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Sample records for hepatic tumours effect

  1. In vivo electrical conductivity of hepatic tumours.

    PubMed

    Haemmerich, Dieter; Staelin, S T; Tsai, J Z; Tungjitkusolmun, S; Mahvi, D M; Webster, J G

    2003-05-01

    Knowledge of electrical tissue conductivity is necessary to determine deposition of electromagnetic energy and can further be used to diagnostically differentiate between normal and neoplastic tissue. We measured 17 rats with a total of 24 tumours of the K12/TRb rat colon cancer cell line. In each animal we measured in vivo hepatic tumour and normal tissue conductivity at seven frequencies from 10 Hz to 1 MHz, at different tumour stages between 6 and 12 weeks after induction. Conductivity of normal liver tissue was 1.26 +/- 0.15 mS cm(-1) at 10 Hz, and 4.61 +/- 0.42 mS cm(-1) at 1 MHz. Conductivity of tumour was 2.69 +/- 0.91 mS cm(-1) at 10 Hz, and 5.23 +/- 0.82 mS cm(-1) at 1 MHz. Conductivity was significantly different between normal and tumour tissue (p < 0.05). We determined the percentage of necrosis and fibrosis at the measurement site. We fitted the conductivity data to the Cole-Cole model. For the tumour data we determined Spearman's correlation coefficients between the Cole-Cole parameters and age, necrosis, fibrosis and tumour volume and found significant correlation between necrosis and the Cole-Cole parameters (p < 0.05). We conclude that necrosis within the tumour and the associated membrane breakdown is likely responsible for the observed change in conductivity.

  2. Synchronous gastric inflammatory myofibroblastic tumour with gastrointestinal stromal tumour of the stomach and hepatic syringious haemangioma

    PubMed Central

    Papadopoulou, D; Chatziralli, IP; Papadopoulos, V; Filitantzi, C; Demertzidis, C

    2012-01-01

    Inflammatory myofibroblastic tumour of the stomach is a very rare lesion. A case of a gastric inflammatory myofibroblastic tumour associated with gastrointestinal stromal tumour of the stomach and hepatic syringious haemangioma is described. We report an 80-year-old male who had an exophytic mass in the area of the pylorus and the duodenum, where hepatic cysts were found in the magnetic resonance (MRI) scan on examination of hypochromic microcytic anaemia, and prolapsus and torsion of the bulb of the stomach found during gastroscopy. During surgical excision of the exophytic mass, a gastrointestinal stromal tumour from the gastric fundus and a syringious haemangioma from the superior hepatic surface were resected. All tumours were treated successfully by surgical excision. The patient had an uneventful recovery. Neither recurrence nor metastasis was found after a 12-month follow-up. To our knowledge, this is the first time that such an association is reported in the literature. PMID:24960722

  3. Induction of hepatic metallothionein I in tumour-bearing mice.

    PubMed

    Kloth, D M; Chin, J L; Cherian, M G

    1995-04-01

    Metallothionein (MT) is an intracellular metal-binding protein which has been implicated in various biological roles, including heavy-metal detoxification and zinc and copper homeostasis, and has putative antioxidant properties. High levels of MT have been detected in certain human tumours, but its functions are unclear. The presence of tumour may cause stress conditions along with alterations in host metabolism, such as the redistribution of metals and, subsequently, in changes in hepatic MT isoforms. The distribution of basal levels of MT-1 and MT-11 isoforms in livers of different strains of mice and their induction in mice inoculated with tumour cells are investigated. While Balb-c, C57/BL and CD1 mice strains had an equal distribution of both hepatic MT isoforms, MT-I and MT-II. In addition, MT-I was the predominant isoform synthesised (> 88%) in the livers of all strains of mice at 24 h after injection with either cadmium or zinc salts. After inoculation with human testicular T7800 or T7799 tumour cells, the major form of MT induced in the livers of nude (nu/nu) mice was Zn-MT-I, and its concentration was positively correlated with the size of the inoculated tumours (r2 = 0.85). A similar positive relation was found in the livers of Balb-c mice inoculated with MM45T mouse bladder tumour cells (r2 = 0.96). Following surgical removal of T7800 tumour, hepatic MT concentrations returned to basal values. There was an increase in plasma MT levels in tumour-bearing mice and it was positively correlated with the increase in hepatic MT levels. These results demonstrate a specific increase in hepatic MT-I isoform in tumour-bearing mice, and this may be due to a generalised stress during tumour growth. PMID:7710933

  4. Hepatic expression of tumour necrosis factor-alpha in chronic hepatitis B virus infection.

    PubMed Central

    Hussain, M J; Lau, J Y; Williams, R; Vergani, D

    1994-01-01

    AIM--To determine the hepatic expression of tumour necrosis factor-alpha (TNF alpha) in patients with chronic hepatitis B virus (HBV) infection. METHODS--Frozen liver biopsy sections from 19 patients with chronic HBV infection were studied, 12 of whom were HBeAg positive and 10 serum HBV DNA positive. Hepatic expression of TNF alpha was determined using immunohistochemistry. RESULTS--Only infiltrating mononuclear cells showed immunoreactive staining for TNF alpha (median 2, range 0-3; n = 19) which appeared as diffuse positive staining material in the cytoplasm. Patients with active liver disease, assessed histologically and biochemically, had a higher level of expression, both in the number of TNF alpha positive cells and the proportion of TNF alpha positive infiltrating mononuclear cells. There was no correlation between the expression of TNF alpha and serological parameters of viral infection (HBeAg and HBV DNA status and HBV DNA concentrations). CONCLUSION--Hepatic expression of TNF alpha is increased in chronic HBV infection and is related to the activity of liver disease and not to the level of HBV replication. Images PMID:7876386

  5. Systemic Effects of Non-Endocrine Tumours

    PubMed Central

    Sullivan, James D.; Rona, George

    1964-01-01

    Tumours of non-endocrine origin may exert deleterious effects by elaborating active principles which disturb body regulation. Systemic manifestations are fairly common with neoplasms of the lung, kidney, gastro-intestinal tract and thymus. The secretion of these tumours may have a known chemical structure (serotonin), may present hormone-like action (parathormone, antidiuretic hormone, insulinoid), or have well-defined biological properties (erythropoietin, gastrin-like principle). Tumours may stimulate endocrine glands by an unknown mechanism, producing disorders such as Cushing's syndrome, hypercalcemia, gynecomastia and hypoglycemia. Thymomas may be associated with autoimmune diseases. Tumours may extensively utilize or excrete some metabolite (glucose) or electrolyte (Na or K). Awareness of the systemic effects of various neoplasms may lead to an early diagnosis and proper treatment of these manifestations. PMID:14204555

  6. Anti-tumour effect of metformin in canine mammary gland tumour cells.

    PubMed

    Saeki, K; Watanabe, M; Tsuboi, M; Sugano, S; Yoshitake, R; Tanaka, Y; Ong, S M; Saito, T; Matsumoto, K; Fujita, N; Nishimura, R; Nakagawa, T

    2015-08-01

    Metformin is an oral hypoglycaemic drug used in type 2 diabetes. Its pharmacological activity reportedly involves mitochondrial respiratory complex I, and mitochondrial respiratory complex inhibitors have a strong inhibitory effect on the growth of metastatic canine mammary gland tumour (CMGT) cell lines. It is hypothesised that metformin has selective anti-tumour effects on metastatic CMGT cells. The aim of this study was to investigate the in vitro effect of metformin on cell growth, production of ATP and reactive oxygen species (ROS), and the AMP-activated protein kinase (AMPK) mammalian target of rapamycin (mTOR) pathway in two CMGT clonal cell lines with different metastatic potential. In addition, transcriptome analysis was used to determine cellular processes disrupted by metformin and in vivo anti-tumour effects were examined in a mouse xenograft model. Metformin inhibited CMGT cell growth in vitro, with the metastatic clone (CHMp-5b) displaying greater sensitivity. ATP depletion and ROS elevation were observed to a similar extent in the metastatic and non-metastatic (CHMp-13a) cell lines after metformin exposure. However, subsequent AMPK activation and mTOR pathway inhibition were prominent only in metformin-insensitive non-metastatic cells. Microarray analysis revealed inhibition of cell cycle progression by metformin treatment in CHMp-5b cells, which was further confirmed by Western blotting and cell cycle analysis. Additionally, metformin significantly suppressed tumour growth in xenografted metastatic CMGT cells. In conclusion, metformin exhibited an anti-tumour effect in metastatic CMGT cells through AMPK-independent cell cycle arrest. Its mechanism of action differed in the non-metastatic clone, where AMPK activation and mTOR inhibition were observed. PMID:25981932

  7. Influences of Allee effects in the spreading of malignant tumours.

    PubMed

    Sewalt, Lotte; Harley, Kristen; van Heijster, Peter; Balasuriya, Sanjeeva

    2016-04-01

    A recent study by Korolev et al. [Nat. Rev. Cancer, 14:371-379, 2014] evidences that the Allee effect-in its strong form, the requirement of a minimum density for cell growth-is important in the spreading of cancerous tumours. We present one of the first mathematical models of tumour invasion that incorporates the Allee effect. Based on analysis of the existence of travelling wave solutions to this model, we argue that it is an improvement on previous models of its kind. We show that, with the strong Allee effect, the model admits biologically relevant travelling wave solutions, with well-defined edges. Furthermore, we uncover an experimentally observed biphasic relationship between the invasion speed of the tumour and the background extracellular matrix density. PMID:26802481

  8. A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts

    PubMed Central

    Pratesi, G; Perego, P; Polizzi, D; Righetti, S C; Supino, R; Caserini, C; Manzotti, C; Giuliani, F C; Pezzoni, G; Tognella, S; Spinelli, S; Farrell, N; Zunino, F

    1999-01-01

    Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against p53-mutant tumours as compared to those carrying the wild-type gene. The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAOS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction of the wild-type p53 gene. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest that the peculiar DNA binding properties of the triplatinum complex may contribute to the striking profile of anti-tumour

  9. Effects of childhood body size on breast cancer tumour characteristics

    PubMed Central

    2010-01-01

    Introduction Although a role of childhood body size in postmenopausal breast cancer risk has been established, less is known about its influence on tumour characteristics. Methods We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P values for heterogeneity were obtained by performing one degree of freedom trend tests. Results A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes. Conclusions Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype. PMID:20398298

  10. DC BeadM1™: towards an optimal transcatheter hepatic tumour therapy.

    PubMed

    Lewis, Andrew L; Dreher, Matthew R; O'Byrne, Vincent; Grey, David; Caine, Marcus; Dunn, Anthony; Tang, Yiqing; Hall, Brenda; Fowers, Kirk D; Johnson, Carmen Gacchina; Sharma, Karun V; Wood, Bradford J

    2016-01-01

    Clinical use of DC Bead™ loaded with doxorubicin (DEBDOX™) or irinotecan (DEBIRI™), for the treatment of primary and secondary tumours of the liver respectively, is showing great promise. Recently there has been a tendency to select smaller bead size ranges to treat tumours in an effort to allow more drug dose to be administered, improve tumoural penetration and resultant drug delivery and tumour coverage. Herein we describe the development and performance characterisation of a new DC Bead size range (DC BeadM1 (TM), 70-150 μm) capable of an increased bead delivery in the distal vasculature, corresponding to greater tumour coverage and drug dose delivered. Both unloaded and drug loaded DC BeadM1 were shown to have a greater density of distal volume of penetration although the ultimate distal level of penetration was the same as that of the 100-300 µm beads in an in vitro penetration model. Elution of doxorubicin was slower than irinotecan elution, but it was similar when comparing the same drug elution from 70 to 150 µm compared to 100-300 µm beads. Radiopaque versions of 70-150 and 100-300 µm beads were prepared in order to evaluate distribution ex vivo using µ-CT and doxorubicin distribution using epifluorescent microscopy. Liver distribution of the radiopaque versions of the beads was shown to be more distal and efficient at filling smaller vessels with the DC BeadM1 and correspondingly more beads were found per vessel histologically with a larger area of drug coverage with the smaller size range. This study indicates that the smaller (70-150 μm) beads should permit an increased dose of drug to be administered to both hypervascular and hypovascular tumours as compared to 100-300 µm beads.

  11. Determination of tumour vascularity using selective hepatic angiography as compared with intrahepatic-arterial technetium-99m macroaggregated albumin scan in hepatocellular carcinoma.

    PubMed

    Leung, T W; Lau, W Y; Ho, S K; Chan, M; Leung, N W; Lin, J; Metreweli, C; Johnson, P J; Li, A K

    1994-01-01

    A total of 51 patients with hepatocellular carcinoma (HCC) were studied to determine the tumour vascularity as determined by selective hepatic angiography (HAG) and by intrahepatic-arterial technetium-99m-labeled macroaggregated albumin (Tc99m-MAA) scan. The tumour vascularity was graded on the HAG films by an interventional radiologist using a scale ranging from 1 (hypovascular) to 4 (extremely hypervascular). The grades of vascularity on HAG were grade 1 in 5 patients, grade 2 in 13 patients, grade 3 in 24 patients and grade 4 in 9 patients. The tumour vascularity on scintigraphy was determined by quantifying the count rates over the tumour and normal liver areas by an analog/digital gamma-camera, and the resultant tumour-to-normal ratio (T/N ratio) gave a quantitative measure of the vascularity. The range of the T/N ratio was 0.9 to 11.1, with a median of 3.7. There was no correlation between the tumour vascularity grading on HAG and the T/N ratio on the Tc99m-MAA scan (Wilcoxon rank test, P = 0.83). Thus, we conclude that HAG cannot reveal the true vascularity nor reflect the T/N ratio in HCC.

  12. Uncaria tomentosa Exerts Extensive Anti-Neoplastic Effects against the Walker-256 Tumour by Modulating Oxidative Stress and Not by Alkaloid Activity

    PubMed Central

    Dreifuss, Arturo Alejandro; Bastos-Pereira, Amanda Leite; Fabossi, Isabella Aviles; Lívero, Francislaine Aparecida dos Reis; Stolf, Aline Maria; Alves de Souza, Carlos Eduardo; Gomes, Liana de Oliveira; Constantin, Rodrigo Polimeni; Furman, Aline Emmer Ferreira; Strapasson, Regiane Lauriano Batista; Teixeira, Simone; Zampronio, Aleksander Roberto; Muscará, Marcelo Nicolás; Stefanello, Maria Elida Alves; Acco, Alexandra

    2013-01-01

    This study aimed to compare the anti-neoplastic effects of an Uncaria tomentosa (UT) brute hydroethanolic (BHE) extract with those of two fractions derived from it. These fractions are choroformic (CHCl3) and n-butanolic (BuOH), rich in pentacyclic oxindole alkaloids (POA) and antioxidant substances, respectively. The cancer model was the subcutaneous inoculation of Walker-256 tumour cells in the pelvic limb of male Wistar rat. Subsequently to the inoculation, gavage with BHE extract (50 mg.kg−1) or its fractions (as per the yield of the fractioning process) or vehicle (Control) was performed during 14 days. Baseline values, corresponding to individuals without tumour or treatment with UT, were also included. After treatment, tumour volume and mass, plasma biochemistry, oxidative stress in liver and tumour, TNF-α level in liver and tumour homogenates, and survival rates were analysed. Both the BHE extract and its BuOH fraction successfully reduced tumour weight and volume, and modulated anti-oxidant systems. The hepatic TNF-α level indicated a greater effect from the BHE extract as compared to its BuOH fraction. Importantly, both the BHE extract and its BuOH fraction increased the survival time of the tumour-bearing animals. Inversely, the CHCl3 fraction was ineffective. These data represent an in vivo demonstration of the importance of the modulation of oxidative stress as part of the anti-neoplastic activity of UT, as well as constitute evidence of the lack of activity of isolated POAs in the primary tumour of this tumour lineage. These effects are possibly resulting from a synergic combination of substances, most of them with antioxidant properties. PMID:23408945

  13. Uncaria tomentosa exerts extensive anti-neoplastic effects against the Walker-256 tumour by modulating oxidative stress and not by alkaloid activity.

    PubMed

    Dreifuss, Arturo Alejandro; Bastos-Pereira, Amanda Leite; Fabossi, Isabella Aviles; Lívero, Francislaine Aparecida Dos Reis; Stolf, Aline Maria; Alves de Souza, Carlos Eduardo; Gomes, Liana de Oliveira; Constantin, Rodrigo Polimeni; Furman, Aline Emmer Ferreira; Strapasson, Regiane Lauriano Batista; Teixeira, Simone; Zampronio, Aleksander Roberto; Muscará, Marcelo Nicolás; Stefanello, Maria Elida Alves; Acco, Alexandra

    2013-01-01

    This study aimed to compare the anti-neoplastic effects of an Uncaria tomentosa (UT) brute hydroethanolic (BHE) extract with those of two fractions derived from it. These fractions are choroformic (CHCl3) and n-butanolic (BuOH), rich in pentacyclic oxindole alkaloids (POA) and antioxidant substances, respectively. The cancer model was the subcutaneous inoculation of Walker-256 tumour cells in the pelvic limb of male Wistar rat. Subsequently to the inoculation, gavage with BHE extract (50 mg.kg(-1)) or its fractions (as per the yield of the fractioning process) or vehicle (Control) was performed during 14 days. Baseline values, corresponding to individuals without tumour or treatment with UT, were also included. After treatment, tumour volume and mass, plasma biochemistry, oxidative stress in liver and tumour, TNF-α level in liver and tumour homogenates, and survival rates were analysed. Both the BHE extract and its BuOH fraction successfully reduced tumour weight and volume, and modulated anti-oxidant systems. The hepatic TNF-α level indicated a greater effect from the BHE extract as compared to its BuOH fraction. Importantly, both the BHE extract and its BuOH fraction increased the survival time of the tumour-bearing animals. Inversely, the CHCl3 fraction was ineffective. These data represent an in vivo demonstration of the importance of the modulation of oxidative stress as part of the anti-neoplastic activity of UT, as well as constitute evidence of the lack of activity of isolated POAs in the primary tumour of this tumour lineage. These effects are possibly resulting from a synergic combination of substances, most of them with antioxidant properties.

