ABSTRACT
Neuroendocrine tumors (NETs) arise from disseminated neuroendocrine cells and express general and specific neuroendocrine markers. Neuropeptide S receptor 1 (NPSR1) is expressed in neuroendocrine cells and its ligand neuropeptide S (NPS) affects cell proliferation. Our aim was to study whether NPS/NPSR1 could be used as a biomarker for neuroendocrine neoplasms and to identify the gene pathways affected by NPS/NPSR1. We collected a cohort of NETs comprised of 91 samples from endocrine glands, digestive tract, skin, and lung. Tumor type was validated by immunostaining of chromogranin-A and synaptophysin expression and tumor grade was analyzed by Ki-67 proliferation index. NPS and NPSR1 expression was quantified by immunohistochemistry using polyclonal antibodies against NPS and monoclonal antibodies against the amino-terminus and carboxy-terminus of NPSR1 isoform A (NPSR1-A). The effects of NPS on downstream signaling were studied in a human SH-SY5Y neuroblastoma cell line which overexpresses NPSR1-A and is of neuroendocrine origin. NPSR1 and NPS were expressed in most NET tissues, with the exception of adrenal pheochromocytomas in which NPS/NPSR1 immunoreactivity was very low. Transcriptome analysis of NPSR1-A overexpressing cells revealed that mitogen-activated protein kinase (MAPK) pathways, circadian activity, focal adhesion, transforming growth factor beta, and cytokine-cytokine interactions were the most altered gene pathways after NPS stimulation. Our results show that NETs are a source of NPS and NPSR1, and that NPS affects cancer-related pathways.
Subject(s)
Endocrine Gland Neoplasms/physiopathology , Gastrointestinal Neoplasms/physiopathology , Neuroendocrine Tumors/physiopathology , Receptors, G-Protein-Coupled/physiology , Signal Transduction/physiology , Skin Neoplasms/physiopathology , Adult , Aged , Antibodies, Monoclonal/immunology , Antibody Specificity , Biomarkers, Tumor/immunology , Biomarkers, Tumor/physiology , Cell Proliferation , Endocrine Gland Neoplasms/pathology , Female , Gastrointestinal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Lung Neoplasms/physiopathology , Male , Middle Aged , Neuroendocrine Tumors/pathology , Neuropeptides/immunology , Neuropeptides/physiology , Receptors, G-Protein-Coupled/immunology , Retrospective Studies , Skin Neoplasms/pathologyABSTRACT
Neuropeptide S receptor 1 (NPSR1) was recently found to be genetically associated with inflammatory bowel disease in addition to asthma and related traits. Epithelia of several organs express NPSR1 isoforms A and B, including the intestine and the skin, and NPSR1 appears to be upregulated in inflammation. In this study, we used cell lines and tissue samples to characterize the expression of NPSR1 and its ligand neuropeptide S (NPS) in inflammation. We used polyclonal and monoclonal antibodies to investigate the expression of NPS and NPSR1 in intestinal diseases, such as celiac disease and food allergy, and in cutaneous inflammatory disorders. We found that NPSR1-A was expressed by the enteroendocrine cells of the gut. Overall, the expression pattern of NPS was similar to its receptor suggesting an autocrine mechanism. In an NPSR1-A overexpressing cell model, stimulation with NPS resulted in a dose-dependent upregulation of glycoprotein hormone, alpha polypeptide (CGA), tachykinin 1 (TAC1), neurotensin (NTS) and galanin (GAL) encoding peptide hormones secreted by enteroendocrine cells. Because NPSR1 was also expressed in macrophages, neutrophils, and intraepithelial lymphocytes, we demonstrated that stimulation with the pro-inflammatory cytokines tumour necrosis factor alpha and interferon gamma increased NPSR1 expression in the THP-1 monocytic cells. In conclusion, similar to other neuropeptides and their receptors, NPSR1 signalling might play a dual role along the gut-brain axis. The NPS/NPSR1 pathway may participate in the regulation of the peptide hormone production in enteroendocrine cells of the small intestine.
Subject(s)
Intestinal Mucosa/metabolism , Peptide Hormones/metabolism , Protein Isoforms/metabolism , Receptors, G-Protein-Coupled/metabolism , Skin/metabolism , Adult , Animals , Cell Line , Child , Humans , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/metabolism , Intestinal Diseases/metabolism , Intestinal Diseases/pathology , Intestines/cytology , Monocytes/immunology , Protein Isoforms/genetics , Rabbits , Receptors, G-Protein-Coupled/genetics , Skin/cytology , Skin Diseases/metabolism , Skin Diseases/pathology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A method was developed for determining the spatial distribution of a source from downward and upward irradiance measurements at a single wavelength in seawater of known optical properties. The algorithm uses measurements at two depths located an arbitrary distance apart and solves two nonlinear equations for two parameters that fit a globally exponential or linear source shape. Complex spatially dependent source shapes can be estimated from an irradiance profile by piecing together estimates from neighboring measurement pairs. Numerical tests illustrate the sensitivity of the algorithm to depth, measurement spacing, chlorophyll concentration, sensor noise, and uncertainty in the a priori assumed inherent optical properties. The algorithm works well with widely spaced measurements, moderate sensor noise, and uncertainties in the optical properties regardless of whether the assumed and true profiles are the same shape.
Subject(s)
Health Services Accessibility , Internal Medicine , Patient Admission , Primary Health Care , Decision Making , Humans , Internal Medicine/organization & administration , Internal Medicine/standards , Internal Medicine/statistics & numerical data , Primary Health Care/organization & administration , Primary Health Care/standards , Primary Health Care/statistics & numerical data , SwedenABSTRACT
The aim of this study was to examine whether observed high mortality from ischaemic heart disease (IHD) among males in the municipality of Hofors, Sweden, is accurate, or the result of some artefact. The validity of death certificates from Hofors municipality and from a control area (Gävle) were ascertained by comparing them with medical records from hospitals and district physician offices, and reports from clinical or medicolegal autopsies. The results indicate that the observed high mortality from IHD among Hofors males cannot be explained by deficiencies in establishing the cause of death. Results from other validity studies indicate, however, that there is a risk of local variation when reporting causes of death. In many instances this motivates checking the validity of data before they are incorporated into official statistics and used as a basis for planning.
Subject(s)
Coronary Disease/mortality , Death Certificates , Adolescent , Adult , Aged , Cause of Death , Humans , Male , Middle Aged , SwedenABSTRACT
A series of 2-acylaminoethanesulfonamides were synthesized by treating the corresponding sulfonyl chlorides with ammonia, a primary, or a secondary amine. A few compounds displayed marked anticonvulsant activity in mice when tested for their potency in the maximal electroshock seizure test. The piperidino, benzamido, phthalimido, and phenylsuccinylimido derivatives were active, whereas the succinylimido, saccharinylimido, and norbornenedicarboxylimido compounds showed no activity. The interference with the sodium-independent taurine binding to mouse brain synaptic membranes was assessed to elucidate the possible mode of anticonvulsant action.
