| 1. |
- Andersson, Christer, et al.
(författare)
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Acute-phase proteins in response to tumor growth.
- 1993
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 0022-4804. ; 55:6, s. 607-14
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Tidskriftsartikel (refereegranskat)abstract
- This study has evaluated the relationship between tumor growth and induction of acute-phase proteins. It has also determined whether an intact cellular immunity is obligatory for a fully expressed acute-phase plasma protein response in the presence of a highly antigenic tumor. Quantitatively, acute-phase responses (protein synthesis, plasma concentrations, hepatic RNA content, anorexia) were proportional to tumor burden. Anti-inflammatory drugs (indomethacin 1 micrograms/g body wt, dexamethasone 0.5 micrograms/g body wt) had no direct effect on the attenuation of the systemic acute-phase responses, but did affect them indirectly by decreasing tumor growth. Immune suppression (cyclosporine A at 20 or 60 micrograms/g body wt) had no effect on either acute-phase reactions or local tumor growth. In endotoxin-stimulated (lipopolysaccharide) normal mice, immune suppression aggravated anorexia and caused high mortality, while dexamethasone partly reversed these effects in endotoxin-stimulated mice. Plasma levels of acute-phase proteins correlated to circulating levels of IL-6 in untreated tumor-bearing mice, but this relationship was not obvious in either drug-treated tumor-bearing or endotoxin-stimulated mice. Tumor tissue induced the synthesis of different acute-phase proteins compared to endotoxin. However, disintegrated normal liver tissue induced the synthesis of serum amyloid protein to the same extent as the growing tumor. This effect was primarily associated with the mitochondrial/lysosomal and microsomal liver cell fractions. In conclusion, the overall acute-phase protein response is not a modulating factor of tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 2. |
- Andersson, Christer, et al.
(författare)
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Identification of tissue sites for increased albumin degradation in sarcoma-bearing mice.
- 1991
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Ingår i: The Journal of surgical research. - 0022-4804. ; 50:2, s. 156-62
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Tidskriftsartikel (refereegranskat)abstract
- Plasma albumin concentration declines in both experimental and clinical cancer. Previous investigations have demonstrated that this is partly explained by increased breakdown of albumin. The present study has identified the tissue sites for increased albumin degradation in a nonmetastasizing sarcoma mouse (C57/BL6J) model. Results have been compared to nontumor-bearing animals either freely fed or food restricted (pair-weighed) so that their body composition was similar to tumor-bearing animals. Tumor-bearing mice had increased albumin degradation (0.13 +/- 0.02 mg/hr/g bw) compared to both freely fed (0.09 +/- 0.007) and pair-weighed control animals (0.05 +/- 0.008). Radioactivity from circulating [3H]raffine aldehyde labeled albumin appeared with maximum peak values in lysosomes isolated from both tumor and nontumor tissues at 48 hr following iv injection. The intralysosomal accumulation of radioactivity was two- to threefold higher in tumor tissue compared to liver tissue, although the specific activity of protease(s) for albumin degradation measured in vitro was not higher in tumor tissue (30.4 +/- 3.6 mg/hr/g tissue) compared to normal liver tissue (36.9 +/- 1.7). Accounting for the entire tumor the proteolytic capacity for albumin breakdown was however much larger in the tumor (161.6 +/- 32.6 mg/organ) compared to both normal liver (37.5 +/- 2.3) and tumor-host liver (56.4 +/- 2.8). Pepstatin inhibited 78 +/- 6% of the proteolytic activity in the tumor measured by 125I-labeled undenatured mouse albumin as the substrate. Leupeptin inhibited 49 +/- 6%. There was a significantly decreased breakdown of albumin in both skeletal muscles and the gastrointestinal tract from tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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| 3. |
- Andersson, Christer, et al.
(författare)
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Isolation of radiopure plasma and hepatic albumin in acute phase conditions.