  14. The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study.

    PubMed

    Comín-Anduix, B; Boren, J; Martinez, S; Moro, C; Centelles, J J; Trebukhina, R; Petushok, N; Lee, W N; Boros, L G; Cascante, M

    2001-08-01

    Thiamine deficiency frequently occurs in patients with advanced cancer and therefore thiamine supplementation is used as nutritional support. Thiamine (vitamin B1) is metabolized to thiamine pyrophosphate, the cofactor of transketolase, which is involved in ribose synthesis, necessary for cell replication. Thus, it is important to determine whether the benefits of thiamine supplementation outweigh the risks of tumor proliferation. Using oxythiamine (an irreversible inhibitor of transketolase) and metabolic control analysis (MCA) methods, we measured an in vivo tumour growth control coefficient of 0.9 for the thiamine-transketolase complex in mice with Ehrlich's ascites tumour. Thus, transketolase enzyme and thiamine clearly determine cell proliferation in the Ehrlich's ascites tumour model. This high control coefficient allows us to predict that in advanced tumours, which are commonly thiamine deficient, supplementation of thiamine could significantly increase tumour growth through transketolase activation. The effect of thiamine supplementation on tumour proliferation was demonstrated by in vivo experiments in mice with the ascites tumour. Thiamine supplementation in doses between 12.5 and 250 times the recommended dietary allowance (RDA) for mice were administered starting on day four of tumour inoculation. We observed a high stimulatory effect on tumour growth of 164% compared to controls at a thiamine dose of 25 times the RDA. This growth stimulatory effect was predicted on the basis of correction of the pre-existing level of thiamine deficiency (42%), as assayed by the cofactor/enzyme ratio. Interestingly, at very high overdoses of thiamine, approximately 2500 times the RDA, thiamine supplementation had the opposite effect and caused 10% inhibition of tumour growth. This effect was heightened, resulting in a 36% decrease, when thiamine supplementation was administered from the 7th day prior to tumour inoculation. Our results show that thiamine supplementation

  15. Multiscale modelling of solid tumour growth: the effect of collagen micromechanics

    PubMed Central

    Wijeratne, Peter A.; Vavourakis, Vasileios; Hipwell, John H.; Voutouri, Chrysovalantis; Papageorgis, Panagiotis; Stylianopoulos, Triantafyllos; Evans, Andrew; Hawkes, David J.

    2015-01-01

    Here we introduce a model of solid tumour growth coupled with a multiscale biomechanical description of the tumour microenvironment, which facilitates the explicit simulation of fibre-fibre and tumour-fibre interactions. We hypothesise that such a model, which provides a purely mechanical description of tumour-host interactions, can be used to explain experimental observations of the effect of collagen micromechanics on solid tumour growth. The model was specified to mouse tumour data and numerical simulations were performed. The multiscale model produced lower stresses than an equivalent continuum-like approach, due to a more realistic remodelling of the collagen microstructure. Furthermore, solid tumour growth was found to cause a passive mechanical realignment of fibres at the tumour boundary from a random to a circumferential orientation. This is in accordance with experimental observations, thus demonstrating that such a response can be explained as purely mechanical. Finally, peritumoural fibre network anisotropy was found to produce anisotropic tumour morphology. The dependency of tumour morphology on the peritumoural microstructure was reduced by adding a load-bearing non-collagenous component to the fibre network constitutive equation. PMID:26564173

  16. Effect of anti-glycolytic agents on tumour cells in vitro

    NASA Astrophysics Data System (ADS)

    Korshunov, D. A.; Kondakova, I. V.

    2016-08-01

    A metabolic change is one of the tumour hallmarks, which has recently attracted a great amount of attention. One of the main metabolic characteristics of tumour cells is a high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in a glycolysis pathway than that in a tricarboxylic acid cycle. The Warburg effect constitutes a fundamental adaptation of tumour cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumour glycolysis may become an attractive target for cancer therapy. Here, we research the effect of potential anticancer agents on tumour cells in vitro. In our study, we found a high sensitivity of tumour cells to anti-glycolityc drugs. In addition, tumour cells are more resistant to the agents studied in comparison with normal cells. We also observed an atypical cooperative interaction of tumour cells in the median lethal dose of drugs. They formed the specific morphological structure of the surviving cells. This behavior is not natural for the culture of tumour cells. Perhaps this is one of the mechanisms of cells' adaptation to the aggressive environment.

  17. The effect of gold salts on tumour immunity and its stimulation by Corynebacterium Parvum.

    PubMed Central

    McBride, W. H.; Tuach, S.; Marmion, B. P.

    1975-01-01

    The anti-inflammatory agent sodium aurothiomalate appears to act upon mononuclear phagocytes, inhibiting their lysosomal enzyme activity. Evidence is presented that gold salts can increase the number of lung tumour nodules that develop following intravenous injection of tumour cells and pretreatment can enhance the take of a subcutaneous tumour inoculum. In contrast, they do not affect the later growth of tumour. Gold salts can also suppress the action of systemically administered C. parvum in inhibiting the growth of subcutaneous tumours. These results are taken as supporting the evidence in favour of a fast acting nonspecific anti-tumour mechanism, probably macrophage mediated, that can be inhibited by gold salts and enhanced by C. parvum. The effect of gold salts upon other biological changes induced by C. parvum is examined, including its adjuvant action, and the results are discussed in the context of the mechanisms underlying the immunotherapeutic action of this organism. PMID:813755

  18. Effect of insulin on weight loss and tumour growth in a cachexia model.

    PubMed Central

    Beck, S. A.; Tisdale, M. J.

    1989-01-01

    A comparison has been made between the effects of daily insulin injection and a ketogenic diet on weight loss and tumour weight in an experimental model of cancer cachexia (MAC16). Weight loss associated with the MAC16 tumour was significantly reduced both by a ketogenic diet (80% MCT) and by daily insulin injections without an increase in either food or water consumption. Animals fed the 80% MCT diet had a significantly reduced tumour weight compared with controls fed a normal laboratory diet, while in animals administered 20 U insulin kg-1 day-1 the tumour weight was 50% greater than in saline infused controls. The stimulation of tumour growth by insulin was counteracted by the inclusion of 3-hydroxybutyrate in the drinking water without any alteration in the extent of weight loss. Depletion of both carcass fat and muscle dry weight in animals bearing the MAC16 tumour was reversed in animals administered either insulin or an 80% MCT diet. Animals bearing the MAC16 tumour had a reduced nitrogen balance compared with non-tumour-bearing controls, mainly due to excess urea excretion, and this was reversed towards control values in animals fed an 80% MCT diet, but not in animals administered insulin. These results suggest that a ketogenic diet is more effective than insulin administration in reversing the cachectic process and has the advantage of a concomitant reduction in tumour weight. PMID:2736199

  19. Hyperthermia-enhanced effectiveness of mitoxantrone in an experimental rat tumour.

    PubMed

    Schopman, E M; Van Bree, C; Bakker, P J; Kipp, J B; Barendsen, G W

    1996-01-01

    The influence of local hyperthermia (HT) on Mitoxantrone (MITOX) effectiveness was studied in an experimental rat tumour. R-1 rhabdomyosarcomas were treated with MITOX (5 mg/kg ip), HT (43 degrees C for 1 h) or combinations applied at various time intervals up to 24 h. Tumour growth delay and tumour cell clonogenicity were assessed in correlation with the pharmacokinetics in blood plasma and with MITOX-concentrations in tumour tissue. Combined treatments were more effective than expected on the basis of simple addition of effects of single treatments. With increasing time intervals between treatments up to 8 h, an increase in effectiveness was observed. Unfortunately, treatment with an 8-h interval resulted in a high mortality: 80% of the rats died with 5-10 days after treatment. Treatment with a 3-h interval between MITOX and HT was the most effective combination resulting in the highest therapeutic ratio. Even local tumour controls (14/18 rats) were observed. These enhanced effects were associated with a higher MITOX-concentration in the fraction of intact cells recovered from tumours. However, no differences were observed in MITOX-concentration in total tumour tissue nor in plasma concentrations. In conclusion, timing between MITOX and HT is important for drug availability, for interaction of the two modalities to increase damage in tumour cells and for limiting the toxicity to normal tissues. PMID:8926392

  20. Effect of heterogeneous microvasculature distribution on drug delivery to solid tumour

    NASA Astrophysics Data System (ADS)

    Zhan, Wenbo; Gedroyc, Wladyslaw; Xu, Xiao Yun

    2014-11-01

    Most of the computational models of drug transport in vascular tumours assume a uniform distribution of blood vessels through which anti-cancer drugs are delivered. However, it is well known that solid tumours are characterized by dilated microvasculature with non-uniform diameters and irregular branching patterns. In this study, the effect of heterogeneous vasculature on drug transport and uptake is investigated by means of mathematical modelling of the key physical and biochemical processes in drug delivery. An anatomically realistic tumour model accounting for heterogeneous distribution of blood vessels is reconstructed based on magnetic resonance images of a liver tumour. Numerical simulations are performed for different drug delivery modes, including direct continuous infusion and thermosensitive liposome-mediated delivery, and the anti-cancer effectiveness is evaluated through changes in tumour cell density based on predicted intracellular concentrations. Comparisons are made between regions of different vascular density, and between the two drug delivery modes. Our numerical results show that both extra- and intra-cellular concentrations in the liver tumour are non-uniform owing to the heterogeneous distribution of tumour vasculature. Drugs accumulate faster in well-vascularized regions, where they are also cleared out more quickly, resulting in less effective tumour cell killing in these regions. Compared with direct continuous infusion, the influence of heterogeneous vasculature on anti-cancer effectiveness is more pronounced for thermosensitive liposome-mediated delivery.

  1. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  2. Neonatal tumours.

    PubMed

    Moore, S W

    2013-12-01

    Neonatal or perinatal tumours frequently relate to prenatal or developmental events and have a short exposure window which provides an opportunity to study tumours in a selective sensitive period of development. As a result, they display a number of host-specific features which include occasional spontaneous maturational changes with cells still responding to developmental influences. Neonatal tumours (NNT) are studied for a number of important reasons. Firstly, many of the benign tumours arising from soft tissue appear to result from disturbances in growth and development and some are associated with other congenital anomalies. Study of these aspects may open the door for investigation of genetic and epigenetic changes in genes controlling foetal development as well as environmental and drug effects during pregnancy. Secondly, the clinical behaviour of NNT differs from that of similar tumours occurring later in childhood. In addition, certain apparently malignant NNT can 'change course' in infancy leading to the maturation of apparently highly malignant tumours. Thirdly, NNT underline the genetic associations of most tumours but appear to differ in the effects of proto-oncogenes and other oncogenic factors. In this context, there are also connections between the foetal and neonatal period and some "adult" cancers. Fourthly, they appear to arise in a period in which minimal environmental interference has occurred, thus providing a unique potential window of opportunity to study the pathogenesis of tumour behaviour. This study will seek to review what is currently known in each of these areas of study as they apply to NNT. Further study of the provocative differences in tumour behaviour in neonates provides insights into the natural history of cancer in humans and promotes novel cancer therapies.

  3. Tumour effect on arginine/ornithine metabolic relationship in hypertrophic mouse kidney.

    PubMed

    Manteuffel-Cymborowska, M; Chmurzyńska, W; Peska, M; Grzelakowska-Sztabert, B

    1997-03-01

    The presence of a tumour significantly changes nitrogen metabolism, including that of amino acids and polyamines, in host animals. In this study, we examine whether developing tumours affect the metabolic relationship of arginine and ornithine, precursors of polyamines, in the testosterone-induced hypertrophic mouse kidney model. Androgen-induced changes in the activity of enzymes involved with ornithine biosynthesis (arginase), its consumption (ornithine aminotransferase, OAT and ornithine decarboxylase, ODC) and the hypertrophy of host mouse kidney were not affected by the presence of an ascitic tumour (EAC) and only slightly by a mammary carcinoma (MaCa). The HPLC determined renal level of arginine and ornithine showed a striking homeostasis and was disturbed neither by testosterone nor EAC. The effect of MaCa and testosterone on the levels of both amino acids, although significant, was not very pronounced. Developing tumours, especially ascitic, altered the renal activity of OAT and ODC, but not of arginase, in testosterone-untreated mice. All examined tumours, EAC, L 1210 and MaCa actively metabolized arginine and ornithine. the tumour content of arginine which coincided with the activity of arginase, resulted in a marked increase of the ornithine/arginine ratio in tumours, when compared with kidneys. These results indicate that the androgen-induced anabolic response in mouse kidney is preserved, in spite of tumour requirements for essential metabolites. PMID:9062893

  4. Systemic anti-tumour effects of local thermally sensitive liposome therapy

    PubMed Central

    Viglianti, Benjamin L.; Dewhirst, Mark W.; Boruta, R.J.; Park, Ji-Young; Landon, Chelsea; Fontanella, Andrew N.; Guo, Jing; Manzoor, Ashley; Hofmann, Christina L.; Palmer, Gregory M.

    2015-01-01

    Purpose There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment. Materials and methods Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL® (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy. Results Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay. Discussion The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment. PMID:25164143

  5. Anti-tumour effects of transcatheter arterial embolisation administered in combination with thalidomide in a rabbit VX2 liver tumour model

    PubMed Central

    Nitta-Seko, A; Nitta, N; Sonoda, A; Otani, H; Tsuchiya, K; Ohta, S; Takahashi, M; Murata, K

    2011-01-01

    Objective Using a liver tumour model we investigated whether thalidomide enhances the anti-tumour effect of transcatheter arterial embolisation (TAE). Method First, the viability of VX2 tumour cells co-cultured with thalidomide in a 21% and 1% O2 atmosphere was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Second, we randomly assigned 20 rabbits bearing VX2 liver tumours to 4 groups: Group 1 (thalidomide plus TAE), Group 2 (TAE only), Group 3 (thalidomide only) and Group 4 (control). Thalidomide was orally administered for 5 days. The anti-tumour effects were assessed by the tumour proliferation rate using MRI and by immunohistochemical analysis of the area of intratumoural vessels. Analysis of variance and Tukey's honestly significant difference test were used for statistical analysis. Results The viability of cells grown under hypoxic and normal conditions was not significantly different, nor was there a difference among the four groups. The tumour size increased by 55.9±29.3% in Group 1, 250.6±73.3% in Group 2, 355.2±51.7% in Group 3 and 424.7±110.7% in Group 4; the difference between Group 1 and the other three groups was significant. The area of intratumour vessels in specimens was 0.22±0.28% in Group 1, 0.42±0.29% in Group 2, 1.44±1.00% in Group 3 and 6.00±2.17% in Group 4; the difference between Group 1 and the other groups was statistically significant, as was the difference between Groups 3 and 4. Conclusion Thalidomide used in combination with TAE enhanced anti-tumour effects in rabbits bearing VX2 liver tumours. PMID:20959369

  6. Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: A retrospective evaluation

    PubMed Central

    ASTOLFI, LAURA; GHISELLI, SARA; GUARAN, VALERIA; CHICCA, MILVIA; SIMONI, EDI; OLIVETTO, ELENA; LELLI, GIORGIO; MARTINI, ALESSANDRO

    2013-01-01

    Cisplatin is the most common antineoplastic drug used for the therapy of solid tumours. To date, researchers have focused on the dosage to be administered for each specific tumour, mainly considering the local adverse effects. The aim of this study was to correlate the severity of the adverse effects with: i) the dosage of cisplatin; ii) the specific site of the tumour; iii) the association with other drugs; and iv) the symptoms. We analysed data from 123 patients with 11 different tumour classes undergoing therapy from 2007 to 2008 at St. Anna Hospital (Ferrara, Italy), using the Spearman non-parametric correlation index. Even though significant correlations were found among the variables, the overall results showed that the main factor influencing the severity of the adverse effects was the dosage of cisplatin administered. PMID:23404427

  7. Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice

    PubMed Central

    2012-01-01

    Background Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system. Methods Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2–8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 β and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry. Results ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1β and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear. Conclusions ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity. PMID:22978453

  8. Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents.

    PubMed Central

    Doherty, G. P.; Leith, M. K.; Wang, X.; Curphey, T. J.; Begleiter, A.

    1998-01-01

    DT-diaphorase is a two-electron-reducing enzyme that is an important activator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and EO9, and is inducible by many compounds, including 1,2-dithiole-3-thiones (D3Ts). We showed previously that D3T selectively increased DT-diaphorase activity in mouse lymphoma cells compared with normal mouse marrow cells, and also increased MMC or EO9 cytotoxic activity in the lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activity in 28 of 38 human tumour cell lines representing ten tissue types with no obvious relationships between the tumour type, or the base level of DT-diaphorase activity, and the ability of D3T to increase the enzyme activity. Induction of DT-diaphorase activity in human tumour cell lines by 12 D3T analogues varied markedly with the D3T structure. D3T also increased DT-diaphorase activity in normal human bone marrow and kidney cells but the increases were small in these cells. In addition, D3T increased the level of enzyme activity in normal human lung cells. Pretreatment of human tumour cells with D3T analogues significantly increased the cytotoxic activity of MMC or EO9 in these cells, and the level of enhancement of anti-tumour activity paralleled the level of DT-diaphorase induction. In contrast, D3T did not effect the toxicity of EO9 in normal kidney cells. These results demonstrate that D3T analogues can increase DT-diaphorase activity in a wide variety of human tumour cells and that this effect can enhance the anti-tumour activity of the bioreductive agents MMC and EO9. PMID:9579829

  9. Divergent effects of flavone acetic acid on established versus developing tumour blood flow.

    PubMed Central

    Mahadevan, V.; Hart, I. R.

