a retrograde catheter introduced into the cervical esophagus. Lambs instilled with gastric juice surrogate presented clinical signs of RL, as well as moderate laryngitis on histological observation. Laryngeal chemoreflexes were thereafter induced during sleep by injection of 0.5 ml of HCl (pH 2), ewe's milk, distilled water or saline into the laryngeal vestibule via a chronic, transcutaneous supraglottal catheter. Overall, RL led to a significantly greater respiratory inhibition compared with the control group during LCR, including longer apnea duration (P = 0.01), lower minimal respiratory rate (P = 0.002), and a more prominent decrease in arterial hemoglobin saturation (SpO(2)) (P = 0.03). No effects were observed on cardiac variables. In conclusion, 1) our unique neonatal ovine model presents clinical and histological characteristics of RL; and 2) the presence of RL in newborn lambs increases the respiratory inhibition observed with LCR, at times leading to severe apneas and desaturations.

Effects of postnatal smoke exposure on laryngeal chemoreflexes in newborn lambs.

Laryngeal chemoreflexes (LCR), which are elicited by the contact of liquids such as gastric refluxate with laryngeal mucosa, may trigger some cases of sudden infant death syndrome. Indeed, while LCR in mature mammals consist of protective responses, previous animal data have shown that LCR in immature newborns can include laryngospasm, apnea, bradycardia, and desaturation. The present study was aimed at testing the hypothesis that postnatal exposure to cigarette smoke is responsible for enhancing cardiorespiratory inhibition observed with LCR. Eight lambs were exposed to cigarette smoke (20 cigarettes/day) over 16 days and compared with seven control lambs. Urinary cotinine/creatinine ratio was measured at a level relevant to previously published levels in infants. On days 15 and 16, 0.5 ml of HCl (pH 2), milk, distilled water, or saline was injected onto the larynx via a chronic supraglottal catheter during sleep. Results showed that exposure to cigarette smoke enhanced respiratory inhibition (P < 0.05) and tended to enhance cardiac inhibition and decrease swallowing and arousal during LCR (P < 0.1). Overall, these results were observed independently of the state of alertness and the experimental solution tested. In conclusion, 16-day postnatal exposure to cigarette smoke increases cardiorespiratory inhibition and decreases protective mechanisms during LCR in nonsedated full-term lambs.

Radiation-induced xerostomia: is octreotide the solution?

OBJECTIVE: In this study, we looked for evidence that octreotide, a drug used specifically in acromegaly and other digestive pathologies, can have a radioprotective effect on salivary glands. This effect has already been proven on the pituitary gland, which is why we postulated that octreotide could act the same way on rat parotid glands. METHOD: A prospective randomized controlled study on animals was conducted. With a noninvasive technique, we collected saliva from the parotid glands of 18 anesthetized rats at time 0 (preirradiation) and 1 month (postirradiation). Each sampling technique lasted 40 minutes, with pilocarpine injection at time 0 and 20 minutes. Saliva was collected bilaterally. Eighteen rats, nine in the saline group and nine in the octreotide group, were randomized. The substance was injected 30 minutes before irradiation. Thirty gray were given with the gamma knife on the left parotid gland of each rat following a computerized targeting method. Each gland was examined after the last saliva collection to determine the percentage of five criteria: fibrosis, ducts, fat, vessels, and acini. RESULTS: Data are available for 17 rats (nine in the octreotide group and eight in the saline group). Statistical analysis was done with a t-test (independent and paired). We noted that the postirradiation secretion in the left (radiated) gland was diminished compared with the right (nonradiated) gland in the saline group (p = .014). Fibrosis was increased in the irradiated (left) gland in both groups (p = .024 in the octreotide group and p = .033 in the saline group). The percentage of duct cells was more important in the left (radiated) gland of the octreotide group (p = .046). A trend appeared for a decrease in acinic cells only in the control group (p = .063). CONCLUSION: Octreotide acted as a radioprotective agent on rat parotid glands 1 month after irradiation with 30 Gy given with the gamma knife.