Pituitary adenylate cyclase-activating peptide-immunoreactive nerve fibers in the cat eye

Purpose: To study the occurrence and distribution of the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) in ocular and orbital structures of the cat. Methods: Immunocytochemistry to localize PACAP and double immunostaining to detect co-localization of PACAP with other neuropeptides. Results: Numerous PACAP-immunoreactive nerve fibers were observed in the lacrimal gland, choroid and retroocular arteries. There was a sparse supply of PACAP-containing nerve fibers in the iris, ciliary body and conjunctiva. Subpopulations of PACAP-containing nerve fibers stored vasoactive intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP). Around 10% of the ganglion cells in the sphenopalatine ganglion harbored PACAP immunoreactivity. In the trigeminal ganglion around 5% of the neuronal cell bodies and in the ciliary ganglion only occasional ganglion cells contained PACAP immunoreactivity. PACAP immunoreactivity co-localized with VIP in the sphenopalatine ganglion and with CGRP in the trigeminal ganglion. Conclusion: PACAP-containing nerves in the eye and associated structures demonstrate a distribution pattern resembling that of VIP. Subpopulations of nerve fibers containing PACAP immunoreactivity store VIP or CGRP immunoreactivity. Neuronal PACAP in the eye and orbit may take part in regulation of smooth muscle tone, glandular secretion and sensory processing.     

Polyamine metabolism in gliomas

Summary Biosynthesis of the polyamines putrescine, spermidine, and spermine has been found to be activated in tissues with cellular proliferation. In the present study we have investigated polyamine levels and the activity of the first rate-limiting enzyme ornithine decarboxylase (ODC) in tumour samples obtained during operation of 202 patients with gliomas. Biochemical data were closely related to the grading of malignancy and to the morphological characteristics of each sample. Mean ODC activity was significantly higher in all gliomas as compared to peritumoural non-neoplastic brain. Furthermore, it was significantly higher (p 0.001) in anaplastic gliomas who grade III and IV (9.0 ± 9.6 nmol/g/h) than in gliomas WHO grade I and II (3.3 ± 4.2 nmol/g/h). Highest enzyme activity (58.5 nmol/g/h) was found in solid and vital parts of malignant tumours, whereas predominantly necrotic areas exhibited low ODC activity (< 1 nmol/g/h). Thus, intra- and interindividual variability of ODC activity corresponded well to histomorphological heterogeneity in high-grade gliomas. Putrescine levels also increased with rising grade of malignancy, whereas spermidine and spermine levels did not correlate with the histological grading. In conclusion, high ODC activity represents a biochemical marker of malignancy in gliomas, but low values do not prove benignity. The present study reinforces the need of further and more extensive tumour sampling closely related to follow-up investigations in the heterogeneous group of gliomas.     

Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer.

PURPOSE: In recent studies, we showed that TP53 gene mutation or high levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen receptor (ER)-alpha-positive primary breast tumors predict a poor disease outcome for patients treated with first-line tamoxifen for advanced disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand, wild-type TP53 may decrease VEGF production. EXPERIMENTAL DESIGN: In the present study, we aimed to assess the combined predictive value of TP53 gene mutation and VEGF status of 160 advanced breast cancer patients with ER-positive tumors who were treated with tamoxifen (median follow-up from start of tamoxifen treatment, 64 months). To assess TP53 gene mutation status, the entire open reading frame was sequenced; for VEGF status, an ELISA was used. RESULTS: In univariate analysis, both TP53 gene mutation (28% of the tumors) and a VEGF level above the median value were significantly associated with a short progression-free survival, post-relapse overall survival, and a poor rate of response to tamoxifen. In Cox multivariate regression analysis including the traditional predictive factors, the addition of TP53 gene mutation and VEGF status, alone or in combination, significantly predicted a poor efficacy of tamoxifen treatment. When the two factors were combined, a significantly decreased odds ratio was seen for the rate of response (odds ratio, 0.27). Similarly, an increased hazard ratio (HR) was seen for progression-free survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the group with mutant TP53 and high VEGF compared with the group with both risk factors absent. CONCLUSIONS: Combined TP53 gene mutation status and high VEGF levels of ER-positive primary breast tumors independently predict a poor course of the disease of patients with advanced breast cancer treated with tamoxifen. These patients, having unfavorable tumor characteristics, might benefit more from other types of (individualized) treatment protocols.     

Systemic and local immunomodulatory effects of intravesical BCG therapy in patients with superficial urinary bladder carcinomas