    1991-01-01

    Flavone Acetic Acid (FAA) exerts much of its effect by reducing tumour blood flow. Previous studies on FAA-induced changes in blood flow have used established tumours with a functional microvasculature. Using radioactive Xenon(133Xe) clearance to monitor local blood flow we show that the effects of FAA are dependent on the presence of this functional microvasculature with no evidence that FAA inhibits the actual development of tumour microcirculation. Thus, administration of multiple doses of FAA around the time of tumour cell injection failed to diminish t1/2 values of 133Xe (e.g. t1/2 16 min for FAA vs 14 min for saline controls at 10 days) or to affect tumour volumes (5.55 +/- 0.06 cm3 in FAA-treated animals vs 5.7 +/- 1.3 cm3 in controls at 25 days). In marked contrast a single dose of FAA (200 mg kg-1 body weight) 2 weeks after tumour cell injection dramatically extended t1/2 times (47 min for FAA vs 7 min for controls; P less than 0.001) and significantly reduced tumour burden. This effect is specific for tumour microvasculature and is not directed simply at new vessels since a similar treatment of animals with implanted-sponge-induced granulation tissue had no effect on t1/2 times (6.8 +/- 1.1 min for FAA at 200 mg kg-1 vs 7.2 +/- 1.0 min for saline-treated controls. PMID:1712621

  10. The Cost Effectiveness of Hepatitis Immunization for US College Students

    ERIC Educational Resources Information Center

    Jacobs, R. Jake; Saab, Sammy; Meyerhoff, Allen S.

    2003-01-01

    Hepatitis B immunization is recommended for all American children, and hepatitis A immunization is recommended for children who live in areas with elevated disease rates. Because hepatitis A and B occur most commonly in young adults, the authors examined the cost effectiveness of college-based vaccination. They developed epidemiologic models to…

  11. In Silico Analysis of Cell Cycle Synchronisation Effects in Radiotherapy of Tumour Spheroids

    PubMed Central

    Kempf, Harald; Hatzikirou, Haralampos; Bleicher, Marcus; Meyer-Hermann, Michael

    2013-01-01

    Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation. PMID:24244120

  12. In silico analysis of cell cycle synchronisation effects in radiotherapy of tumour spheroids.

    PubMed

    Kempf, Harald; Hatzikirou, Haralampos; Bleicher, Marcus; Meyer-Hermann, Michael

    2013-01-01

    Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.

  13. A cellular automaton model examining the effects of oxygen, hydrogen ions and lactate on early tumour growth.

    PubMed

    Al-Husari, Maymona; Murdoch, Craig; Webb, Steven D

    2014-10-01

    Some tumours are known to exhibit an extracellular pH that is more acidic than the intracellular, creating a 'reversed pH gradient' across the cell membrane and this has been shown to affect their invasive and metastatic potential. Tumour hypoxia also plays an important role in tumour development and has been directly linked to both tumour morphology and aggressiveness. In this paper, we present a hybrid mathematical model of intracellular pH regulation that examines the effect of oxygen and pH on tumour growth and morphology. In particular, we investigate the impact of pH regulatory mechanisms on the cellular pH gradient and tumour morphology. Analysis of the model shows that: low activity of the Na+/H+ exchanger or a high rate of anaerobic glycolysis can give rise to a "fingering" tumour morphology; and a high activity of the lactate/H+ symporter can result in a reversed transmembrane pH gradient across a large portion of the tumour mass. Also, the reversed pH gradient is spatially heterogeneous within the tumour, with a normal pH gradient observed within an intermediate growth layer within the spheroid. We also include a fractal dimension analysis of the simulated tumour contours, in which we compare the fractal dimensions of the simulated tumour surfaces with those found experimentally via photomicrographs.

  14. HIFU and Chemotherapy Synergistic Inhibitory Effect on Dunning AT2 Tumour-Bearing Rats

    NASA Astrophysics Data System (ADS)

    Curiel, Laura; Paparel, Philipe; Chesnais, Sabrina; Gelet, Albert; Chapelon, Jean-Yves

    2005-03-01

    Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty-one Dunning AT2 tumour-bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU-chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control group volumes were significantly greater than those of the chemotherapy-only (p = 0.006) or HIFU-only group (p = 0.006). The greatest difference was observed between the chemotherapy plus HIFU combined group and the control group. Additionally, tumour-doubling times were 7.7 days for the control group, 13.2 days for the HIFU-only group, and 31.2 days for the chemotherapy plus HIFU group. The differences in tumour growth rates between the chemotherapy plus HIFU combined group and a chemotherapy-only + HIFU-only grouping was 3.8% (p = 0.0020). Thus, the combined chemotherapy plus HIFU treatment was clearly more effective in reducing the tumour size than HIFU only or chemotherapy only, which indicates a synergy between the two types of treatment. Our results suggest that this combined therapy could be useful for the treatment of high-risk prostate cancer.

  15. The effect of neutering on the risk of mammary tumours in dogs--a systematic review.

    PubMed

    Beauvais, W; Cardwell, J M; Brodbelt, D C

    2012-06-01

    A commonly-stated advantage of neutering bitches is a significant reduction in the risk of mammary tumours, however the evidence for this has not previously been assessed by systematic review. The objectives of this study were to estimate the magnitude and strength of evidence for any effect of neutering, or age of neutering, on the risk of mammary tumours in bitches. A systematic review was conducted based on Cochrane guidelines. Peer-reviewed analytic journal articles in English were eligible and were assessed for risk of bias by two reviewers independently. Of 11,149 search results, 13 reports in English-language peer-reviewed journals addressed the association between neutering/age at neutering and mammary tumours. Nine were judged to have a high risk of bias. The remaining four were classified as having a moderate risk of bias. One study found an association between neutering and a reduced risk of mammary tumours. Two studies found no evidence of an association. One reported "some protective effect" of neutering on the risk of mammary tumours, but no numbers were presented. Due to the limited evidence available and the risk of bias in the published results, the evidence that neutering reduces the risk of mammary neoplasia, and the evidence that age at neutering has an effect, are judged to be weak and are not a sound basis for firm recommendations.

  16. Local hyperthermic treatment does not enhance mitoxantrone effectiveness for responses of a rat solid tumour regrowing after irradiation.

    PubMed

    van Bree, C; Schopman, E M; Bakker, P J; Kipp, J B; Barendsen, G W

    1996-01-01

    Tumours regrowing after irradiation may respond differently to chemo-hyperthermia as compared to non- irradiated tumours. In this study, the efficacy of combined treatment of previously irradiated tumors with mitoxantrone and local hyperthermia (HT) was investigated. Rat R-1 tumours were irradiated with dose fractions of 5Gy X-rays applied on 4 consecutive days. Animals were retreated with mitoxantrone (5mg/kg i.p.), HT (1 h at 43 degrees C) or mitoxantrone + HT (3-h interval) on day 9 after the start of irradiation when tumour volumes were decreasing, or on day 16 when tumour volumes were increasing again. Pharmacokinetics were studied in relation to tumor cell survival and tumour growth delay. No Ht=induced changes in the pharmacokinetics of mitoxantrone were observed. The data on clonogenic survival correlated well with these findings and combined treatment were not more effective than mitoxantrone alone. In the treatment schedule applied, HT did not induce pharmacokinetic changes in irradiated tumours leading to an enhanced cytotoxicity of mitoxantrone. The HT- enhanced effectiveness of the drug observed in non- irradiated tumours is much less in pre-irradiated tumours. Responses of regrowing tumours to combined chemo- hyperthermia depend in a complex way on the stage of regrowth and on the treatment schedule. PMID:8601562

  17. A systematic overview of radiation therapy effects in brain tumours.

    PubMed

    Berg, Gertrud; Blomquist, Erik; Cavallin-Ståhl, Eva

    2003-01-01

    A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for brain tumours is based on data from 9 randomized trials and 1 meta-analysis. Moreover, data from 2 prospective studies, 3 retrospective studies and 4 other articles were used. In total, 19 scientific articles are included, involving 4,266 patients. The results were compared with those of a similar overview from 1996 including 11,252 patients. The conclusions reached can be summarized as follows: The conclusion from SBU 129/2 that curative treatment is not available for patients with high-grade malignant glioma (grade III and IV) is still valid. The survival benefit from postoperative radiotherapy compared to supportive care only or chemotherapy is about 3-4 months, as demonstrated in earlier randomized studies. Quality of life is now currently estimated and considered to be of major importance when reporting the outcome of treatment for patients with brain tumours. There is no scientific evidence that radiotherapy using hyper- and hypofractionation leads to longer survival for patients with high-grade malignant glioma than conventional radiotherapy. There is large documentation, but only one randomized study. There is some documentation to support the view that patients with grade IV glioma and poor prognosis can be treated with hypofractionation and with an outcome similar to that after conventional fractionation. A shorter treatment time should be convenient for the patient. Documentation of the benefit of a radiotherapy boost with brachytherapy is limited and no conclusion can be drawn. There is no scientific evidence that radiotherapy prolongs life for patients with low-grade glioma. There are some data supporting that radiotherapy can

  18. Liver tumour-promoting effects of oxfendazole in rats.

    PubMed

    Mitsumori, K; Onodera, H; Shoda, T; Uneyama, C; Imazawa, T; Takegawa, K; Yasuhara, K; Watanabe, T; Takahashi, M

    1997-08-01

    To examine whether oxfendazole has tumour-promoting activity, a total of 100 male Fisher 344 rats were initiated with a single ip injection of 100 mg/kg of diethylnitrosamine (DEN) or given saline vehicle alone and starting 1 wk later given diet containing 500, 250, 100, 10 or 0 ppm of oxfendazole for 8 wk. Sub-groups of five rats each from the DEN plus 250 and 0 ppm groups were killed after wk 1 of oxfendazole treatment and the remaining animals at wk 8. At the termination relative liver weights were significantly increased in the DEN-initiated and non-initiated groups treated with 250 ppm and 100 ppm or more, respectively, compared with the corresponding controls values. Light microscopical examination showed centrilobular hepatocellular hypertrophy in all animals receiving 100 ppm or more. Electron microscopy also revealed marked increases in smooth endoplasmic reticulum in hepatocytes of the DEN plus 500 ppm group. Furthermore, induction of cytochrome P-450 (CYP) 1A1/2, 2B1/2 or 4A1 was observed in the DEN plus 100 ppm group, that of CYP 1A1/2 being most marked. A similar change in CYP 1A1/2 was seen in the DEN plus 10 ppm group. The numbers and areas of connexin 32 (Cx32)-positive spots per hepatocyte were also significantly decreased in a dose-dependent manner. Similar changes in liver weights, P-450 isozymes and Cx32 immunohistochemistry were already evident in the DEN plus 250 ppm group at wk 1. The number of placental form glutathione S-transferase positive single cells was significantly increased in the DEN-initiated groups treated with 250 ppm or more. The results therefore strongly suggest that oxfendazole exerts liver tumour promotion potential.

  19. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  20. Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model.

    PubMed

    Orendáš, Peter; Kubatka, Peter; Bojková, Bianka; Kassayová, Monika; Kajo, Karol; Výbohová, Desanka; Kružliak, Peter; Péč, Martin; Adamkov, Marián; Kapinová, Andrea; Adamicová, Katarína; Sadloňová, Vladimíra; Chmelová, Martina; Stollárová, Nadežda

    2014-12-01

    Previous studies in the field of cancer research have suggested a possible role for statins in the reduction of risk in certain malignancies. The purpose of these studies was to examine the chemopreventive effects of pravastatin alone and in combination with pineal hormone melatonin in the N-methyl-N-nitrosourea-induced mammary carcinogenesis model. Pravastatin was given orally (1 00 mg/kg) and melatonin was added to the water (20 μg/ml). Chemoprevention began seven days prior to carcinogen administration and subsequently continued for 15 weeks until autopsy. At autopsy, mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. Parameters of experimental carcinogenesis, mechanism of action (biomarkers of apoptosis, angiogenesis and proliferation) and side effects after long-term treatment in animals were assessed. Pravastatin alone suppressed tumour frequency by 20.5% and average tumour volume by 15% compared with controls. Combined administration of the drugs decreased tumour frequency by 69% and lengthened tumour latency by nine days compared with control animals. The ration between high and low grade carcinomas was apparently reduced in both treated groups. The analysis of carcinoma cells showed significant expression increase in caspase-3 and caspase-7 after pravastatin treatment; however, combined treatment even more pronounced increase in the expression of both caspases. Regarding VEGFR-2 expression, a small effect in carcinomas of both treated groups was found. In plasma metabolism evaluation, pravastatin alone significantly decreased levels of glucose and triacylglycerols. Our results suggest a mild anti-neoplastic effect of pravastatin in this rat mammary gland carcinoma model. Statins co-administered with other suitable drug (e.g. melatonin) should be further evaluated for tumour-preventive properties. PMID:25270735

  1. The effect of a somatostatin analogue on the release of hormones from human midgut carcinoid tumour cells.

    PubMed

    Wängberg, B; Nilsson, O; Theodorsson, E; Dahlström, A; Ahlman, H

    1991-07-01

    The use of a somatostatin analogue (SMS 201-995) has greatly facilitated the treatment of patients with the midgut carcinoid syndrome. Clinical studies have shown that SMS reduces the peripheral levels of tumour-produced serotonin (5-HT) and tachykinins, e.g. neuropeptide K (NPK), basally and after pentagastrin provocation. Some studies have indicated an inhibitory effect of SMS on tumour cell growth as well. In the present study we have investigated the effects of SMS on four different human midgut carcinoid tumours maintained in long term culture. Media levels of 5-HT and NPK-LI in tumour cell cultures decreased rapidly during incubation with SMS (10(-8)-10(-10) M) in all four tumours studied without evidence for tachyphylaxis (up to 6 weeks observation period). SMS treatment (10(-8) M) during 4 days reduced the media concentrations of 5-HT by 56%, while the intracellular contents of 5-HT were decreased by 27% indicating dual inhibitory effects on synthesis and secretion of 5-HT from tumour cells. The DNA contents of cultures were not affected by SMS (10(-8) M or 10(-10) M) treatment for 4 or 14 days. When tumour cell cultures were challenged with isoprenaline (IP) (10(-6) M) no reduction of the IP induced release of 5-HT could be detected after pretreatment of tumour cell cultures with SMS (10(-8) M) for 1 h, 4 h or 4 days. These studies provide evidence for a direct action of the somatostatin analogue on midgut carcinoid tumour cells, reducing both synthesis and secretion of hormones from tumour cells. This effect appears not to be related to inhibition of tumour cell growth. The inhibition of 5-HT secretion from tumour cells by SMS seems to operate via a second messenger system different from the one mediating the beta-adrenoceptor stimulated release of 5-HT. PMID:1713051

  2. Radiofrequency ablation of lung tumours

    PubMed Central

    Goh, PYT

    2006-01-01

    Radiofrequency ablation (RFA) is a well-established local therapy for hepatic malignancies. It is rapidly emerging as an effective treatment modality for small lesions elsewhere in the body, in particular, the kidney and the lung. It is a relatively safe and minimally invasive treatment for small lung malignancies, both primary and secondary. In particular, it is the preferred form of treatment for non-surgical candidates. This paper describes the technique employed for radiofrequency ablation of lung tumours, as well as the protocol established, at the Mount Elizabeth Hospital, Singapore. PMID:21614247

  3. Effects of tandem shock waves combined with photosan and cytostatics on the growth of tumours.

    PubMed

    Beneš, J; Poučková, P; Zeman, J; Zadinová, M; Sunka, P; Lukeš, P; Kolářová, H

    2011-01-01

    Shock waves, pressure waves manifested as a sharp increase in positive pressure followed by a decrease and the negative part of the wave, are not only used to treat concrements in medicine. Recently, research has been focused on the possibility of their use for damaging the tumour tissue. In contrast to concrements, which are different from the surrounding tissue by their acoustic impedance, the tumour tissue has the same acoustic impedance as the surrounding soft tissue. Therefore, we have developed a new source of shock waves, which is based on the principle of multichannel discharge. This new source generates two successive shock waves (tandem shock waves). The first shock creates acoustic non-homogeneity and cavitations in the tissue, and the second shock is damped in it. In this work we demonstrated the effect of tandem shock waves on the muscle tissue in depth. The damage is shown on the images from the magnetic resonance imaging and histological sections. In the further part of the experiment, we investigated the in vivo effects of tandem shock waves in combination with Photosan and cisplatin on the tumour tissue. The application of tandem shock waves resulted in the inhibition of tumour growth, compared with controls, in both parts of the experiment. The largest inhibition effect was observed in the groups of tandem shock waves combined with Photosan and in the second part with cisplatin.

