Pre‐ and postoperative 68Ga‐DOTATOC positron emission tomography for hormone‐secreting pituitary neuroendocrine tumors

Objectives: Somatostatin receptors (SSTRs) are potential targets for detecting pituitary neuroendocrine tumours (PitNETs) that can be visualized effectively with 68Ga-labelled PET tracers. With this study, we have evaluated the diagnostic properties of such a tracer, 68Ga-DOTATOC, in patients with hormone-producing PitNETs before and after surgery. Design/Methods: This prospective case-control study presents preoperative positron emission tomography (PET) and histopathological data in 18 patients with somatotroph (n = 8), corticotroph (n = 7) and thyrotroph (n = 3) PitNETs. Patients were scanned pre- and postoperatively with 68Ga-DOTATOC PET. For the postoperative part of the study, patients with gonadotroph tumours (n = 7) were also included. Fifteen pituitary healthy controls underwent the same protocol once. The maximum standard uptake value (SUVmax) was analysed in manually outlined regions around the tumour in patients and around the pituitary gland in controls. specimens were collected during surgery in subjects for assessment of adenohypophyseal tumour cell type and the SSTR expression. Results: Thyrotroph tumours showed higher uptake (median SUVmax 41.1; IQR 37.4-60.0) and corticotroph tumours lower uptake (SUVmax 6.8; 2.6-9.3) than normal pituitary gland (SUVmax 13.8; 12.1-15.5). The uptake in somatotroph tumours (SUVmax 15.9; 11.6-19.7) was similar to the uptake in the pituitary gland. There was a strong correlation between SUVmax and SSTR2 expression (r = .75 (P 13.8. Conclusions: 68Ga-DOTATOC PET can be used to detect thyrotroph tumours in the pre- and postoperative imaging assessment. Corticotroph tumours had a significantly lower uptake compared to the pituitary gland but without a distinct increased tumour uptake the clinical postoperative value is limited

Lower 68 Ga-DOTATOC Uptake in Non-Functioning Pituitary Neuroendocrine Tumors Compared to Normal Pituitary Gland - a Proof-of-Concept Study

OBJECTIVES: 68 Ga-DOTATOC PET targets somatostatin receptors (SSTRs) and is well established for the detection of SSTR-expressing tumors, such as gastrointestinal neuroendocrine tumors. Pituitary adenomas, recently designated as pituitary neuroendocrine tumors (PitNETs), also express SSTRs, but there has been no previous evaluations of 68 Ga-DOTATOC PET in PitNET patients. The aim of this pilot study was to evaluate the diagnostic properties of 68 Ga-DOTATOC PET in the most common PitNET, i.e. non-functioning (NF)-PitNET. DESIGN/METHODS: NF-PitNET patients (n = 9) and controls (n = 13) were examined preoperatively with 68 Ga-DOTATOC PET for 45 min after tracer injection in dynamic list mode. Tumor specimens were collected during surgery in patients. MRI and PET images were co-registered using PMOD software. The maximum standard uptake value (SUVmax ) was analyzed in manually outlined regions of interest (ROC) around the tumor in patients and around the pituitary gland in controls. Immunohistochemical analyses were conducted on tumor specimens for assessment of tumor cell type and SSTR expression. RESULTS: Median SUVmax (IQR) was lower in patients than in controls (3.9 [3.4-8.5] vs 14.1 [12.5-15.9]; P < .01]. In ROC analysis, the area under the curve was 0.87 (P < .01) for SUVmax , with 78% sensitivity and 92% specificity. Immunohistochemical analysis showed NF-PitNETs were of gonadotroph (n = 7) and corticotroph (n = 2) origin. SSTR expression was high for SSTR3, low-to-moderate for SSTR2, and low for SSTR1 and SSTR5. CONCLUSIONS: This proof-of-concept study shows that 68 Ga-DOTATOC PET can be used to differentiate between normal pituitary tissue and NF-PitNET

