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Dysregulation of neuropeptides may play an important role in aging-induced impairments. Among them, pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well-known general cytoprotective effects of PACAP lead to age-related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre-senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age-related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry-based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein-AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age-related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro-inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene-deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

In head and neck squamous cell carcinoma (HNSCC) pathologic cervical lymph nodes (LN) remain important negative predictors. Current criteria for LN-classification in contrast-enhanced computed-tomography scans (contrast-CT) are shape-based; contrast-CT imagery allows extraction of additional quantitative data (“features”). The data-driven technique to extract, process, and analyze features from contrast-CTs is termed “radiomics”. Extracted features from contrast-CTs at various levels are typically redundant and correlated. Current sets of features for LN-classification are too complex for clinical application. Effective eliminative feature selection (EFS) is a crucial preprocessing step to reduce the complexity of sets identified. We aimed at exploring EFS-algorithms for their potential to identify sets of features, which were as small as feasible and yet retained as much accuracy as possible for LN-classification. In this retrospective cohort-study, which adhered to the STROBE guidelines, in total 252 LNs were classified as “non-pathologic” (n = 70), “pathologic” (n = 182) or “pathologic with extracapsular spread” (n = 52) by two experienced head-and-neck radiologists based on established criteria which served as a reference. The combination of sparse discriminant analysis and genetic optimization retained up to 90% of the classification accuracy with only 10% of the original numbers of features. From a clinical perspective, the selected features appeared plausible and potentially capable of correctly classifying LNs. Both the identified EFS-algorithm and the identified features need further exploration to assess their potential to prospectively classify LNs in HNSCC.

PACAP is a neuropeptide with diverse functions in various organs, including reproductive system. It is present in the testis in high concentrations, and in addition to the stage-specific expression within the seminiferous tubules, PACAP affects spermatogenesis and the functions of Leydig and Sertoli cells. Mice lacking endogenous PACAP show reduced fertility, but the possibility of abnormalities in spermatogenic signaling has not yet been investigated. Therefore, we performed a detailed morphological analysis of spermatozoa, sperm motility and investigated signaling pathways that play a role during spermatogenesis in knockout mice. No significant alterations were found in testicular morphology or motility of sperm in homozygous and heterozygous PACAP-deficient mice in spite of the moderately increased number of severely damaged sperms. However, we found robust changes in mRNA and/or protein expression of several factors that play an important role in spermatogenesis. Protein kinase A expression was markedly reduced, while downstream phospho-ERK and p38 were elevated in knockout animals. Expression of major transcription factors, such as Sox9 and phospho-Sox9, was decreased, while that of Sox10, as a redundant factor, was increased in PACAP-deficient mice. The reduced phospho-Sox9 expression was partly due to increased expression and activity of phosphatase PP2A in knockout mice. Targets of Sox transcription factors, such as collagen type IV, were reduced in knockout mice. In summary, our results show that lack of PACAP leads to disturbed signaling in spermatogenesis, which could be a factor responsible for reduced fertility in PACAP knockout mice, and further support the role of PACAP in reproduction.

Pancreatic carcinoma is one of the most malignant diseases and is associated with a poor survival rate. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide that acts on three different G protein-coupled receptors: the specific PAC1 and the VPAC1/2 that also bind vasoactive intestinal peptide. PACAP is widely distributed in the body and has diverse physiological effects. Among other things, it acts as a trophic factor and influences proliferation and differentiation of several different cells both under normal circumstances and tumourous transformation. Changes of PACAP and its receptors have been shown in various tumour types. However, it is not known whether PACAP and its specific receptor are altered in pancreatic cancer. Perioperative data of patients with pancreas carcinoma was investigated over a five-year period. Histological results showed Grade 2 or Grade 3 adenocarcinoma in most cases. PACAP and PAC1 receptor expression were investigated by immunohistochemistry. Staining intensity of PAC1 receptor was strong in normal tissues both in the exocrine and endocrine parts of the pancreas, the receptor staining was markedly weaker in the adenocarcinoma. PACAP immunostaining was weak in the exocrine part and very strong in the islets and nerve elements in non-tumourous tissues. The PACAP immunostaining almost disappeared in the adenocarcinoma samples. Based on these findings a decrease or lack of the PAC1 receptor/PACAP signalling might have an influence on tumour growth and/or differentiation.

Pituitary adenylate cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal peptide-secretin-glucagon peptide family, isolated first from ovine hypothalamus. The diverse physiological effects of PACAP are known mainly from animal experiments, including several actions in endocrine glands. Alteration of PACAP expression has been shown in several tumors, but changes in expression of PACAP and its specific PAC1 receptor in human thyroid gland pathologies have not yet been investigated. Therefore, the aim of the present study was to investigate expression of PACAP and its PAC1 receptor in human thyroid papillary carcinoma, the most common endocrine malignant tumor. PACAP and PAC1 receptor expressions were investigated from thyroid gland samples of patients with papillary carcinomas. The staining intensity of follicular epithelial cells and thyroid colloid of tumor tissue was compared to that of tumor-free tissue in the same thyroid glands in a semi-quantitative way. Our results reveal that both PACAP(-like) and PAC1 receptor(-like) immunoreactivities are altered in papillary carcinoma. Stronger PACAP immunoreactivity was observed in active follicles. Colloidal PACAP immunostaining was either lacking or very weak, and more tumorous cells displayed strong apical immunoreactivity. Regarding PAC1 receptor, cells of the normal thyroid tissue showed strong granular expression, which was lacking in the tumor cells. The cytoplasm of tumor cells displayed weak, minimal staining, while in a few tumor cells we observed strong PAC1 receptor expression. This pattern was similar to that observed in the PACAP expression, but fewer in number. In summary, we showed alteration of PACAP and PAC1 receptor expression in human thyroid papillary carcinoma, indicating that PACAP regulation is disturbed in tumorous tissue of the thyroid gland. The exact role of PACAP in thyroid tumor growth should be further explored.

Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclase–activating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro- and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxidative stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.

According to the "Population-based cancer register" of the Federal Republic of Germany only malignant neoplasms of the buccal cavity, the pharynx and larynx as well as cancers of the respiratory tract show an increasing rate of incidence and mortality. The molecular mechanisms and etiological factors causing this phenomenon are still little understood despite intensive research work. Recognition between receptors on a cellular level may be mediated by specific amino acid sequences on the level of protein-protein recognition. Additionally, the interactions between cell sugars and the corresponding protein receptor may play a decisive role in development, regeneration and organisation of cells and tissue. The high specificity of the binding of biotinylated neoglycoproteins in tissue sections enables to detect glycohistochemically binding sites for the carbohydrate ligands of the glycosylated carrier protein. The evidence of lectins in squamous cell cancer of the oral cavity, oropharynx, larynx, and hypopharynx has not been established so far. Squamous cell cancer tissue samples of twelve patients with different tumour locations were investigated by incubation of sections of paraffin-embedded samples and application of an avidin-biotin-peroxidase complex for visualisation with synthetic biotinylated neoglycoproteins. Altogether 168 stained sections were evaluated including controls. Pronounced cytoplasmatic staining was seen with the following neoglycoproteins: sialic acid-bovine serum albumin (BSA), glucuronic acid-BSA, N-acetylglucosamine (glcNAc)-BSA, N-acetylgalactosamine (beta-galNAc)-BSA, lactose-BSA, maltose-BSA, mannose-BSA, mannose-6-phosphate-BSA. No corresponding lectins seems to exist for the following investigated sugars: fucoidan, heparin, and the alpha-anomeric form of N-acetylgalactosamine, because no specific staining was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose The fiducial localization error distribution (FLE) and fiducial configuration govern the application accuracy of point-based registration and drive target registration error (TRE) prediction models. The error of physically localizing patient fiducials (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{patient}$$\end{document}FLEpatient) is negligible when a registration probe matches the implanted screws with mechanical precision. Reliable trackers provide an unbiased estimate of the positional error (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{tracker}$$\end{document}FLEtracker) with cheap repetitions. FLE further contains the localization error in the imaging data (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{image}$$\end{document}FLEimage), sampling of which in general is expensive and possibly biased. Finding the best techniques for estimating \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{image}$$\end{document}FLEimage is crucial for the applicability of the TRE prediction methods. Methods We built a ground-truth (gt)-based unbiased estimator (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\widehat{{\hbox {FLE}}_\mathrm{gt}}$$\end{document}FLEgt^) of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{image}$$\end{document}FLEimage from the samples collected in a virtual CT dataset in which the true locations of image fiducials are known by definition. Replacing true locations in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{gt}$$\end{document}FLEgt by the sample mean creates a practical difference-to-mean (dtm)-based estimator (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\widehat{{\hbox {FLE}}_\mathrm{dtm}}$$\end{document}FLEdtm^) that is applicable on any dataset. To check the practical validity of the dtm estimator, ten persons manually localized nine fiducials ten times in the virtual CT and the resulting \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{dtm}$$\end{document}FLEdtm and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{gt}$$\end{document}FLEgt distributions were tested for statistical equality with a kernel-based two-sample test using the maximum mean discrepancy (MMD) (Gretton in J Mach Learn Res 13:723–773, 2012) statistics at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\alpha =0.05$$\end{document}α=0.05. Results \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{dtm}$$\end{document}FLEdtm and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{gt}$$\end{document}FLEgt were found (for most of the cases) not to be statistically significantly different; conditioning them on persons and/or screws however yielded statistically significant differences much more often. Conclusions We conclude that \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\widehat{{\hbox {FLE}}_\mathrm{dtm}}$$\end{document}FLEdtm^ is the best candidate (within our model) for estimating \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{image}$$\end{document}FLEimage in homogeneous TRE prediction models. The presented approach also allows ground-truth-based numerical validation of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\hbox {FLE}}_\mathrm{image}$$\end{document}FLEimage estimators and (manual/automatic) image fiducial localization methods in phantoms with parameters similar to clinical datasets.

Binary morphological operations are fundamental tools in image processing but the processing time scales with the number of pixels thus making them expensive operations on the CPU for larger 3D datasets that typically appear in medical imaging. Since erosion and dilatation are special neighborhood operators, each pixel in the output depends only on the neighborhood region which makes them fit for massive GPU parallelization. This document introduces a new ITK module that implements generic (OpenCL based) GPU accelerated binary morphology image filters for erosion and dilatation. The filter can be executed within the standard ITKGPU pipeline.

Inhalation anaesthetic agents are known to depress phagocytic functions such as mobilization, attachment, chemotactic motility, engulfment and intracellular killing. Mannose-specific sugar receptors on the surface of leukocytes are involved in a series of phagocytosis-related activities. To investigate the effect of anaesthesia on the expression of this type of sugar receptor, mice were anaesthetized with halothane, enflurane and isoflurane. The presence of mannose-binding receptors on peripheral blood polymorphonuclear leukocytes was examined glycocytochemically using the biotinylated neoglycoprotein mannosylated bovine serum albumin. Prolonged administration of inhalation anaesthetic agents, especially halothane, markedly depressed expression of mannose-specific receptors. This reduction may possibly contribute to postoperative immunodepression, resulting from the impaired cellular interaction which is involved in the phagocytic function of granulocytes.