  4. Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy

    PubMed Central

    Tan, Q; Joshua, A M; Saggar, J K; Yu, M; Wang, M; Kanga, N; Zhang, J Y; Chen, X; Wouters, B G; Tannock, I F

    2015-01-01

    Background: Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. Pantoprazole inhibits proton pumps and is reported to inhibit autophagy. Here we evaluate the effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel, and underlying mechanisms. Methods: Effects of docetaxel±pantoprazole were studied against wild-type and autophagy-deficient PC3 cells and against four human xenografts. Effects of pantoprazole on autophagy were evaluated by quantifying LC3-I, LC3-II and p62 proteins in western blots, and by fluorescent microscopy of cells transfected with RFP-GFP-LC3. The distribution of drug effects and of autophagy was quantified in tumour sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3, Ki67 and LC3/ p62. Results: Pantoprazole increased the toxicity of docetaxel in vitro, increased docetaxel-induced expression of γH2AX and cleaved caspase-3, and decreased Ki67 in tumour sections. Pantoprazole increased growth delay of four human xenografts of low, moderate and high sensitivity to docetaxel, with minimal increase in toxicity. Docetaxel led to increased autophagy throughout tumour sections. Pantoprazole inhibited autophagy, and effects of pantoprazole were reduced against genetically modified cells with decreased ability to undergo autophagy. Conclusions: Autophagy is a mechanism of resistance to docetaxel chemotherapy that may be modified by pantoprazole to improve therapeutic index. PMID:25647012

  5. Study on the effect of polysaccharides from Solanum nigrum Linne on cellular immune function in tumour-bearing mice.

    PubMed

    Chen, Hai; Qi, Xiaodong

    2013-01-01

    We investigated the anti-tumour effect of polysaccharides from Solanum nigrum Linne, and its relationship with the immune function of tumour-bearing organisms. MTT assay was used to observe the effect of different doses of polysaccharides from Solanum nigrum Linne on proliferation of lymphocytes in tumour-bearing mice. ELISA assay was also used to detect the levels of IL-2 in mice, and a laser scanning confocal microscope was used to detect the effect of polysaccharides from Solanum nigrum Linne on intralymphocytic free calcium ion concentration in tumour-bearing mice. Different doses of polysaccharides from Solanum nigrum Linne significantly inhibited the growth of mouse H22 solid tumours, improved the survival time of tumour-bearing mice, increased the proliferation of lymphocytes, elevated the levels of IL-2, and increased the concentration of calcium ions in the lymphocytes. Polysaccharides from Solanum nigrum Linne have certain anti-tumour effect, which is related with the cellular immune function that regulates the body. PMID:24146499

  6. Effect of VEGF receptor inhibitor PTK787/ZK222548 combined with ionizing radiation on endothelial cells and tumour growth

    PubMed Central

    Hess, C; Vuong, V; Hegyi, I; Riesterer, O; Wood, J; Fabbro, D; Glanzmann, C; Bodis, S; Pruschy, M

    2001-01-01

    The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 × 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 × 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-disfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative antitumoural effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11747347

  7. Investigation of the effect of physical parameters on the design of tumour targeting agents

    NASA Astrophysics Data System (ADS)

    Casey, Joanne Lois

    Tumour targeting using radiolabelled antibodies for radioimmunodetection (RAID) and radioimmunotherapy (RIT) has been studied for many years. The main factors that have limited clinical success are low tumour uptake, immunogenicity and poor therapeutic ratios. This thesis has applied current technology to make advances in this area of research. The effect of physical parameters (antibody size, valency, affinity and charge) on the design of tumour targeting agents was studied by constructing divalent (DFM) and trivalent (TFM) forms of the murine anti-CEA antibody A5B7 Fab' by chemical cross-linking. This involves partial reduction of the hinge disulphides to expose thiol (-SH) groups and subsequent reaction with a maleimide cross-linker to form a thioether bond at the hinge region. Previous studies have suggested that the stability of thioether bonds is superior to naturally occurring disulphide bonds present at the hinge region of IgG and F(ab')2. The aim was to compare the functional affinities and in vivo tumour targeting in nude mice bearing human tumour xenografts of DFM and TFM to similar sized parent IgG and F(ab')2. Radiolabelling with 131I and 90Y was also compared with a view to determine which combination would be optimal for RIT. Results clearly demonstrated a significantly faster on-rate of DFM compared to all other antibody forms and estimated dosimetry analysis suggested that DFM would be the most suitable antibody form radiolabelled with 131I for RIT. Both F(ab')2 and DFM showed high kidney uptake levels on labelling with which is unacceptable for RIT. Despite the improved tumour: blood ratios for TFM, the increased estimated dose to normal tissues and lower therapeutic effect in RIT studies suggests that the most promising combination with the radionuclide appears to be IgG. A humanised version of A5B7 hFab' has been constructed previously in order to reduce its immunogenicity in man. The in vivo stability of hDFM proved to be superior to hF(ab')2

  8. The effect of lithium chloride on tumour appearance and survival of melanoma-bearing mice.

    PubMed

    Ballin, A; Aladjem, M; Banyash, M; Boichis, H; Barzilay, Z; Gal, R; Witz, I P

    1983-07-01

    The possible effect of lithium chloride, a compound which reduces the incidence of infection in cancer patients, was investigated on murine melanoma. C57 BL syngeneic mice were inoculated i.p. with B16 melanoma cells. The animals were divided into 4 groups, receiving daily i.p. treatment with saline--group 1, controls; lithium chloride--group 2, bleomycin and vinblastine--group 3, and lithium chloride with bleomycin and vinblastine--group 4. Animals in group 4 had a significant delay in tumour appearance, a higher degree of tumour necrosis, and a longer survival rate. In addition a significant reduction of serum lithium concentration was noted in animals of this group in comparison with animals in group 2, treated with lithium chloride alone. There was no lithium-induced leukocytosis.

  9. A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity.

    PubMed

    Takahashi, Hidenori; Ebihara, Satoru; Okazaki, Tatsuma; Asada, Masanori; Sasaki, Hidetada; Yamaya, Mutsuo

    2005-10-01

    Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg(-1) day(-1)), dalteparin (75 units kg(-1) day(-1)) or danaparoid (50 units kg(-1) day(-1)). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours.

  10. Imaging and radiation effects of gold nanoparticles in tumour cells

    PubMed Central

    McQuaid, Harold N.; Muir, Mark F.; Taggart, Laura E.; McMahon, Stephen J.; Coulter, Jonathan A.; Hyland, Wendy B.; Jain, Suneil; Butterworth, Karl T.; Schettino, Giuseppe; Prise, Kevin M.; Hirst, David G.; Botchway, Stanley W.; Currell, Fred J.

    2016-01-01

    Gold nanoparticle radiosensitization represents a novel technique in enhancement of ionising radiation dose and its effect on biological systems. Variation between theoretical predictions and experimental measurement is significant enough that the mechanism leading to an increase in cell killing and DNA damage is still not clear. We present the first experimental results that take into account both the measured biodistribution of gold nanoparticles at the cellular level and the range of the product electrons responsible for energy deposition. Combining synchrotron-generated monoenergetic X-rays, intracellular gold particle imaging and DNA damage assays, has enabled a DNA damage model to be generated that includes the production of intermediate electrons. We can therefore show for the first time good agreement between the prediction of biological outcomes from both the Local Effect Model and a DNA damage model with experimentally observed cell killing and DNA damage induction via the combination of X-rays and GNPs. However, the requirement of two distinct models as indicated by this mechanistic study, one for short-term DNA damage and another for cell survival, indicates that, at least for nanoparticle enhancement, it is not safe to equate the lethal lesions invoked in the local effect model with DNA damage events. PMID:26787230

  11. Imaging and radiation effects of gold nanoparticles in tumour cells

    NASA Astrophysics Data System (ADS)

    McQuaid, Harold N.; Muir, Mark F.; Taggart, Laura E.; McMahon, Stephen J.; Coulter, Jonathan A.; Hyland, Wendy B.; Jain, Suneil; Butterworth, Karl T.; Schettino, Giuseppe; Prise, Kevin M.; Hirst, David G.; Botchway, Stanley W.; Currell, Fred J.

    2016-01-01

    Gold nanoparticle radiosensitization represents a novel technique in enhancement of ionising radiation dose and its effect on biological systems. Variation between theoretical predictions and experimental measurement is significant enough that the mechanism leading to an increase in cell killing and DNA damage is still not clear. We present the first experimental results that take into account both the measured biodistribution of gold nanoparticles at the cellular level and the range of the product electrons responsible for energy deposition. Combining synchrotron-generated monoenergetic X-rays, intracellular gold particle imaging and DNA damage assays, has enabled a DNA damage model to be generated that includes the production of intermediate electrons. We can therefore show for the first time good agreement between the prediction of biological outcomes from both the Local Effect Model and a DNA damage model with experimentally observed cell killing and DNA damage induction via the combination of X-rays and GNPs. However, the requirement of two distinct models as indicated by this mechanistic study, one for short-term DNA damage and another for cell survival, indicates that, at least for nanoparticle enhancement, it is not safe to equate the lethal lesions invoked in the local effect model with DNA damage events.

  12. Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting.

    PubMed Central

    Blackham, M; Cesar, D; Park, O J; Vary, T C; Wu, K; Kaempfer, S; Shackleton, C H; Hellerstein, M K

    1992-01-01

    1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain. PMID:1599392

  13. Enhancement of the effectiveness of methotrexate for the treatment of solid tumours by application of local hyperthermia.

    PubMed

    Schopman, E M; Van Bree, C; Kipp, J B; Barendsen, G W

    1995-01-01

    Investigations were performed to assess the influence of hyperthermia on the pharmacokinetics of a chemotherapeutic drug and on the effectiveness of combined treatments for induction of tumour cell death and growth delay of experimental tumours. Treatments consisted of methotrexate (MTX, 20 mg/kg ip), hyperthermia at 43 degrees C during 60 min (HT60) or 90 min (HT90) and combined chemo-hyperthermia using various time intervals up to 24 h. The results indicate that, for MTX + HT90, concentrations in excess of 0.02 mg/kg are maintained in tumour tissue during at least 22 days, whereas after the other single and combined treatments, the concentration decreased below this level within 5-8 days. The combinations of MTX + HT90 also were more effective with respect to tumour growth delay, 26-28 days, and frequency of partial remissions, 75-100%, as compared to the other treatments: 7-12 days and 0-28% respectively. These observations correlate well with cell survival data. It is concluded that hyperthermia can enhance the effectiveness of MTX and that variation of time-intervals between administration of MTX and hyperthermia as well as the duration of the hyperthermic treatment have a great influence on tumour responses. Unfortunately, also toxic effects were induced distantly from the site of local hyperthermic treatment by the combination of MTX + HT90 which was most effective with respect to tumour eradication. PMID:7594809

  14. 4D radiobiological modelling of the interplay effect in conventionally and hypofractionated lung tumour IMRT

    PubMed Central

    Uzan, J; Baker, C; Nahum, A

    2015-01-01

    Objective: To study the impact of the interplay between respiration-induced tumour motion and multileaf collimator leaf movements in intensity-modulated radiotherapy (IMRT) as a function of number of fractions, dose rate on population mean tumour control probability () using an in-house developed dose model. Methods: Delivered dose was accumulated in a voxel-by-voxel basis inclusive of tumour motion over the course of treatment. The effect of interplay on dose and was studied for conventionally and hypofractionated treatments using digital imaging and communications in medicine data sets. Moreover, the effect of dose rate on interplay was also studied for single-fraction treatments. Simulations were repeated several times to obtain for each plan. Results: The average variation observed in mean dose to the target volumes were −0.76% ± 0.36% for the 20-fraction treatment and −0.26% ± 0.68% and −1.05% ± 0.98% for the three- and single-fraction treatments, respectively. For the 20-fraction treatment, the drop in was −1.05% ± 0.39%, whereas for the three- and single-fraction treatments, it was −2.80% ± 1.68% and −4.00% ± 2.84%, respectively. By reducing the dose rate from 600 to 300 MU min−1 for the single-fraction treatments, the drop in was reduced by approximately 1.5%. Conclusion: The effect of interplay on is negligible for conventionally fractionated treatments, whereas considerable drop in is observed for the three- and single-fraction treatments. Reduced dose rate could be used in hypofractionated treatments to reduce the interplay effect. Advances in knowledge: A novel in silico dose model is presented to determine the impact of interplay effect in IMRT treatments on . PMID:25251400

  15. Delivery of methoxymorpholinyl doxorubicin by interleukin 2-activated NK cells: effect in mice bearing hepatic metastases

    PubMed Central

    Quintieri, L; Rosato, A; Amboldi, N; Vizler, C; Ballinari, D; Zanovello, P; Collavo, D

    1999-01-01

    The possibility of using interleukin 2 (IL-2)-activated natural killer cells (A-NK) to carry methoxymorpholinyl doxorubicin (MMDX; PNU 152243) to liver-infiltrating tumours was explored in mice bearing 2-day established M5076 reticulum cell sarcoma hepatic metastases. In vitro, MMDX was 5.5-fold more potent than doxorubicin against M5076 tumour cells. MMDX uptake by A-NK cells correlated linearly with drug concentration in the incubation medium [correlation coefficient (r) = 0.999]; furthermore, as MMDX incorporation was readily reproducible in different experiments, the amount of drug delivered by A-NK cells could be modulated. In vivo experiments showed that intravenous (i.v.) injection of MMDX-loaded A-NK cells exerted a greater therapeutic effect than equivalent or even higher doses of free drug. The increase in lifespan (ILS) following A-NK cell delivery of 53 μg kg−1 MMDX, a dosage that is ineffective when administered in free form, was similar to that observed in response to 92 μg kg−1 free drug, a dosage close to the 10% lethal dose (ILS 42% vs. 38% respectively). These results correlated with pharmacokinetic studies showing that MMDX encapsulation in A-NK cells strongly modifies its organ distribution and targets it to tissues in which IL-2 activated lymphocytes are preferentially entrapped after i.v. injection. © 1999 Cancer Research Campaign PMID:10098738

  16. Effect of acid-base alterations on hepatic lactate utilization

    PubMed Central

    Goldstein, Philip J.; Simmons, Daniel H.; Tashkin, Donald P.

    1972-01-01

    1. The effect of acid-base changes on hepatic lactate utilization was investigated in anaesthetized, mechanically ventilated dogs. 2. Portal vein flow and hepatic artery flow were measured with electromagnetic flowmeters, lactate concentration of portal vein, arterial and mixed hepatic venous blood was determined by an enzymatic technique, and hepatic lactate uptake was calculated using the Fick principle. 3. Respiratory alkalosis (Δ pH 0·25 ± 0·02) in four dogs resulted in a significant fall in total hepatic blood flow (-22 ± 4%) and a significant rise in both arterial lactate concentration (2·18 ± 0·32 m-mole/l.) and hepatic lactate utilization (3·9 ± 1·2 μmole/min.kg). 4. 0·6 M-Tris buffer infusion (Δ pH 0·21 ± 0·02) in four dogs produced no significant changes in liver blood flow, arterial lactate concentration or hepatic lactate uptake. 5. Respiratory acidosis (Δ pH -0·20 ± 0·03) in six dogs and metabolic acidosis (Δ pH -0·20 ± 0·02) in four dogs produced no significant changes in liver blood flow, decreases in arterial lactate concentration of 0·38 ± 0·09 m-mole/l. (P < 0·05) and 0·13 ± 0·13 m-mole/l., respectively, and no significant changes in hepatic lactate uptake. 6. A significant correlation (r = 0·63; P < 0·01) was found between hepatic lactate utilization and arterial lactate concentration during the hyperlactataemia associated with respiratory alkalosis. 7. Hyperlactataemia induced in four dogs by infusion of buffered sodium lactate (Δ pH 0·05 ± 0·01;% Δ liver blood flow 29 ± 7%) was also significantly correlated with hepatic lactate utilization (r = 0·70; P < 0·01) and the slope of the regression was similar to that during respiratory alkalosis. 8. These data suggest that the hyperlactataemia of alkalosis is not due to impaired hepatic utilization of lactate and that the principal determinant of hepatic lactate uptake during alkalosis or lactate infusion is blood lactate concentration, rather than liver

  17. Improved cytotoxic effects of Salmonella-producing cytosine deaminase in tumour cells

    PubMed Central

    Mesa-Pereira, Beatriz; Medina, Carlos; Camacho, Eva María; Flores, Amando; Santero, Eduardo

    2015-01-01

    In order to increase the cytotoxic activity of a Salmonella strain carrying a salicylate-inducible expression system that controls cytosine deaminase production, we have modified both, the vector and the producer bacterium. First, the translation rates of the expression module containing the Escherichia coli codA gene cloned under the control of the Pm promoter have been improved by using the T7 phage gene 10 ribosome binding site sequence and replacing the original GUG start codon by AUG. Second, to increase the time span in which cytosine deaminase may be produced by the bacteria in the presence of 5-fluorocytosine, a 5-fluorouracyl resistant Salmonella strain has been constructed by deleting its upp gene sequence. This new Salmonella strain shows increased cytosine deaminase activity and, after infecting tumour cell cultures, increased cytotoxic and bystander effects under standard induction conditions. In addition, we have generated a purD mutation in the producer strain to control its intracellular proliferation by the presence of adenine and avoid the intrinsic Salmonella cell death induction. This strategy allows the analysis and comparison of the cytotoxic effects of cytosine deaminase produced by different Salmonella strains in tumour cell cultures. PMID:25227763

  18. Production of oxygen free radicals by Ehrlich ascites tumour cells: effect of lipids

    PubMed Central

    D'Souza, Cletus J. M.