- 1994
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Ingår i: Clinical nutrition (Edinburgh, Scotland). - 0261-5614. ; 13:1, s. 35-41
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Tidskriftsartikel (refereegranskat)abstract
- It is essential to obtain biochemically and radioactively pure albumin in studies on albumin metabolism and kinetics in stress and nutrition related conditions. However, published work on albumin metabolism, in both animals and man with acute phase reactions has usually been based on inadequate chemical methods for isolation of homogeneous albumin free from acute phase proteins and other contaminants. Applications of conventional antibody precipitating techniques was usually either not sufficient to give radiopure albumin, or did not allow determination of the true specific radioactivity during in vivo experiments. Thus, the lack of applicable methods to achieve radiopure albumin from small plasma and tissue samples for subsequent analyses and determination of the true specific radioactivity in albumin initiated the present method development. The combination of HPLC ionchromatography (DEAE-sepharose), affinity chromatography (Blue sepharose CL-6B, Con A sepharose) and HPLC based size exclusion chromatography (Protein PAK 300 SW, Waters) was applied. By this procedure we obtained radiopure albumin from both plasma and hepatic samples from individual mice with acute phase response as confirmed by two-dimensional electrophoresis and immune precipitation.
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| 4. |
- Arner, P., et al.
(författare)
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Circulating Carnosine Dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects: Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results: Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions: In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.
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| 5. |
- Burgos, Jonathan R, et al.
(författare)
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LPS immune challenge reduces arcuate nucleus TSHR and CART mRNA and elevates plasma CART peptides.
- 2019
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Ingår i: BMC neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to examine the impact of lipopolysaccharide-induced systemic inflammation on expression of mRNA for cocaine- and amphetamine-regulated transcript (CART) and the thyrotropin receptor (TSHR) and its ligands in CNS areas of relevance for feeding controls and metabolism. Lipopolysaccharide effects on plasma levels of TSH and CART peptides were also examined.Lipopolysaccharide (150-200μg/mouse) was injected in C57BL/6J mice and tissue and plasma samples taken after 24h. To establish if plasma increase in CART peptide levels were prostanoid dependent, indomethacin was given via the drinking water beginning 48h prior to LPS. We evaluated mRNA expression for CART, TSHR, TSHβ, and thyrostimulin in brain and pituitary extracts. Plasma levels of TSH, CARTp, and serum amyloid P component were analyzed by ELISA.Lipopolysaccharide suppressed TSHR mRNA expression in the arcuate nucleus and the pituitary. CART mRNA expression was reduced in the arcuate nucleus but elevated in the pituitary of mice treated with Lipopolysaccharide, whereas plasma TSH remained unchanged. Plasma CART peptide concentration increased after LPS treatment in a prostanoid-independent manner, and CART peptide levels correlated positively to degree of inflammation.Our findings suggest that central and peripheral CART is affected by acute inflammation. Considering the role of the arcuate nucleus in feeding controls, our data highlight TSHR and CART as putative neuroendocrine signaling components that respond to inflammation, perhaps to maintain weight and metabolic homeostasis during states of disease.
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| 6. |
- Burgos, Jonathan R, et al.
(författare)
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MCG101-induced cancer anorexia-cachexia features altered expression of hypothalamic Nucb2 and Cartpt and increased plasma levels of cocaine- and amphetamine-regulated transcript peptides.
- 2016
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Ingår i: Oncology reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 35:4, s. 2425-2430
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to explore central and peripheral host responses to an anorexia-cachexia producing tumor. We focused on neuroendocrine anorexigenic signals in the hypothalamus, brainstem, pituitary and from the tumor perse. Expression of mRNA for corticotropin-releasing hormone (CRH), cocaine- and amphetamine-regulated transcript (CART), nesfatin-1, thyrotropin (TSH) and the TSH receptor were explored. In addition, we examined changes in plasma TSH, CART peptides (CARTp) and serum amyloid Pcomponent (SAP). C57BL/6 mice were implanted with MCG101 tumors or sham-treated. A sham-implanted, pair‑fed (PF) group was included to delineate between primary tumor and secondary effects from reduced feeding. Food intake and body weight were measured daily. mRNA levels from microdissected mouse brain samples were assayed using qPCR, and plasma levels were determined using ELISA. MCG101 tumors expectedly induced anorexia and loss of body weight. Tumor-bearing (TB) mice exhibited an increase in nesfatin-1 mRNA as well as a decrease in CART mRNA in the paraventricular area (PVN). The CART mRNA response was secondary to reduced caloric intake whereas nesfatin-1 mRNA appeared to be tumor-specifically induced. In the pituitary, CART and TSH mRNA were upregulated in the TB and PF animals compared to the freely fed controls. Plasma levels for CARTp were significantly elevated in TB but not PF mice whereas levels of TSH were unaffected. The plasma CARTp response was correlated to the degree of inflammation represented by SAP. The increase in nesfatin-1 mRNA in the PVN highlights nesfatin-1 as a plausible candidate for causing tumor-induced anorexia. CART mRNA expression in the PVN is likely an adaptation to reduced caloric intake secondary to a cancer anorexia-cachexia syndrome (CACS)‑inducing tumor. The MCG101 tumor did not express CART mRNA, thus the elevation of plasma CARTp is host derived and likely driven by inflammation.