PURPOSE: The aim of the present study was to elucidate whether only local, or also systemic immunomodulatory effects may be induced by intravesical BCG therapy of superficial urinary bladder cancer. MATERIALS AND METHODS: A total of 37 patients with stages Ta to T1b superficial transitional cell bladder carcinomas received 6 weekly BCG instillations after transurethral resection of the tumor. In a first group of 19 patients blood was taken before each BCG instillation and 6 weeks after the last one. In a second group of 18 patients blood and urine was taken before and 2, 6, and 24 hours after each BCG instillation. In the mitogen-stimulated whole blood cell cultures and in the urine samples the levels of the cytokines IL-1beta, IL-2, IL-10, TNF-alpha and IFN-gamma were determined by enzymoimmunological tests. Additionally, in all plasma and urine samples the levels of TNF-p75-receptor (TNF-p75-R) were measured. RESULTS: Comparison of ex vivo leukocyte cytokine production in the blood cell cultures of the patients of group I revealed no significant change in the levels of the cytokines. In contrast, TNF-p75-R plasma levels increased significantly during the experimental time of 12 weeks (p < or =0.01). In the blood cell cultures of the group II patients a different daytime variation of cytokine production was seen, compared to the 19 healthy controls. After BCG instillation the normal peak cytokine production in the evening was suppressed. A significant rise in plasma TNF-p-75-R levels was measured 24 hours after BCG instillation (p < or =0.05). In the urine of these patients significantly higher levels of all measured cytokines and TNF-p75-R were observed 6 to 24 hours after the instillation. CONCLUSIONS: The results suggest that besides the well known local immune activation, BCG instillation also leads to a modulation of peripheral immune mechanisms.     

Fatigue and relating factors in high-risk breast cancer patients treated with adjuvant standard or high-dose chemotherapy: a longitudinal study.

PURPOSE: Determine whether standard or high-dose chemotherapy leads to changes in fatigue, hemoglobin (Hb), mental health, muscle and joint pain, and menopausal status from pre- to post-treatment and to evaluate whether fatigue is associated with these factors in disease-free breast cancer patients. PATIENTS AND METHODS: Eight hundred eighty-five patients were randomly assigned between two chemotherapy regimens both followed by radiotherapy and tamoxifen. Fatigue was assessed using vitality scale (score < or = 46 defined as fatigue), poor mental health using mental health scale (score < or = 56 defined as poor mental health) both of Short-Form 36, muscle and joint pain with Rotterdam Symptom Checklist, and Hb levels were assessed before and 1, 2, and 3 years after chemotherapy. RESULTS: Fatigue was reported in 20% of 430 assessable patients (202 standard-dose, 228 high-dose) with at least a 3-year follow-up, without change over time or difference between treatment arms. Mean Hb levels were lower following high-dose chemotherapy. Only 5% of patients experienced fatigue and anemia. Mental health score was the strongest fatigue predictor at all assessment moments. Menopausal status had no effect on fatigue. Linear mixed effect models showed that the higher the Hb level (P = .0006) and mental health score (P < .0001), the less fatigue was experienced. Joint (P < .0001) and muscle pain (P = .0283) were associated with more fatigue. CONCLUSION: In 3 years after treatment, no significant differences in fatigue were found between standard and high-dose chemotherapy. Fatigue did not change over time. The strongest fatigue predictor was poor mental health.     

Pore Narrowing of Mesoporous Silica Materials

To use mesoporous silicas as low-k materials, the pore entrances must be really small to avoid diffusion of metals that can increase the dielectric constant of the low-k dielectric. In this paper we present a new method to narrow the pores of mesoporous materials through grafting of a cyclic-bridged organosilane precursor. As mesoporous material, the well-studied MCM-41 powder was selected to allow an easy characterization of the grafting reactions. Firstly, the successful grafting of the cyclic-bridged organosilane precursor on MCM-41 is presented. Secondly, it is demonstrated that pore narrowing can be obtained without losing porosity by removing the porogen template after grafting. The remaining silanols in the pores can then be end-capped with hexamethyl disilazane (HMDS) to make the material completely hydrophobic. Finally, we applied the pore narrowing method on organosilica films to prove that this method is also successful on existing low-k materials.     

Disconnectedness from the here-and-now: a phenomenological perspective as a counteract on the medicalisation of death wishes in elderly people

When elderly people are ideating on manners to end their lives, because they feel life is over and no longer worth living, it is important to understand their lived experiences, thoughts and behaviour in order to appropriately align care, support and policy to the needs of these people. In the literature, the wish to die in elderly people is often understood from a medical, psychopathological paradigm, referred to as cognitive impairment, depressive disorder, pathological bereavement, and suicidality. In this paper, we evaluate this dominant paradigm by considering three serious limitations, namely: (1) the risk of epistemic transformation; (2) the risk of reduction; and (3) the risk of obscuring the social and cultural embeddedness. Drawing on insights from our empirical–phenomenological research on the issue of elderly and the self-chosen death, this paper argues for a phenomenological perspective to counteract the medicalisation of death wishes in elderly people.     

Activation of RhoA,B,C by Yersinia Cytotoxic Necrotizing Factor (CNFy) Induces Apoptosis in LNCaP Prostate Cancer Cells

Prostate cancer is the most common malignancy, accounting for about 25% of all incident cases among men in industrialized countries. The human androgen-dependent prostate cancer cell line LNCaP, which is derived from a metastatic lesion of human prostatic adenocarcinoma, is frequently used to study prostate cancer associated signaling pathways in vitro. Recently it was described that Rho GTPase activation in these cells leads to apoptotic responses. We used the bacterial toxins CNFy and CNF1, which specifically and directly activate Rho GTPases by deamidation of a single glutamine. We asked whether these Rho activators could induce apoptosis in LNCaP cells. Our results indicate that RhoA activation, induced by CNFy, does lead to intrinsic apoptosis of the cells. Analysis of the underlying signaling pathway reveals that apoptosis induction requires the activity of Rho kinase (ROCK) and myosin activation, an apoptotic pathway previously identified in cancer stem cells.