    1993-01-01

    Phorbol-12-myristate-13-acetate (PMA), calcium ionophore A23187 and platelet activating factor (PAF) stimulated the generation of oxygen free radicals (nitro-blue tetrazolium reduction) in Ehrlich ascites tumour (EAT) cells. PAF was effective at an optimal concentration of 4 μM, but was inhibited by BN 52021, a specific PAF antagonist. Lyso-PAF was ineffective. Inclusion of different lipids during incubation prior to the addition of PAF, resulted in the activation/inhibition of free radical generation. Among the phospholipids at a concentration of 50 μg/ml, the order of activation was phosphatidylserine > phosphatidylglycerol > phosphoinositides > phosphatidylinositol > phosphatidylethanolamine. Phosphatidylcholine was not effective, while sphingolipids were inhibitory. In addition, Ehrlich ascites tumour cells grown in mice under marginal vitamin A deficiency, showed an augmented production of free radicals compared to control cells. This was suppressed by exogenous addition of vitamin A or superoxide dismutase. These results suggest that membrane lipids and dietary factors like vitamin A probably function as physiological modulators in regulating the free radical generation. PMID:18475503

  19. Edge effects in game-theoretic dynamics of spatially structured tumours.

    PubMed

    Kaznatcheev, Artem; Scott, Jacob G; Basanta, David

    2015-07-01

    Cancer dynamics are an evolutionary game between cellular phenotypes. A typical assumption in this modelling paradigm is that the probability of a given phenotypic strategy interacting with another depends exclusively on the abundance of those strategies without regard for local neighbourhood structure. We address this limitation by using the Ohtsuki-Nowak transform to introduce spatial structure to the go versus grow game. We show that spatial structure can promote the invasive (go) strategy. By considering the change in neighbourhood size at a static boundary--such as a blood vessel, organ capsule or basement membrane--we show an edge effect that allows a tumour without invasive phenotypes in the bulk to have a polyclonal boundary with invasive cells. We present an example of this promotion of invasive (epithelial-mesenchymal transition-positive) cells in a metastatic colony of prostate adenocarcinoma in bone marrow. Our results caution that pathologic analyses that do not distinguish between cells in the bulk and cells at a static edge of a tumour can underestimate the number of invasive cells. Although we concentrate on applications in mathematical oncology, we expect our approach to extend to other evolutionary game models where interaction neighbourhoods change at fixed system boundaries.

  20. Effect of Spilanthes acmella hydroethanolic extract activity on tumour cell actin cytoskeleton.

    PubMed

    Pacheco Soares, Cristina; Lemos, Valeria Rosseto; da Silva, Ary Gomes; Campoy, Renan Meyer; da Silva, Carlos Augusto Priante; Menegon, Renato Farina; Rojahn, Iuri; Joaquim, Walderez Moreira

    2014-01-01

    Numerous natural products have pharmacological activity such that many biologically active compounds have led to the development of cancer chemotherapy drugs. Spilanthes acmella (Asteraceae) is widely cultivated in the State of Pará, Brazil, being employed in folk medicine for its anti-inflammatory, antimicrobial, antioxidant, analgesic, insecticide, and larvicidal properties. However, its cytotoxicity and influence on actin cytoskeleton organisation in tumour cell lines are practically nonexistent. We have verified the cytotoxicity of a hydroethanolic extract of the inflorescence of S. acmella, and examined its effects on the cytoskeleton of tumour cells. Decreasing concentrations of the extract (250, 500 and 1,000 µg/mL) were given to cultures of neoplastic cells (HEp-2). Cytotoxicity was assessed by the MTT test, and the influence on cytoskeleton organisation was examined by fluorescence microscopy. The IC50 of the hydroethanolic extract was 513 µg/mL, confirming the data obtained from the MTT assay that gave high cytotoxicity. The actin cytoskeleton arrangement of HEp2 cells at 500 and 1,000 µg/mL showed depolymerisation of the filaments, causing loss of morphology and consequently compromising cell adhesion. PMID:24038906

  1. Edge effects in game-theoretic dynamics of spatially structured tumours

    PubMed Central

    Kaznatcheev, Artem; Scott, Jacob G.; Basanta, David

    2015-01-01

    Cancer dynamics are an evolutionary game between cellular phenotypes. A typical assumption in this modelling paradigm is that the probability of a given phenotypic strategy interacting with another depends exclusively on the abundance of those strategies without regard for local neighbourhood structure. We address this limitation by using the Ohtsuki–Nowak transform to introduce spatial structure to the go versus grow game. We show that spatial structure can promote the invasive (go) strategy. By considering the change in neighbourhood size at a static boundary—such as a blood vessel, organ capsule or basement membrane—we show an edge effect that allows a tumour without invasive phenotypes in the bulk to have a polyclonal boundary with invasive cells. We present an example of this promotion of invasive (epithelial–mesenchymal transition-positive) cells in a metastatic colony of prostate adenocarcinoma in bone marrow. Our results caution that pathologic analyses that do not distinguish between cells in the bulk and cells at a static edge of a tumour can underestimate the number of invasive cells. Although we concentrate on applications in mathematical oncology, we expect our approach to extend to other evolutionary game models where interaction neighbourhoods change at fixed system boundaries. PMID:26040596

  2. Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides.

    PubMed

    Buhtoiarov, Ilia N; Sondel, Paul M; Eickhoff, Jens C; Rakhmilevich, Alexander L

    2007-03-01

    We explored the mechanisms of class B CpG-oligodeoxynucleotide-induced antitumour effects against weakly immunogenic tumours. Treatment with CpG-oligodeoxynucleotide 1826 (CpG) induced similar antitumour effects in B16 melanoma-bearing immunocompetent C57BL/6 mice and T-cell-deficient severe combined immunodeficient (SCID) mice, and NXS2 neuroblastoma-bearing T-cell-depleted A/J mice. Both macrophages (Mphi) and natural killer (NK) cells from CpG-treated C57BL/6 mice could mediate cytotoxicity in vitro, suggesting that these cell types might control tumour growth in vivo. However, CpG treatment of SCID/beige mice or T-cell-depleted and NK-cell-depleted A/J mice still induced antitumour effects in vivo, arguing against a major role of NK cells in the antitumour effects of CpG in the absence of T cells. In contrast, CpG treatment of interferon-gamma knockout (IFN-gamma(-/-)) C57BL/6 mice resulted in no antitumour effects in vivo and no Mphi-mediated tumoristasis in vitro despite unaltered cytolytic function of NK cells in vitro. Moreover, Mphi inactivation by silica substantially reduced CpG-induced suppression of tumour growth in vivo, revealing an important role of Mphi in CpG-induced antitumour effects. The in vitro tumouritoxicity by CpG-stimulated Mphi (CpG-Mphi) correlated with tumour cell mitochondria dysfunction and involved nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma, whereas interleukin-1alpha (IL-1alpha), IL-1beta, IFN-alpha, TNF-related apoptosis-inducing ligand and Fas ligand played insignificant roles in CpG-Mphi tumouritoxicity. Taken together, our results indicate that the growth control of weakly immunogenic tumours during CpG-immunotherapy is mediated predominantly by Mphi, rather than T cells or NK cells.

  3. Quantification of the effect of electrical and thermal parameters on radiofrequency ablation for concentric tumour model of different sizes.

    PubMed

    Jamil, Muhammad; Ng, E Y K

    2015-07-01

    Radiofrequency ablation (RFA) has been increasingly used in treating cancer for multitude of situations in various tissue types. To perform the therapy safely and reliably, the effect of critical parameters needs to be known beforehand. Temperature plays an important role in the outcome of the therapy and any uncertainties in temperature assessment can be lethal. This study presents the RFA case of fixed tip temperature where we've analysed the effect of electrical conductivity, thermal conductivity and blood perfusion rate of the tumour and surrounding normal tissue on the radiofrequency ablation. Ablation volume was chosen as the characteristic to be optimised and temperature control was achieved via PID controller. The effect of all 6 parameters each having 3 levels was quantified with minimum number of experiments harnessing the fractional factorial characteristic of Taguchi's orthogonal arrays. It was observed that as the blood perfusion increases the ablation volume decreases. Increasing electrical conductivity of the tumour results in increase of ablation volume whereas increase in normal tissue conductivity tends to decrease the ablation volume and vice versa. Likewise, increasing thermal conductivity of the tumour results in enhanced ablation volume whereas an increase in thermal conductivity of the surrounding normal tissue has a debilitating effect on the ablation volume and vice versa. With increase in the size of the tumour (i.e., 2-3cm) the effect of each parameter is not linear. The parameter effect varies with change in size of the tumour that is manifested by the different gradient observed in ablation volume. Most important is the relative insensitivity of ablation volume to blood perfusion rate for smaller tumour size (2cm) that is also in accordance with the previous results presented in literature. These findings will provide initial insight for safe, reliable and improved treatment planning perceptively.

  4. Effectiveness of 10-year vaccination (2001-2010) on Hepatitis A in Tianjin, China.

    PubMed

    Zhang, Zhi-lun; Zhu, Xiang-jun; Shan, Ai-lan; Gao, Zhi-gang; Zhang, Ying; Ding, Ya-xing; Liu, Hui; Wu, Wei-shen; Liu, Yong; He, Hai-yan; Xie, Xiao-hua; Xia, Wei-dong; Li, Chao; Xu, Wen-ti; Li, Zhi-yuan; Lin, Hua-liang; Fu, Wei-ming

    2014-01-01

    Vaccination is an effective strategy to prevent and control the transmission of hepatitis A. Hepatitis A immunization program has been taken into effect since 2001 in Tianjin, China. This study evaluated the effectiveness of strategies in the prevention and control of hepatitis A. Data of serological survey, annual hepatitis A incidence, immunization coverage and the positive rate of hepatitis A IgG before and after the immunization program in residents under 15 years old were used to do the analysis. The results indicated that hepatitis A vaccine induced a striking decrease of hepatitis A incidence and a significant increase in the positive rate of anti-HAV IgG among the children younger than 15 years old. Hepatitis A vaccination in children was proved to be effective in the prevention and control of hepatitis A in Tianjin, China.

  5. Effectiveness of 10-year vaccination (2001–2010) for Hepatitis A in Tianjin, China

    PubMed Central

    Zhang, Zhi-lun; Zhu, Xiang-jun; Shan, Ai-lan; Gao, Zhi-gang; Zhang, Ying; Ding, Ya-xing; Liu, Hui; Wu, Wei-shen; Liu, Yong; He, Hai-yan; Xie, Xiao-hua; Xia, Wei-dong; Li, Chao; Xu, Wen-ti; Li, Zhi-yuan; Lin, Hua-Liang; Fu, Wei-ming

    2014-01-01

    Vaccination is an effective strategy to prevent and control the transmission of hepatitis A. Hepatitis A immunization program has been taken into effect since 2001 in Tianjin, China. This study evaluated the effectiveness of strategies in the prevention and control of hepatitis A. Data of serological survey, annual hepatitis A incidence, immunization coverage and the positive rate of hepatitis A IgG before and after the immunization program in residents under 15 years old were used to do the analysis. The results indicated that hepatitis A vaccine induced a striking decrease of hepatitis A incidence and a significant increase in the positive rate of anti-HAV IgG among the children younger than 15 years old. Hepatitis A vaccination in children was proved to be effective in the prevention and control of hepatitis A in Tianjin, China. PMID:24503599

  6. Relative biological effectiveness of light ions in human tumoural cell lines: role of protein p53

    NASA Technical Reports Server (NTRS)

    Baggio, L.; Cavinato, M.; Cherubini, R.; Conzato, M.; Cucinotta, F.; Favaretto, S.; Gerardi, S.; Lora, S.; Stoppa, P.; Williams, J. R.

    2002-01-01

    Protons and alpha particles of high linear energy transfer (LET) have shown an increased relative biological effectiveness (RBE) with respect to X/gamma rays for several cellular and molecular endpoints in different in vitro cell systems. To contribute to understanding the biochemical mechanisms involved in the increased effectiveness of high LET radiation, an extensive study has been designed. The present work reports the preliminary result of this study on two human tumoural cell lines, DLD1 and HCT116, (with different p53 status), which indicate that for these cell lines, p53 does not appear to take a part in the response to radiation induced DNA damage, suggesting an alternative p53-independent pathway and a cell biochemical mechanism dependent on the cell type.

  7. The improving effects on hepatic fibrosis of interferon-γ liposomes targeted to hepatic stellate cells

    NASA Astrophysics Data System (ADS)

    Li, Qinghua; Yan, Zhiqiang; Li, Feng; Lu, Weiyue; Wang, Jiyao; Guo, Chuanyong

    2012-07-01

    No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor-β (PDGFR-β), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR-β to deliver interferon (IFN)-γ to HSCs. The pPB-SSL-IFN-γ showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN-γ mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN-γ showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN-γ were less than those treated with SSL-IFN-γ, IFN-γ and the control group. In vitro pPB-SSL-IFN-γ was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN-γ might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis.

  8. A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity

    PubMed Central

    Takahashi, Hidenori; Ebihara, Satoru; Okazaki, Tatsuma; Asada, Masanori; Sasaki, Hidetada; Yamaya, Mutsuo

    2005-01-01

    Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg−1 day−1), dalteparin (75 units kg−1 day−1) or danaparoid (50 units kg−1 day−1). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours. PMID:16041398

  9. A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity.

    PubMed

    Takahashi, Hidenori; Ebihara, Satoru; Okazaki, Tatsuma; Asada, Masanori; Sasaki, Hidetada; Yamaya, Mutsuo

    2005-10-01

    Disseminated intravascular coagulation (DIC) is the most common complication of solid tumours. In this study, the effectiveness of three polysaccharide anticoagulants (PSAs), at therapeutic doses, at inhibiting solid tumour growth was investigated. Mice with tumour xenografts were subcutaneously injected with either unfractionated heparin (UFH; 200 units kg(-1) day(-1)), dalteparin (75 units kg(-1) day(-1)) or danaparoid (50 units kg(-1) day(-1)). At these concentrations, these PSAs are equieffective at inhibiting blood coagulation activated factor X. In mice with Lewis lung carcinoma (LLC) tumours dalteparin and, to a lesser extent, UFH inhibited both tumour growth and angiogenesis, whereas danaparoid did not. In contrast, in mice with KLN205 tumours, all the PSAs inhibited tumour growth and angiogenesis. All the PSAs significantly inhibited proliferation, migration of endothelial cells and vessel formation in matrigel plugs containing vascular endothelial growth factor (VEGF) and there were no significant differences between these effects of the PSAs. The PSAs had no effect on endothelial cell tubular formation in vitro. Although all the PSAs inhibited VEGF production in KLN205 tumours in vivo and cells in vitro, in LLC tumours and cells only UFH and dalteparin inhibited VEGF production, whereas danaparoid did not. In both LLC and KLN205 tumours in vivo, heparanase activity was inhibited by UFH and dalteparin, but not by danaparoid. Hence, UFH and dalteparin may be more effective than danaparoid at inhibiting cancer progression in DIC patients with solid tumours, due at least in part to their ability to suppress VEGF and heparanase in tumours. PMID:16041398

  10. [Inflammatory myofibroblastic tumour (so-called pseudotumour) of the hepatobiliary system].

    PubMed

    Stuckmann, G; Flury, R; Heinz, W; Strunk, H

    2004-09-01

    The purpose of this report is to describe the ultrasonographic features of hepatic inflammatory myofibroblastic tumour (IMT). This tumour presented as an area of periportal soft-tissue infiltration. Because periportal infiltration is a common feature in both IMT and other malignant tumours of the hepatic portal, histological examination should be considered before final diagnosis and treatment. PMID:15368142

  11. Piroxicam, indomethacin and aspirin action on a murine fibrosarcoma. Effects on tumour-associated and peritoneal macrophages.

    PubMed Central

    Valdéz, J C; Perdigón, G

    1991-01-01

    Growth of a methylcholanthrene-induced fibrosarcoma in BALB/c mice was accompanied by an increase in the activation state of tumour-associated macrophages (TAM), as measured by their FcIgG receptor expression, phagocytic index and beta-glucuronidase levels. All of these parameters were markedly higher in TAM than in peritoneal macrophages (PM) derived from the same animal. On the other hand, PM from tumour-bearing mice showed lower activation parameters than PM from normal animals. We also studied the effect on tumour development of three inhibitors of prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45% regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached different volumes by the end of the treatment, was delayed to a similar extent by the three anti-inflammatory non-steroidal drugs (NSAID). With respect to TAM, the treatment did not induce any significant change in their activation state, though both piroxicam and indomethacin increased slightly the TAM number. In contrast, NSAID administration was followed by a remarkable increase in the activation parameters of PM when compared with PM from tumour-bearing mice receiving no treatment. Indeed, these parameters were in some cases higher than those of PM from normal mice. The leukocytosis (60,000/microliters) with neutrophilia (80%) induced by tumour growth on peripheral blood leukocytes (PBL) was reversed by the treatment to values close to normal, in parallel with the reduction of tumour size. A drop in haematocrit was also noted which was most probably a consequence of tumour growth rather than of the treatment. This study reveals that the three NSAID tested have a remarkable antitumour activity, which

  12. Effect on tumour control of time interval between surgery and postoperative radiotherapy: an empirical approach using Monte Carlo simulation

    NASA Astrophysics Data System (ADS)

    Al-Dweri, Feras M. O.; Guirado, Damián; Lallena, Antonio M.; Pedraza, Vicente

    2004-07-01

    In this work, a procedure, based on Monte Carlo techniques, to analyse the effect on the tumour control probability of the time interval between surgery and postoperative radiotherapy is presented. The approach includes the tumour growth as well as the survival of tumour cells undergoing fractionated radiotherapy. Both processes are described in terms of the binomial distribution. We have considered two different growth models, exponential and Gompertz, the parameters of which have been fixed to reproduce the clinical outcome corresponding to a retrospective study for patients with head and neck squamous cell carcinomas. In the cases analysed, we have not found significant differences between the results obtained for both growth models. The mean doubling times found for residual clonogens after surgery are less than 40 days. The rate of decrease in local control is around 0.09% per day of delay between surgery and radiotherapy and the corresponding time factor is about 0.11 Gy per day.