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| 7. |
- Burgos, Jonathan R, et al.
(författare)
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Pituitary adenylate cyclase-activating polypeptide 6-38 blocks cocaine- and amphetamine-regulated transcript Peptide-induced hypophagia in rats.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine- and amphetamine-regulated transcript peptides (CARTp) suppress nutritional intake after administration into the fourth intracerebral ventricle. Recent in vitro studies have shown that PACAP 6-38, a pituitary adenylate cyclase-activating polypeptide (PACAP) fragment, could act as a competitive antagonist against CARTp 55-102 on a common CARTp-sensitive receptor structure. Here, we show for the first time in vivo that the reduction in solid food intake induced by exogenous CARTp 55-102 (0.3 nmol: 1.5 µg) administered fourth i.c.v. is blocked by pretreatment with PACAP 6-38 (3 nmol). The PACAP 6-38 fragment had no effect by itself either when given into the fourth ventricle or subcutaneously. Although effective to block the CARTp-effect on feeding and short-term body weight, PACAP 6-38 failed to attenuate CARTp-associated gross motor behavioral changes suggesting at least two CARTp-sensitive receptor subtypes. In conclusion, PACAP 6-38 acts as a functional CARTp antagonist in vivo and blocks its effects on feeding and short term weight gain.
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| 8. |
- Burgos, Jonathan R, et al.
(författare)
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Presence of TSH receptors in discrete areas of the hypothalamus and caudal brainstem with relevance for feeding controls—Support for functional significance
- 2016
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1642, s. 278-286
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that brain-derived thyroid-stimulating hormone (TSH) and its receptor (TSHr) are present in hypothalamic extracts. No studies investigating both the anatomical location and functional significance of putative TSHr proteins in specific central nervous system (CNS) nuclei involved in feeding controls have yet been conducted. The aim was thus to determine whether TSHr are present in nuclei associated with feeding behavior, and if such receptors may be functional.
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| 9. |
- Dambrauskas, Zilvinas, et al.
(författare)
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Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.
- 2014
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 44:1, s. 99-104
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Tidskriftsartikel (refereegranskat)abstract
- Major histocompatibility complex classI-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and Tcells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.
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| 10. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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EGFR, but not COX-2, protein in resected pancreatic ductal adenocarcinoma is associated with poor survival.
- 2019
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Ingår i: Oncology letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 17:6, s. 5361-5368
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Tidskriftsartikel (refereegranskat)abstract
- The effects of EGFR and COX-2 protein overexpression on clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients remains unclear. Therefore, the aim of the present study was to evaluate the protein expression of epithelial growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in tumor cells in surgically resected PDAC, in comparison with clinicopathological characteristics and clinical outcomes. Immunohistochemical staining of formalin-fixed paraffin-embedded tissue derived from surgically resected tumors was performed. Tissue slides were evaluated for membrane wild-type EGFR and cytoplasmic COX-2 staining using a histoscore system. Statistical associations between EGFR and COX-2 staining and clinicopathological characteristics were examined to predict survival. In a cohort of 32 resected PDAC patients, high EGFR protein expression in tumor cells was significantly associated with shorter median overall survival (7.9 vs. 39.2 months, P=0.0038). The corresponding hazard ratio (HR) for patients with high EGFR protein expression in tumor cells was 3.12 [95% confidence interval (CI): 1.39-7.00, P=0.006]. COX-2 protein expression was not associated with survival (22.6 vs. 24.5 months P=0.60; HR 1.22 95% CI: 0.59-2.51, P=0.60). Following multivariate Cox regression analysis, high EGFR protein expression in tumor cells (P=0.043) remained as significant independent prognostic factor for survival. In conclusion, high wild-type EGFR protein expression, but not COX-2 protein expression, in tumor cells is a prognostic factor for reduced overall survival following pancreatic tumor resection, supporting a role for EGFR in identifying resected patients that may benefit from EGFR-targeted therapy.
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