Green's functions for parabolic systems of second order in time-varying domains

We construct Green's functions for divergence form, second order parabolic systems in non-smooth time-varying domains whose boundaries are locally represented as graph of functions that are Lipschitz continuous in the spatial variables and 1/2-H\"older continuous in the time variable, under the assumption that weak solutions of the system satisfy an interior H\"older continuity estimate. We also derive global pointwise estimates for Green's function in such time-varying domains under the assumption that weak solutions of the system vanishing on a portion of the boundary satisfy a certain local boundedness estimate and a local H\"older continuity estimate. In particular, our results apply to complex perturbations of a single real equation.Comment: 25 pages, 0 figur

The potent vasodilator ethyl nitrite is formed upon reaction of nitrite and ethanol under gastric conditions

By acting as a bioreactor, affording chemical and mechanical conditions for the reaction between dietary components, the stomach may be a source of new bioactive molecules. Using gas chromatography-mass spectrometry we here demonstrate that, under acidic gastric conditions, ethyl nitrite is formed in µM concentrations from the reaction of red wine or distilled alcoholic drinks with physiological amounts of nitrite. Rat femoral artery rings and gastric fundus strips dose-dependently relaxed upon exposure to nitrite:ethanol mixtures. In contrast, when administered separately in the same dose ranges, nitrite evoked only minor vasorelaxation while ethanol actually caused a slight vasoconstriction. Mechanistically, the relaxation effect was assigned to generation of nitric oxide (-NO) as supported by direct demonstration of -NO release from ethyl nitrite and the absence of relaxation in the presence of the soluble guanylyl cyclase inhibitor, ODQ. In conclusion, these results suggest that ethanol in alcoholic drinks interacts with salivary-derived nitrite in the acidic stomach leading to the production of the potent smooth muscle relaxant ethyl nitrite. These findings reveal an alternative chemical reaction pathway for dietary nitrate and nitrite with possible impact on gastric physiology and pathophysiology.http://www.sciencedirect.com/science/article/B6T38-4SCDB0R-4/1/5f2ae4cd1ef8af7eca3f5d4ee8f353a

Microbial risk assessment of drinking water based on hydrodynamic modelling of pathogen concentrations in source water

Norovirus contamination of drinking water sources is an important cause of waterborne disease outbreaks. Knowledge on pathogen concentrations in source water is needed to assess the ability of a drinking water treatment plant (DWTP) to provide safe drinking water. However, pathogen enumeration in source water samples is often not sufficient to describe the source water quality. In this study, the norovirus concentrations were characterised at the contamination source, i.e. in sewage discharges. Then, the transport of norovirus within the water source (the river Gota alv in Sweden) under different loading conditions was simulated using a hydrodynamic model. Based on the estimated concentrations in source water, the required reduction of norovirus at the DWTP was calculated using quantitative microbial risk assessment (QMRA). The required reduction was compared with the estimated treatment performance at the DWTP. The average estimated concentration in source water varied between 4.8 x 10(2) and 7.5 x 10(3) genome equivalents L-1; and the average required reduction by treatment was between 7.6 and 8.8 Log(10). The treatment performance at the DWTP was estimated to be adequate to deal with all tested loading conditions, but was heavily dependent on chlorine disinfection, with the risk of poor reduction by conventional treatment and slow sand filtration. To our knowledge, this is the first article to employ discharge-based QMRA, combined with hydrodynamic modelling, in the context of drinking water. (C) 2015 Elsevier B.V. All rights reserved

Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice

Human mutations in keratin 8 (K8) and keratin 18 (K18), the intermediate filament proteins of hepatocytes, predispose to several liver diseases. K8‐null mice develop chronic liver injury and fragile hepatocytes, dysfunctional mitochondria, and Th2‐type colitis. We tested the hypothesis that autoantibody formation accompanies the liver damage that associates with K8/K18 absence. Sera from wild‐type control, K8‐null, and K18‐null mice were analyzed by immunoblotting and immunofluorescence staining of cell and mouse tissue homogenates. Autoantibodies to several antigens were identified in 81 % of K8‐null male mice 8 mo or older. Similar autoantibodies were detected in aging K18‐null male mice that had a related liver phenotype but normal colon compared with K8‐null mice, suggesting that the autoantibodies are linked to liver rather than colonic disease. However, these autoantibodies were not observed in nontransgenic mice subjected to 4 chronic injury models. The autoantigens are ubiquitous and partition with mitochondria. Mass spectrometry and purified protein analysis identified, mitochondrial HMG‐CoA synthase, aldehyde dehydrogenase, and catalase as the primary autoantigens, and glutamate dehydrogenase and epoxide hydrolase‐2 as additional autoantigens. Therefore, absence of the hepatocyte keratins results in production of anti‐mitochondrial autoantibodies (AMA) that recognize proteins involved in energy metabolism and oxidative stress, raising the possibility that AMA may be found in patients with keratin mutations that associate with liver and other diseases.—Toivola, D. M., Habtezion, A., Misiorek, J. O., Zhang, L., Nyström, J. H., Sharpe, O., Robinson, W. H., Kwan, R., Omary, M. B. Absence of keratin 8 or 18 promotes antimitochondrial autoantibody formation in aging male mice. FASEB J. 29, 5081–5089 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/1/fsb2029012032.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/2/fsb2029012032-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154363/3/fsb2029012032-sup-0003.pd

Asymmetric Inheritance of Aggregated Proteins and Age Reset in Yeast Are Regulated by Vac17-Dependent Vacuolar Functions

SummaryAge can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae, we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan. The link between damage asymmetry and vesicle trafficking can be explained by a direct interaction between aggregates and vesicles. We also show that the protein disaggregase Hsp104 interacts physically with endocytic vesicle-associated proteins, such as the dynamin-like protein, Vps1, which was also shown to be required for Vac17-dependent sequestration of protein aggregates. These data demonstrate that two physiognomies of aging—reduced endocytosis and protein aggregation—are interconnected and regulated by Vac17

Keratins Are Altered in Intestinal Disease-Related Stress Responses

Keratin (K) intermediate filaments can be divided into type I/type II proteins, which form obligate heteropolymers. Epithelial cells express type I-type II keratin pairs, and K7, K8 (type II) and K18, K19 and K20 (type I) are the primary keratins found in the single-layered intestinal epithelium. Keratins are upregulated during stress in liver, pancreas, lung, kidney and skin, however, little is known about their dynamics in the intestinal stress response. Here, keratin mRNA, protein and phosphorylation levels were studied in response to murine colonic stresses modeling human conditions, and in colorectal cancer HT29 cells. Dextran sulphate sodium (DSS)-colitis was used as a model for intestinal inflammatory stress, which elicited a strong upregulation and widened crypt distribution of K7 and K20. K8 levels were slightly downregulated in acute DSS, while stress-responsive K8 serine-74 phosphorylation (K8 pS74) was increased. By eliminating colonic microflora using antibiotics, K8 pS74 in proliferating cells was significantly increased, together with an upregulation of K8 and K19. In the aging mouse colon, most colonic keratins were upregulated. In vitro, K8, K19 and K8 pS74 levels were increased in response to lipopolysaccharide (LPS)-induced inflammation in HT29 cells. In conclusion, intestinal keratins are differentially and dynamically upregulated and post-translationally modified during stress and recovery.</p

Ecological speciation in European whitefish is driven by a large-gaped predator

Lake-dwelling fish that form species pairs/flocks characterized by body size divergence are important model systems for speciation research. Although several sources of divergent selection have been identified in these systems, their importance for driving the speciation process remains elusive. A major problem is that in retrospect, we cannot distinguish selection pressures that initiated divergence from those acting later in the process. To address this issue, we studied the initial stages of speciation in European whitefish (Coregonus lavaretus) using data from 358 populations of varying age (26-10,000 years). We find that whitefish speciation is driven by a large-growing predator, the northern pike (Esox lucius). Pike initiates divergence by causing a largely plastic differentiation into benthic giants and pelagic dwarfs: ecotypes that will subsequently develop partial reproductive isolation and heritable differences in gill raker number. Using an eco-evolutionary model, we demonstrate how pike's habitat specificity and large gape size are critical for imposing a between-habitat trade-off, causing prey to mature in a safer place or at a safer size. Thereby, we propose a novel mechanism for how predators may cause dwarf/giant speciation in lake-dwelling fish species.Peer reviewe