  13. The effects of ultrasound and light on indocyanine-green-treated tumour cells and tissues.

    PubMed

    Nomikou, Nikolitsa; Sterrett, Christine; Arthur, Ciara; McCaughan, Bridgeen; Callan, John F; McHale, Anthony P

    2012-08-01

    Photodynamic therapy (PDT) is emerging as a treatment modality for the management of neoplastic disease. Despite considerable clinical success, its application for the treatment of deep-seated lesions is constrained by the inability of visible light to penetrate deeply into tissues. An emerging alternative approach exploits the fact that many photosensitisers respond to ultrasound, eliciting cytotoxic effects on target cells and tissues; this has become known as sonodynamic therapy (SDT). The objectives of this study were 1) to determine whether the IR-absorbing dye, indocyanine green (ICG), can be employed as a sonosensitiser and 2) to determine whether ultrasound can be used to enhance ICG-mediated PDT. Exposing ICG-treated mouse fibrosarcoma cells to ultrasound at an energy density of 30 J cm(-2) decreased cell viability by 65 %. Prior exposure of ICG-treated cells to light (λ 830 nm) and subsequent treatment with ultrasound led to a 90 % decrease in cell viability. In combination treatments a synergistic effect was observed at lower doses of ultrasound. Microscopic examination of cell populations treated with light or ultrasound demonstrated the production of intracellular reactive oxygen species (ROS). Using a mouse tumour model, treatment with light, ultrasound, or a combination thereof led to respective decreases in tumour growth of 42, 67, and 98 % at day 27 post-treatment. These results could provide a means of circumventing light-penetration issues that currently challenge the widespread use of PDT in the treatment of cancer.

  14. Effect of spermine synthase on the sensitivity of cells to anti-tumour agents.

    PubMed Central

    Ikeguchi, Yoshihiko; Mackintosh, Caroline A; McCloskey, Diane E; Pegg, Anthony E

    2003-01-01

    The role of spermine in the sensitivity of cells to various established and experimental anti-tumour agents was examined, using paired cell lines that possess or lack spermine synthase. All spermine-synthase-deficient cells had no detectable spermine, and elevated spermidine, content. Spermine content did not alter the cell growth rate. There was little or no difference in sensitivity of immortalized mouse embryonic fibroblasts to doxorubicin, etoposide, cisplatin, methylglyoxal bis(guanylhydrazone) or H(2)O(2) and only a slight increase in sensitivity to vinblastine and nocodazole. However, the absence of spermine clearly increased the sensitivity to 1,3-bis(2-chloroethyl)- N -nitrosourea, suggesting that depletion of spermine may be a useful way to increase the anti-neoplastic effects of anti-tumour agents that form chloroethyl-mediated interstrand DNA cross-links. The effects of spermine on the response to polyamine analogues (which have been proposed to be useful anti-neoplastic agents) were complex, and depended on the compound examined and on the cells tested. Sensitivity to CHENSpm ( N (1)-ethyl- N (11)-[(cycloheptyl)methyl]-4,8-diazaundecane) was substantially greater in immortalized fibroblasts that lack spermine. In contrast, BE-3-4-3 [ N (1), N (12)-bis(ethyl)spermine] and BE-3-3-3 [ N (1), N (11)-bis(ethyl)norspermine] were more active against cells that contained spermine. The presence of spermine correlated with a greater induction of spermidine/spermine- N (1)-acetyltransferase by BE-3-3-3, which is consistent with suggestions that this induction is important for the response to this drug. These findings support the concepts that different polyamine analogues have different sites of action and that CHENSpm has a different site of action from BE-3-3-3. PMID:12737625

  15. Keratocystic Odontogenic Tumour with Extraosseal Spread: Evaluation of the Effect Carnoy's Solution.

    PubMed

    Levorová, Jitka; Machoň, Vladimír; Grill, Pavel; Hirjak, Dušan; Foltán, René

    2015-01-01

    Keratocystic odontogenic tumour is relatively rare benign tumour. It is characterized by its fast aggressive growth and high risk of recurrence. Treatment is always surgical: conservative (enucleation, marsupialization) or aggressive (enucleation followed by application of Carnoy's solution, cryotherapy; peripheral ostectomy or en block resection of the jaw). Authors analysed retrospectively 22 patients who fulfilled inclusion criteria, i.e. had odontogenic keratocystic tumour of mandible, wherein antero-posterior dimension was at least 30 mm, and the tumour penetrated into the surrounding soft tissues. All patients underwent tumour enucleation, in 11 patients Carnoy's solution was given into the bone cavity after enucleation. The recurrence rate in the evaluation at least 36 months after surgery was both patient groups the same: 45.4%. PMID:26654803

  16. Effects of He-Ne laser acupuncture-point irradiation on serology hepatitis virus markers in chronic hepatitis B

    NASA Astrophysics Data System (ADS)

    Wang, Yue-lan; Huang, Bing-chen; Ni, Liu-da

    1993-03-01

    For most of the patients with chronic hepatitis B the immunologic function is deficient. Immunopotentiation and immunoregulation can be used as effective treatments. Laser irradiation can potentiate the cellular immune function of the human body and has good effects on improving clinical symptoms, cutting short the process of diseases, and promoting HBsAg negative change. Thereby we have a randomized opportunity to study the effect of He-Ne laser acupoint irradiation on serological HBV markers (HBVM) in chronic hepatitis B (CHB).

  17. The effects of shortening lactoferrin derived peptides against tumour cells, bacteria and normal human cells.

    PubMed

    Yang, Nannan; Strøm, Morten B; Mekonnen, Seble M; Svendsen, John S; Rekdal, Oystein

    2004-01-01

    A number of shortened derivatives of the lactoferrin model peptide L12, PAWRKAFRWAKRMLKKAA, were designed in order to elucidate the structural basis for antitumour activity of lactoferrin derivatives. Three tumour cell lines were included in the study and toxicity determined by measuring lysis of human red blood cells and fibroblasts. The results demonstrated a strong correlation between antitumour activity and net positive charge, in which a net charge close to +7 was essential for a high antitumour activity. In order to increase the antitumour activity of the shortest peptide with a net charge less than +7, the hydrophobicity had to be increased by adding a bulky Trp residue. None of the peptides were haemolytic, but toxicity against fibroblasts was observed. However, modifications of the peptides had a higher effect on reducing fibroblast toxicity than antitumour activity and thereby resulted in peptides displaying an almost 7-fold selectivity for tumour cells compared with fibroblasts. The antimicrobial activity against the Gram-negative bacteria Escherichia coil and the Gram-positive bacteria Staphylococcus aureus was also included in order to compare the structural requirements for antitumour activity with those required for a high antimicrobial activity. The results showed that most of the peptides were highly active against both bacterial strains. Less modification by shortening the peptide sequences was tolerated for maintaining a high antitumour activity and selectivity compared with antimicrobial activity. The order of the amino acid residues and thereby the conformation of the peptides was highly essential for antitumour activity, whereas the antimicrobial activity was hardly influenced by changes in this parameter. Thus, in addition to a certain net positive charge and hydrophobicity, the ability to adopt an amphipathic conformation was a more critical structural parameter for antitumour activity than for antimicrobial activity, and implied that a

  18. pH in human tumour xenografts: effect of intravenous administration of glucose.

    PubMed Central

    Volk, T.; Jähde, E.; Fortmeyer, H. P.; Glüsenkamp, K. H.; Rajewsky, M. F.

    1993-01-01

    pH frequency distributions of tumours grown s.c. from 30 human tumour xenograft lines in rnu/rnu rats were analysed with the use of H+ ion-sensitive semi-microelectrodes prior to and following stimulation of tumour cell glycolysis by i.v. infusion of glucose. At normoglycemia, the average pH of the tumours investigated was 6.83 (range, 6.72-7.01; n = 268). Without exception, all xenografts responded to the temporary increase in plasma glucose concentration (PGC) from 6 +/- 1 to 30 +/- 3 mM by an accumulation of acidic metabolites, as indicated by a pH reduction to an average value of 6.43 (range, 6.12-6.78; n = 292). This pH value corresponds to a ten-fold increase in H+ ion activity in tumour tissue as compared to arterial blood. Tumour pH approached minimum values at 2-4 h after the onset of glucose administration and could be maintained at acidic levels for 24 h by controlled glucose infusion. Irrespective of pH variations between tumours grown from individual xenograft lines, there was no major difference in pH response to glucose between the four main histopathological tumour entities investigated, i.e. breast, lung and gastrointestinal carcinomas, and sarcomas. In tumours from several xenograft lines, an increase in blood glucose to only 2.5-times the normal value (14 mM) was sufficient to reduce the mean pH to 6.4. Glucose-induced acidosis was tumour-specific. The pH frequency distributions in liver, kidney and skeletal muscle of tumour-bearing rnu/rnu rats were only marginally sensitive to hyperglycemia (average pH, 6.97 vs normal value of 7.14). Tumour-selective activation of pH-sensitive anti-cancer agents, e.g. alkylating drugs, acid-labile prodrugs or pH-sensitive immunoconjugates may thus be feasible in a wide variety of human cancers. PMID:8353039

  19. The effect of silymarin on hepatic regeneration after partial hepatectomy: is silymarin effective in hepatic regeneration?

    PubMed Central

    Cetinkunar, Suleyman; Tokgoz, Serhat; Bilgin, Bulent Caglar; Erdem, Hasan; Aktimur, Recep; Can, Serpil; Erol, Huseyin Serkan; Isgoren, Atilla; Sozen, Selim; Polat, Yilmaz

    2015-01-01

    Aim: Silymarin from Silybum marianum was found to reduce liver injury. The aim of the present study was to investigate the effects of silymarin on hepatic regeneration in partially hepatectomized rats. Methods: Thirty Wistar-Albino rats were divided into 3 groups of 10 animals as sham, control and experimental groups. In the sham group (n=10) abdominal incision was closed after laparotomy. In the control group (n=10), the rats underwent 70% hepatectomy after laparotomy. In the experimental group (n=10) after partial 70% hepatectomy, silymarin (200 mg/kg/d) were given to rats for 10 days. Rats in three groups were sacrificed on 10 days. Aspartate (AST) and alanine transaminase (ALT), gamma glutamyl transferase (GGT), ALP, LDH and total bilirubin levels were measured using intracardiac blood samples. Tissue malondialdehyde (MDA) and tissue glutathion (GSH) and Superoxide dismutase (SOD) levels were measured. To reveal the increase in the mass of the remnant liver tissue in the control and experimental groups relative weight of the liver was calculated. Histopathological analysis of the liver was performed using a semi-quantitative scoring system. Results: A statistically significant difference among three groups was not shown for AST and ALT levels. A statistically significant difference was found between the groups as for total bilirubin and gamma glutamyl transferase levels. Increases in relative liver weights were seen with time in Groups 2 and 3. A statistically significant difference was not found for tissue malondialdehyde, Glutathion and Superoxide dismutase levels between hepatectomy and hepatectomy + silymarin groups. On liver tissue sections of the rats in the hepatectomy + silymarin group, increased regeneration and lipid peroxidation were observed accompanied by decreased antioxidant response. Conclusion: It has been observed that silymarin with many established functions such as antiproliferative, anti-inflammatory and energy antioxidant effects, does

  20. Tumour growth results in changes in placental amino acid transport in the rat: a tumour necrosis factor alpha-mediated effect.

    PubMed

    Carbó, N; López-Soriano, F J; Fiers, W; Argilés, J M

    1996-01-01

    The implantation of a fast growing tumour (Yoshida AH-130 ascites hepatoma) to late pregnant rats resulted in no changes in fetal growth, this possibly being associated with an important increase in the fetal uptake of maternal-derived amino acids [Carbó, López-Soriano and Argilés (1995) Endocrinology 136, 3579-3584]. The present investigation was undertaken to see whether the presence of the tumour induced changes in placental transport systems. For alanine transport, although no changes in affinity (Km) were observed, tumour growth resulted in a 192% increase in Vmax in the Na(+)-independent component. Kinetic analysis of the Na(+)-dependent component resulted in two clearly different components: while the low-affinity and high-capacity component was unaffected by tumour growth, the high-affinity, low-capacity component of the tumour-bearing rats showed an important increase in Vmax. (78%). With regard to leucine transport, tumour burden induced important increases in the Na(+)-independent component, not only in Km (262%) but also in Vmax. (189%). Since elevated tumour necrosis factor-alpha (TNF) concentrations have been reported in this kind of tumour model, we performed the same type of transport experiments in rats chronically treated with TNF, the results obtained showing great similarities with those observed with tumour growth. The Vmax. of Na(+)-independent alanine transport was also increased by the cytokine (104%) while no changes were observed in affinity. TNF treatment also induced an increase in the Vmax. (67%) of the Na(+)-dependent (high-affinity, low-capacity) component while no changes in affinity were observed. Concerning leucine kinetics, TNF treatment, as in the case of tumour growth, also increased Km (155%) and Vmax. (72%) associated with Na(+)-independent transport. Interestingly, treatment with the cytokine increased both the Km (43%) and Vmax. (64%) of the Na(+)-dependent component. The inhibition patterns suggest the existence of more

  1. Clinical features of gastroenteropancreatic tumours

    PubMed Central

    Czarnywojtek, Agata; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Wrotkowska, Elżbieta; Ruchała, Marek

    2015-01-01

    Gastroenteropancreatic (GEP) endocrine tumours (carcinoids and pancreatic islet cell tumours) are composed of multipotent neuroendocrine cells that exhibit a unique ability to produce, store, and secrete biologically active substances and cause distinct clinical syndromes. The classification of GEP tumours as functioning or non-functioning is based on the presence of symptoms that accompany these syndromes secondary to the secretion of hormones, neuropeptides and/or neurotransmitters (functioning tumours). Non-functioning tumours are considered to be neoplasms of neuroendocrine differentiation that are not associated with obvious symptoms attributed to the hypersecretion of metabolically active substances. However, a number of these tumours are either capable of producing low levels of such substances, which can be detected by immunohistochemistry but are insufficient to cause symptoms related to a clinical syndrome, or alternatively, they may secrete substances that are either metabolically inactive or inappropriately processed. In some cases, GEP tumours are not associated with the production of any hormone or neurotransmitter. Both functioning and non-functioning tumours can also produce symptoms due to mass effects compressing vital surrounding structures. Gastroenteropancreatic tumours are usually classified further according to the anatomic site of origin: foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, and right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups the biological and clinical characteristics of the tumours vary considerably, but this classification is still in use because a significant number of previous studies, mainly observational, have used it extensively. PMID:26516377

  2. The potential effect of patulin on mice bearing melanoma cells: an anti-tumour or carcinogenic effect?

    PubMed

    Boussabbeh, Manel; Ben Salem, Intidhar; Rjiba-Touati, Karima; Bouyahya, Chedy; Neffati, Fadwa; Najjar, Mohamed Fadhel; Bacha, Hassen; Abid-Essefi, Salwa

    2016-05-01

    Mycotoxins are bioactive compounds that are noxious to human. Their effects on oncogenesis have been satisfactorily elucidated, and some of mycotoxins have been classified as carcinogenic to humans. Nevertheless, patulin (PAT) is considered by the International Agency of Research on Cancer as 'not carcinogenic to humans'. The present study was designed to understand the effect of this mycotoxin on melanoma cells (B16F10) by measuring cell proliferation and assessing the anti-tumour effect in vivo in Balb/c mice. Our results revealed that intraperitoneally administration of PAT for 20 days significantly induces tumour regression in B16F10 cell-implanted mice. This effect was evidenced by the activation of apoptosis which is supported by the increase in p53 and Bax expressions, the downregulation of the protein levels of Bcl2, and the increase in caspase-3 activity. Moreover, systemic toxicity analysis demonstrated that there is no potential toxicity following PAT treatment unlike untreated melanoma mice which suffer from anaemia, inflammation and liver dysfunction. Remarkably, this is the first published report demonstrating the therapeutic efficacy of PAT in vivo models. PMID:26619846

  3. VEGF targets the tumour cell.

    PubMed

    Goel, Hira Lal; Mercurio, Arthur M

    2013-12-01

    The function of vascular endothelial growth factor (VEGF) in cancer is not limited to angiogenesis and vascular permeability. VEGF-mediated signalling occurs in tumour cells, and this signalling contributes to key aspects of tumorigenesis, including the function of cancer stem cells and tumour initiation. In addition to VEGF receptor tyrosine kinases, the neuropilins are crucial for mediating the effects of VEGF on tumour cells, primarily because of their ability to regulate the function and the trafficking of growth factor receptors and integrins. This has important implications for our understanding of tumour biology and for the development of more effective therapeutic approaches.

  4. Effects of saturated and unsaturated fats given with and without dietary cholesterol on hepatic cholesterol synthesis and hepatic lipid metabolism.

    PubMed

    Bochenek, W; Rodgers, J B

    1978-01-27

    Hepatic cholesterol synthesis was studied in rats after consuming diets of varying neutral lipid and cholesterol content. Cholesterol synthesis was evaluated by measuring 3-hydroxy-3-methylglutaryl-CoA reductase and by determining the rate of 3H-labeled sterol production from [3H]mevalonate. Results were correlated with sterol balance data and hepatic lipid content. Hepatic cholesterol synthesis was relatively great when cholesterol was excluded from the diet. The source of neutral dietary lipids, saturated vs. unsaturated, produced no change in hepatic sterol synthesis. Values for fecal sterol outputs and hepatic cholesterol levels were also similar in rats consuming either saturated or unsaturated fats. When 1% cholesterol was added to the diet, hepatic cholesterol synthesis was suppressed but the degree of suppression was greater in rats consuming unsaturated vs. saturated fats. This was associated with greater accumulation of cholesterol in livers from rats consuming unsaturates and a reduction in fecal neutral sterol output in this group as opposed to results from rats on saturated fats. Cholesterol consumption also altered the fatty acid composition of hepatic phospholipids producing decreases in the percentages of essential polyunsaturated fatty acids. It is concluded that dietary cholesterol alters cholesterol and fatty acid metabolism in the liver and that this effect is enhanced by dietary unsaturated fats.

  5. Light-oxygen effect in cells and its potential applications in tumour therapy (review)

    SciTech Connect

    Zakharov, S D; Ivanov, Andrei V

    1999-12-31

    The light-oxygen effect (POE) represents damage (and at low optical doses, activation) of cells by photogeneration of molecular singlet oxygen from O{sub 2} dissolved in cells, in accordance with the reaction: {sup 3}O{sub 2}+h{nu}{yields}{sup 1}O{sub 2}{yields} biological effect. The phases of evolution of the LOE are similar to the phases, observed in cell experiments, of the photodynamic effect (PDE) the mechanism of which is the basis of the familiar method of photodynamic cancer therapy. The reported proofs of the occurrence of the LOE are in the form of detailed spectra of the biological action of optical radiation on cells recorded in four spectral intervals with the aid of tunable lasers. Allowances are made for the relationships governing a new type of cell excitation, associated with reversible structural transitions in the biomembrane. A demonstration is reported of the same efficiency of cw and pulsed irradiation. An analysis is made of the reasons why the optical doses initiating the PDE and the LOE are comparable. The results are given of the first experimental applications of the LOE in tumour therapy. Identification of the primary photoacceptor (O{sub 2}) in cell biostimulation and photodestruction provides a scientific basis for the development of low-intensity laser light-oxygen cancer therapy methods. (lasers in medicine)

  6. Tumour necrosis factor-α inhibits hepatic lipid deposition through GSK-3β/β-catenin signaling in juvenile turbot (Scophthalmus maximus L.).

    PubMed

    Liu, Dongwu; Mai, Kangsen; Zhang, Yanjiao; Xu, Wei; Ai, Qinghui

    2016-03-01

    In this study, the mechanism that TNFα inhibits lipid deposition through GSK-3β/β-catenin signaling was investigated in the liver of juvenile turbot (Scophthalmus maximus L.) by injection of TNFα or TNFα inhibitor pomalidomide (POM). It was found that TNFα inhibited the expression of GSK-3β and induced β-catenin expression. TNFα inhibited the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα), as well as the activity of lipoprotein lipase (LPL) and fatty acid synthetase (FAS). In addition, the level of triglyceride (TG), total cholesterol (TC), nonesterified fatty acid (NEFA), and glycerol was decreased by TNFα treatment in the liver. In the plasma, the level of TG, TC, low density lipoprotein cholesterol (LDL-C), NEFA, and glycerol was decreased, but high density lipoprotein cholesterol (HDL-C) was increased by TNFα treatment. However, compared to TNFα, POM had the opposite effect on the biochemical indexes and genes related to lipid deposition in the liver. The results indicated that TNFα may regulate hepatic lipid metabolism and fat distribution through GSK-3β/β-catenin signaling as well as transcription factors PPARγ and C/EBPα in juvenile turbot. PMID:26747182

  7. Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity.

    PubMed Central

    Vizler, C.; Rosato, A.; Calderazzo, F.; Quintieri, L.; Fruscella, P.; Wainstok de Calmanovici, R.; Mantovani, A.; Vecchi, A.; Zanovello, P.; Collavo, D.

    1998-01-01

    In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-gamma monoclonal antibody (MAb) co-administration. These results strongly suggest that the anti-tumour effect of IL-12 is principally mediated by IFN-gamma release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis. PMID:9484826

  8. Analysis of tumour cell composition in tumours composed of paired mixtures of mammary tumour cell lines.

    PubMed Central

    Miller, B. E.; Miller, F. R.; Wilburn, D. J.; Heppner, G. H.

    1987-01-01

    In order to quantitate the effects of tumour subpopulation interactions, we have devised a method to determine the subpopulation composition of tumours by using paired tumour cell lines able to grow in different selective media. Line 4T07 forms colonies in thioguanine but not in HAT and line 168 forms colonies in HAT but not in thioguanine. An independent technique of determining tumour cell content was used to validate this method: line 168 and 4T07 cells are distinguishable by flow cytometry after staining with propidium iodide for DNA content. Mixtures of cell suspensions prepared from each unmixed tumour, as well as from tumours arising from mixtures of these lines, were analysed by both the colony formation assay and by the DNA content assay. The colony formation assay yielded values in good agreement with the DNA content assay, but was considerably more sensitive in that it was able to quantitate minority subpopulations that constituted less than 10% of the tumour. Both methods revealed that in tumours arising from mixtures, the tumour cells were almost entirely line 4T07, even when the inoculum had contained a high proportion of 168 cells. Since line 168 cells are very tumorigenic per se, these results suggest that line 4T07 cells are capable of interfering with 168 proliferation in mixed tumours, either directly or through a host-mediated mechanism. PMID:3426919

  9. The cardiodepressant and vasodepressant effects of tumour necrosis factor in rat isolated atrial and aortic tissues.

    PubMed Central

    Foulkes, R.; Shaw, S.

    1992-01-01

    1. The ability of recombinant human tumour necrosis factor-alpha (rec huTNF) to elicit cardiodepressor and vasodepressor effects in rat isolated tissues was investigated. 2. rec huTNF (3 x 10(-11)-3 x 10(-8) M) administered directly to the organ bath, caused a concentration-dependent relaxation of the isoprenaline-induced inotropic response in electrically stimulated rat left atria. This occurred within 20 min of administration. In contrast, rec huTNF was without effect on the chronotropic response to isoprenaline in isolated spontaneously beating atria. 3. rec huTNF (1 microgram kg-1) was also given systemically to rats and the atria studied in vitro. Only 60 min of rec huTNF pretreatment was sufficient to cause a marked attenuation of the isoprenaline-induced inotropic response. This effect was not further augmented when rats were pretreated with rec huTNF for 24 h. 4. In isolated aortic rings taken from rats 60 min after rec huTNF (1 microgram kg-1, i.v.) administration, there was no effect seen on the constriction induced by phenylephrine in either endothelium-intact or denuded tissues. In addition, any responses to L-arginine or NG-nitro-L-arginine methyl ester (L-NAME) administration were unaffected by rec huTNF pretreatment. 5. In aortic rings taken from rats 24 h after rec huTNF administration, the phenylephrine-induced constriction was significantly attenuated in tissues with an intact endothelium. Furthermore, the relaxation to subsequent L-arginine administration was greater in these tissues than in those saline-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1382789

  10. In silico modelling of a cancer stem cell-targeting agent and its effects on tumour control during radiotherapy

    PubMed Central

    Marcu, Loredana G.; Marcu, David

    2016-01-01

    Head and neck cancers (HNC), like most solid tumours, contain a subpopulation of cancer stem cells (CSC) that are commonly responsible for treatment failure. Conventional therapies are unsuccessful in controlling CSCs, thus novel, targeting therapies are needed. A promising agent is ATRA (All-trans-retinoic acid) that was shown to induce CSC differentiation, cell cycle redistribution and CSCs radiosensitisation. To add to the limited data, this work simulated the effects of ATRA on a virtual HNC and evaluated tumour response to radiotherapy. A Monte Carlo technique was employed to grow a HNC consisting of all lineages of cancer cells. The biologically realistic input parameters led to a pre-treatment CSC population of 5.9%. The Linear Quadratic model was employed to simulate radiotherapy. ATRA-induced differentiation, cell arrest and apoptosis were modelled, based on literature data. While the effect of differentiation was marginal, the strongest influence on CSC subpopulation was displayed by ATRA’s cell arrest effect via an exponential behaviour of the dose-response curve. The apoptotic effect induced by ATRA shows linear correlation between the percentage of apoptotic cells and dose required to eradicate CSCs. In conclusion, ATRA is a potent CSC-targeting agent with viable impact on tumour control when combined with radiotherapy. PMID:27573059

  11. Effect of hepatitis B virus X protein on the expression of retinoblastoma gene product.

    PubMed

    Farshid, M; Nedjar, S; Mitchell, F; Biswas, R

    1997-06-01

    Hepatitis B virus X protein (HBX) was studied for its capacity to form a specific complex with the retinoblastoma tumour suppressor protein (pRB), and for its effect on the expression of pRB. HBX was synthesized by in vitro transcription and translation in the presence of [35S]methionine. The synthesized HBX was assayed for its binding to a glutathione-S-transferase (GST)-pRB fusion protein bound to Sepharose beads. The in vivo binding was investigated by a co-immunoprecipitation and Western blot analysis of the cell extract from a CMV-HBX-transfected hepatoblastoma cell line, Hep G2 cells. These experiments demonstrated that HBX was unable to form a detectable complex with pRB. However, the level of pRB increased considerably in Hep G2 cells transfected with CMV-HBX clone. The alteration of pRB expression by HBX could be a mechanism, contributing to the development of hepatocellular carcinoma (HCC) in human.

  12. Microencapsulation of human cells: its effects on growth of normal and tumour cells in vitro.

    PubMed Central

    Shimi, S. M.; Hopwood, D.; Newman, E. L.; Cuschieri, A.

    1991-01-01

    The growth kinetics of established human colorectal tumour cell lines (HT29, HT115 and COLO 320DM) and human diploid fibroblasts (Flow 2002) were studied in conventional culture and in microcapsules formed from alginate-poly(L-lysine)-alginate membranes. The tumour lines grew rapidly in microcapsules but, in the case of the substrate-adherent lines HT29 and HT115, only after a prolonged lag phase. This phase was reduced by serial passage in microcapsules. The anchorage-independent line COLO 320DM showed no lengthening in lag phase. Microencapsulated fibroblasts underwent negligible growth but remained viable. Some evidence for functional differentiation (microvilli, cell-cell junctions) of the tumour line HT115 within the microcapsules was observed. We conclude that the use of microcapsules provides an alternative system with some advantages for the study of human cancer and its metastases in vitro. Images Figure 4 Figure 6 PMID:2039691

  13. Hepatitis C

    MedlinePlus

    ... 2014 Select a Language: Fact Sheet 507 Hepatitis C WHAT IS HEPATITIS C? HOW IS IT DIAGNOSED? ... treatment may be less likely to work. Hep C treatment is less effective for coinfected people. Cure ...

  14. Improvement effect on the depth-dose distribution by CSF drainage and air infusion of a tumour-removed cavity in boron neutron capture therapy for malignant brain tumours.

    PubMed

    Sakurai, Yoshinori; Ono, Koji; Miyatake, Shin-Ichi; Maruhashi, Akira

    2006-03-01

    Boron neutron capture therapy (BNCT) without craniotomy for malignant brain tumours was started using an epi-thermal neutron beam at the Kyoto University Reactor in June 2002. We have tried some techniques to overcome the treatable-depth limit in BNCT. One of the effective techniques is void formation utilizing a tumour-removed cavity. The tumorous part is removed by craniotomy about 1 week before a BNCT treatment in our protocol. Just before the BNCT irradiation, the cerebro-spinal fluid (CSF) in the tumour-removed cavity is drained out, air is infused to the cavity and then the void is made. This void improves the neutron penetration, and the thermal neutron flux at depth increases. The phantom experiments and survey simulations modelling the CSF drainage and air infusion of the tumour-removed cavity were performed for the size and shape of the void. The advantage of the CSF drainage and air infusion is confirmed for the improvement in the depth-dose distribution. From the parametric surveys, it was confirmed that the cavity volume had good correlation with the improvement effect, and the larger effect was expected as the cavity volume was larger.

  15. Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours.

    PubMed

    Vitali, Eleonora; Cambiaghi, Valeria; Zerbi, Alessandro; Carnaghi, Carlo; Colombo, Piergiuseppe; Peverelli, Erika; Spada, Anna; Mantovani, Giovanna; Lania, Andrea G

    2016-03-01

    Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (-43 ± 21%, P < 0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (-46 ± 18%, P < 0.05 vs untreated cells), P-ERK1/2 levels (-42 ± 14%; P < 0.05 vs untreated cells), cAMP accumulation (-24 ± 3%, P < 0.05 vs untreated cells), VEGF expression (-31 ± 5%, P < 0.01 vs untreated cells) and in vitro release (-40 ± 24%, P < 0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (+86 ± 45%, P < 0.05 vs untreated cells) and inhibited cell migration (-24 ± 2%, P < 0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients. PMID:26733502

  16. Naming manipulable objects: anatomy of a category specific effect in left temporal tumours.

    PubMed

    Campanella, Fabio; D'Agostini, Serena; Skrap, Miran; Shallice, Tim

    2010-05-01

    Whether semantic knowledge is categorically organized or is based in an undifferentiated distributed network within the temporal lobes or it is at least partially organized in property-based networks is still an open issue. With a naming task involving living and nonliving entities, the latter divided according to degree of manipulability, we studied a group of 30 tumour patients with either right, left anterior or left posterior temporal lobes' lesions and a herpes simplex encephalitis patient (MU). Both cross-subject and cross-stimulus analyses were conducted. Left hemisphere patients were overall worse than both right hemisphere patients and controls in the naming task. They moreover named nonliving items worse than living. This effect was larger in left posterior temporal than both right temporal and also left anterior temporal patients and significant both at a cross-subject and cross-stimulus levels of analysis. In addition the left posterior temporal group had more difficulties with highly manipulable objects than left anterior temporal patients, but the effect was significant only on a cross-subject analysis. VLSM lesion analysis revealed that the area most critically associated with the larger naming deficit for manipulable objects was the posterior superior portion of the left temporal lobe, particularly the posterior middle temporal gyrus. These results support a 'property-based networks' account of semantic knowledge rather than an 'undifferentiated network' account. For manipulable objects, this would be a posterior-temporal/inferior-parietal left hemisphere "action/manipulation-property-based" network related to the dorsal pathways which is thought to be important in action control, as suggested by neuroimaging results. PMID:20144630

  17. LET-painting increases tumour control probability in hypoxic tumours.

    PubMed

    Bassler, Niels; Toftegaard, Jakob; Lühr, Armin; Sørensen, Brita Singers; Scifoni, Emanuele; Krämer, Michael; Jäkel, Oliver; Mortensen, Lise Saksø; Overgaard, Jens; Petersen, Jørgen B

    2014-01-01

    LET-painting was suggested as a method to overcome tumour hypoxia. In vitro experiments have demonstrated a well-established relationship between the oxygen enhancement ratio (OER) and linear energy transfer (LET), where OER approaches unity for high-LET values. However, high-LET radiation also increases the risk for side effects in normal tissue. LET-painting attempts to restrict high-LET radiation to compartments that are found to be hypoxic, while applying lower LET radiation to normoxic tissues. Methods. Carbon-12 and oxygen-16 ion treatment plans with four fields and with homogeneous dose in the target volume, are applied on an oropharyngeal cancer case with an identified hypoxic entity within the tumour. The target dose is optimised to achieve a tumour control probability (TCP) of 95% when assuming a fully normoxic tissue. Using the same primary particle energy fluence needed for this plan, TCP is recalculated for three cases assuming hypoxia: first, redistributing LET to match the hypoxic structure (LET-painting). Second, plans are recalculated for varying hypoxic tumour volume in order to investigate the threshold volume where TCP can be established. Finally, a slight dose boost (5-20%) is additionally allowed in the hypoxic subvolume to assess its impact on TCP. Results. LET-painting with carbon-12 ions can only achieve tumour control for hypoxic subvolumes smaller than 0.5 cm(3). Using oxygen-16 ions, tumour control can be achieved for tumours with hypoxic subvolumes of up to 1 or 2 cm(3). Tumour control can be achieved for tumours with even larger hypoxic subvolumes, if a slight dose boost is allowed in combination with LET-painting. Conclusion. Our findings clearly indicate that a substantial increase in tumour control can be achieved when applying the LET-painting concept using oxygen-16 ions on hypoxic tumours, ideally with a slight dose boost.

  18. Effects of insulin and insulin-like growth factors on protein and energy metabolism in tumour-bearing rats.

    PubMed Central

    Tomas, F M; Chandler, C S; Coyle, P; Bourgeois, C S; Burgoyne, J L; Rofe, A M

    1994-01-01

    The effects of insulin-like growth factor-1 (IGF-I), and a more potent variant LR3-IGF-I, which binds poorly to IGF-binding proteins, were investigated in rats bearing a mammary adenocarcinoma. The effect of insulin, either alone or in combination with LR3-IGF-I, was also investigated. Peptides were infused via osmotic minipumps for 6-7 days after tumour size reached 5% of body weight. Infusion of IGFs alone at either 200 or 500 microgram/day significantly decreased food intakes as well as circulating levels of insulin and glucose, and consequently failed to promote muscle protein accretion in the host. Tumour growth was increased by the IGFs, especially by LR3-IGF-I, even though these peptides did not promote growth of the adenocarcinoma in cell culture. Infusion of LR3-IGF-I, and to a lesser extent IGF-I, led to decreased rates of muscle protein synthesis and increased muscle protein breakdown, but each of these measures was closely related to the final tumour burden (r2 = 0.454 and 0.810 respectively; P < 0.01) and possibly resulted from a decrease in substrate supply to the host tissues. Insulin infusion (100 micrograms/day) increased food consumption by more than 50% and significantly decreased tumour growth. Insulin and LR3-IGF-I had a synergistic effect on host weight, which increased by 19.1 +/- 1.9, -1.1 +/- 4.7 and 37.9 +/- 1.5 g for insulin, LR3-IGF-I and combined treatments respectively. Carcass protein was increased by more than 10% with insulin treatment, due to increased rates of synthesis and decreased rates of muscle protein breakdown, but LR3-IGF-I had no positive effect on carcass protein accretion, either alone or in combination with insulin. Similarly, the amount of carcass fat was increased almost 2-fold by insulin treatment, whereas it was decreased by 30% by LR3-IGF-I. These changes may have arisen either from direct hormone effects on metabolism or from the indirect effects of food intake, or both. Our results suggest that IGF

  19. Expanding the prion concept to cancer biology: dominant-negative effect of aggregates of mutant p53 tumour suppressor

    PubMed Central

    Silva, Jerson L.; Rangel, Luciana P.; Costa, Danielly C. F.; Cordeiro, Yraima; De Moura Gallo, Claudia V.

    2013-01-01

    p53 is a key protein that participates in cell-cycle control, and its malfunction can lead to cancer. This tumour suppressor protein has three main domains; the N-terminal transactivation domain, the CTD (C-terminal domain) and the core domain (p53C) that constitutes the sequence-specific DBD (DNA-binding region). Most p53 mutations related to cancer development are found in the DBD. Aggregation of p53 into amyloid oligomers and fibrils has been shown. Moreover, amyloid aggregates of both the mutant and WT (wild-type) forms of p53 were detected in tumour tissues. We propose that if p53 aggregation occurred, it would be a crucial aspect of cancer development, as p53 would lose its WT functions in an aggregated state. Mutant p53 can also exert a dominant-negative regulatory effect on WT p53. Herein, we discuss the dominant-negative effect in light of p53 aggregation and the fact that amyloid-like mutant p53 can convert WT p53 into more aggregated species, leading into gain of function in addition to the loss of tumour suppressor function. In summary, the results obtained in the last decade indicate that cancer may have characteristics in common with amyloidogenic and prion diseases. PMID:24003888

  20. Engineering Salmonella as intracellular factory for effective killing of tumour cells.

    PubMed

    Camacho, Eva María; Mesa-Pereira, Beatriz; Medina, Carlos; Flores, Amando; Santero, Eduardo

    2016-01-01

    Salmonella have many desirable properties as antitumour-agent due to its ability to proliferate inside tumours and induce tumour regression. Additionally, this bacterium can be genetically engineered to deliver therapeutic proteins intratumourally. The main limitation of this approach is the efficient release of therapeutic molecules from intratumoural bacteria. Here we have developed an inducible autolysis system based in the lysis operon of the lambda phage that, in response to anhydrotetracycline, lysates Salmonella thus releasing its content. The system was combined with a salicylate cascade system that allows efficient production of therapeutic molecules in response to aspirin and with a sifA mutation that liberates bacteria from the vacuoles to a cytosolic location. The combination of these three elements makes this strain a putative powerful instrument in cancer treatment. We have used this engineered strain for the intracellular production and delivery of Cp53 peptide. The engineered strain is able to sequentially produce and release the cytotoxic peptide while proliferating inside tumour cells, thus inducing host cell death. Our results show that temporal separation of protein production from protein release is essential to efficiently kill tumour cells. The combined system is a further step in the engineering of more efficient bacteria for cancer therapy. PMID:27464652

  1. Engineering Salmonella as intracellular factory for effective killing of tumour cells.

    PubMed

    Camacho, Eva María; Mesa-Pereira, Beatriz; Medina, Carlos; Flores, Amando; Santero, Eduardo

    2016-07-28

    Salmonella have many desirable properties as antitumour-agent due to its ability to proliferate inside tumours and induce tumour regression. Additionally, this bacterium can be genetically engineered to deliver therapeutic proteins intratumourally. The main limitation of this approach is the efficient release of therapeutic molecules from intratumoural bacteria. Here we have developed an inducible autolysis system based in the lysis operon of the lambda phage that, in response to anhydrotetracycline, lysates Salmonella thus releasing its content. The system was combined with a salicylate cascade system that allows efficient production of therapeutic molecules in response to aspirin and with a sifA mutation that liberates bacteria from the vacuoles to a cytosolic location. The combination of these three elements makes this strain a putative powerful instrument in cancer treatment. We have used this engineered strain for the intracellular production and delivery of Cp53 peptide. The engineered strain is able to sequentially produce and release the cytotoxic peptide while proliferating inside tumour cells, thus inducing host cell death. Our results show that temporal separation of protein production from protein release is essential to efficiently kill tumour cells. The combined system is a further step in the engineering of more efficient bacteria for cancer therapy.

  2. Engineering Salmonella as intracellular factory for effective killing of tumour cells

    PubMed Central

    Camacho, Eva María; Mesa-Pereira, Beatriz; Medina, Carlos; Flores, Amando; Santero, Eduardo

    2016-01-01

    Salmonella have many desirable properties as antitumour-agent due to its ability to proliferate inside tumours and induce tumour regression. Additionally, this bacterium can be genetically engineered to deliver therapeutic proteins intratumourally. The main limitation of this approach is the efficient release of therapeutic molecules from intratumoural bacteria. Here we have developed an inducible autolysis system based in the lysis operon of the lambda phage that, in response to anhydrotetracycline, lysates Salmonella thus releasing its content. The system was combined with a salicylate cascade system that allows efficient production of therapeutic molecules in response to aspirin and with a sifA mutation that liberates bacteria from the vacuoles to a cytosolic location. The combination of these three elements makes this strain a putative powerful instrument in cancer treatment. We have used this engineered strain for the intracellular production and delivery of Cp53 peptide. The engineered strain is able to sequentially produce and release the cytotoxic peptide while proliferating inside tumour cells, thus inducing host cell death. Our results show that temporal separation of protein production from protein release is essential to efficiently kill tumour cells. The combined system is a further step in the engineering of more efficient bacteria for cancer therapy. PMID:27464652

  3. Inhibitory effects of armepavine against hepatic fibrosis in rats

    PubMed Central

    Weng, Ting-Chun; Shen, Chien-Chang; Chiu, Yung-Tsung; Lin, Yun-Lian; Kuo, Cheng-Deng; Huang, Yi-Tsau

    2009-01-01

    Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 μM) concentration-dependently attenuated TNF-α- and LPS-stimulated α-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-α-induced collagen collagen deposition, NFκB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic α-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1α2, TGF-β1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-κB activation pathways. PMID:19723340

  4. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

  5. Pro- and anti-tumour effects of B cells and antibodies in cancer: a comparison of clinical studies and preclinical models.

    PubMed

    Guy, Thomas V; Terry, Alexandra M; Bolton, Holly A; Hancock, David G; Shklovskaya, Elena; Fazekas de St. Groth, Barbara

    2016-08-01

    The primary immune role of B cells is to produce antibodies, but they can also influence T cell function via antigen presentation and, in some contexts, immune regulation. Whether their roles in tumour immunity are similar to those in other chronic immune responses such as autoimmunity and chronic infection, where both pro- and anti-inflammatory roles have been described, remains controversial. Many studies have aimed to define the role of B cells in antitumor immune responses, but despite this considerable body of work, it is not yet possible to predict how they will affect immunity to any given tumour. In many human cancers, the presence of tumour-infiltrating B cells and tumour-reactive antibodies correlates with extended patient survival, and this clinical observation is supported by data from some animal models. On the other hand, T cell responses can be adversely affected by B cell production of immunoregulatory cytokines, a phenomenon that has been demonstrated in humans and in animal models. The isotype and concentration of tumour-reactive antibodies may also influence tumour progression. Recruitment of B cells into tumours may directly reflect the subtype and strength of the anti-tumour T cell response. As the response becomes chronic, B cells may attenuate T cell responses in an attempt to decrease host damage, similar to their described role in chronic infection and autoimmunity. Understanding how B cell responses in cancer are related to the effectiveness of the overall anti-tumour response is likely to aid in the development of new therapeutic interventions against cancer.

  6. Gastric calcifying fibrous tumour

    PubMed Central

    Attila, Tan; Chen, Dean; Gardiner, Geoffrey W; Ptak, Theadore W; Marcon, Norman E

    2006-01-01

    Intramucosal gastric tumours are most commonly found to be gastrointestinal stromal tumours or leiomyomas (smooth muscle tumours); however, a variety of other uncommon mesenchymal tumours can occur in the stomach wall. A rare benign calcifying fibrous tumour is reported and the endoscopic appearance, ultrasound findings and morphology are documented. A review of the literature found only two similar cases. PMID:16858502

  7. The effects of granulocyte-macrophage colony-stimulating factor on tumour-infiltrating lymphocytes from renal cell carcinoma.

    PubMed Central

    Steger, G. G.; Kaboo, R.; deKernion, J. B.; Figlin, R.; Belldegrun, A.

    1995-01-01

    It has been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce specific and non-specific anti-tumour cytotoxicity and also stimulates the proliferation and function of peripheral lymphocytes and thymocytes. GM-CSF and interleukin 2 (IL-2) act synergistically on peripheral lymphocytes for the induction of a highly effective cytotoxic cell population. Thus, the goal of our investigation was to study the effects of GM-CSF upon expansion, proliferation and in vitro killing activity of tumour-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC). TILs from seven consecutive tumours were cultured with GM-CSF (500 or 1000 nmol ml-1) without IL-2 supplementation, with suboptimal doses of IL-2 (8 and 40 U ml-1) plus GM-CSF (1000 nmol ml-1), and with a dose of IL-2 (400 U ml-1) which sufficed alone to induce TIL development plus GM-CSF (500 or 1000 nmol ml-1). GM-CSF alone or together with suboptimal doses of IL-2 was not able to induce or facilitate TIL development in these cultures. When GM-CSF at both concentrations studied was added to optimal doses of IL-2 the resulting TIL populations proliferated significantly better and faster (+66%), resulting in a higher cell yield (+24%) at the time of maximal expansion of the TIL cultures. The length of the culture periods of TILs was not affected by GM-CSF when compared with the control cultures supplemented with IL-2 alone. In vitro killing activity of TIL populations stimulated with IL-2 and GM-CSF remained unspecific, but lysis of the autologous tumour targets as well as the allogeneic renal tumour targets was significantly enhanced (+138%) as compared with the corresponding control TILs stimulated with IL-2 alone. Lysis of the natural killer (NK)-sensitive control cell line K562 and the NK-resistant Daudi cell line remained unchanged even though FACS analysis of TILs cultured with IL-2 and 1000 nmol of GM-CSF demonstrated a significantly higher proportion of cells expressing the CD56

  8. Effect of swine hepatitis E virus on the livers of experimentally infected Mongolian gerbils by swine hepatitis E virus.

    PubMed

    Yang, Yifei; Shi, Ruihan; She, Ruiping; Soomro, Majid Hussain; Mao, Jingjing; Du, Fang; Zhao, Yue; Liu, Can

    2015-10-01

    Previous studies have shown that hepatitis E virus (HEV) can be transmitted between rats, pigs, cattle, rabbits, chicken, cats, and deer. Because wild and domestic rodents have anti-HEV antibodies, they are considered potential reservoirs of HEV. In the current study, Mongolian gerbils were experimentally infected with swine hepatitis E virus and the effects of this infection were investigated. After inoculation with HEV, the liver-to-body weight ratio increased at 7 dpi. Mongolian gerbils demonstrated significant increase (p<0.05) in Aspartate Transaminase (AST), alanine transaminase (ALT) and total bilirubin (T-BIL) concentrations in the sera, and HEV IgG was detected at 21 days post-inoculation (dpi). Real-time PCR revealed that the copies of HEV RNA in the liver were detected at 7 dpi, and peaked at 28 dpi at a concentration of 7.73 logs g(-1). Using both light and electron microscopy, hepatic lesions were observed in the HEV inoculated animals. In the experimental group, characteristic viral hepatitis lesions were prominent in the liver. HEV antigen was detected in the liver by immunohistochemistry, and HEV ORF3 antigen was detectable in liver by Western blot. These results clearly demonstrate that viral load of HEV in livers was dynamic, and ultrastructural hepatic injury in HEV infected Mongolian gerbils and anti-HEV IgG positive seroconversion were observed during infection. PMID:26093307

  9. Cardiac and hepatic role of r-AtHSP70: basal effects and protection against ischemic and sepsis conditions.

    PubMed

    Pasqua, Teresa; Filice, Elisabetta; Mazza, Rosa; Quintieri, Anna Maria; Carmela Cerra, Maria; Iannacone, Rina; Melfi, Donato; Indiveri, Cesare; Gattuso, Alfonsina; Angelone, Tommaso

    2015-07-01

    Heat shock proteins (HSPs), highly conserved in all organisms, act as molecular chaperones activated by several stresses. The HSP70 class of stress-induced proteins is the most studied subtype in cardiovascular and inflammatory disease. Because of the high similarity between plant and mammalian HSP70, the aim of this work was to evaluate whether recombinant HSP70 of plant origin (r-AtHSP70) was able to protect rat cardiac and hepatic function under ischemic and sepsis conditions. We demonstrated for the first time that, in ex vivo isolated and perfused rat heart, exogenous r-AtHSP70 exerted direct negative inotropic and lusitropic effects via Akt/endothelial nitric oxide synthase pathway, induced post-conditioning cardioprotection via Reperfusion Injury Salvage Kinase and Survivor Activating Factor Enhancement pathways, and did not cause hepatic damage. In vivo administration of r-AtHSP70 protected both heart and liver against lipopolysaccharide-dependent sepsis, as revealed by the reduced plasma levels of interleukin-1β, tumour necrosis factor alpha, aspartate aminotransferase and alanine aminotransferase. These results suggest exogenous r-AtHSP70 as a molecular modulator able to protect myocardial function and to prevent cardiac and liver dysfunctions during inflammatory conditions. PMID:25904190

  10. Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats.

    PubMed

    Klieverik, Lars P; Sauerwein, Hans P; Ackermans, Mariëtte T; Boelen, Anita; Kalsbeek, Andries; Fliers, Eric

    2008-03-01

    Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition. PMID:18182466

  11. The effect of PLC-γ2 inhibitors on the growth of human tumour cells.

    PubMed

    Feng, Linda; Reynisdóttir, Inga; Reynisson, Jóhannes

    2012-08-01

    The phosphoinositide specific-phospholipase C-γ (PLC-γ1 and 2) enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells. A host of known PLC-γ2 inhibitors were tested against the NCI60 panel of human tumour cell lines as well as their commercially available structural derivatives. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 3 giving GI(50) = 58 nM for the melanoma MDA-MB-435 cell line. The PLC-γ2 is uniquely expressed in haematopoietic cells and the leukaemia tumour cell lines were growth restricted on average GI(50) = 275 nM by derivative 3 indicating a specific interaction with this isoform. Furthermore, a moderate growth inhibition was found for compound classes of indoles and 1H-pyrazoles. It is likely that the active compounds do not only inhibit the PLC-γ2 isoform but other PLCs as well due to their conserved binding site. The compounds tested were identified by applying the tools of chemoinformatics, which supports the use of in silico methods in drug design.

  12. The effect of calcium ions on the glycolytic activity of Ehrlich ascites-tumour cells

    PubMed Central

    Bygrave, F. L.

    1966-01-01

    1. Added Ca2+ inhibited lactate formation from sugar phosphates by intact Ehrlich ascites-tumour cells. Lactate formation from glucose by these cells was unaffected by added Ca2+. 2. The Ca2+ inhibition of lactate formation by intact cells occurred in the extracellular medium. 3. Intact ascites-tumour cells did not take up Ca2+ in vitro. 4. Glycolysis of sugar phosphates by cell extracts as well as pyruvate formation from 3-phosphoglycerate and phosphoenolpyruvate was inhibited by Ca2+. 5. It was concluded that Ca2+ inhibited the pyruvate-kinase (EC 2.7.1.40) reaction. Further, Ca2+ inhibition of pyruvate kinase could be correlated with the overall inhibition of glycolysis. 6. Concentrations of Ca2+ usually present in Krebs–Ringer buffers, inhibited glycolysis and pyruvate-kinase activity by approx. 50%. 7. The inhibition of glycolysis by added Ca2+ could be partially reversed by K+ and completely reversed by Mg2+ or by stoicheiometric amounts of EDTA. 8. The hypothesis is advanced that the inability of tumour cells to take up Ca2+ is a factor contributing towards their high rate of glycolysis. PMID:6007855

  13. CT/MRI of neuroendocrine tumours

    PubMed Central

    Reznek, Rodney H

    2006-01-01

    Neuroendocrine tumours (NETs) are often thought to be rare and rather recherché cancers which are of little concern to the general physician, surgeon or radiologist because of their rarity and esoteric nature. In fact, while relatively uncommon, the total group of gastro-entero-pancreatic (GEP) tumours incorporates the spectrum of all types of carcinoids, incuding bronchial carcinoids, and the whole gamut of islet-cell tumours. Some of these may present as functioning tumours, with a plethora of hormonal secretions and concomitant clinical syndromes, and GEPs in general have an incidence around 30 per million population per year. This means that in the whole European Union, for example, there will be in the region of 12000 new patients every year presenting with one or another manifestation of these tumours. Furthermore, the comparatively long survival of many of these patients, compared to more common adenocarcinomas or epithelial tumours, implies that the point prevalence is also not inconsiderable. However, it is undoubtedly true that these tumours can be difficult to identify, especially in their early stages, and it is then that radiological investigation becomes of paramount importance. Having taken into account all these considerations, most investigators would initiate investigation of a suspected or biochemically proven islet-cell tumour with cross-sectional imaging—either CT or MRI. This will clearly identify the larger lesions, allow assessment of the entire abdomen, and provide valuable information on the presence of hepatic metastates. PMID:17114072

  14. Cost-Effectiveness of Testing Hepatitis B–Positive Pregnant Women for Hepatitis B e Antigen or Viral Load

    PubMed Central

    Fan, Lin; Owusu-Edusei, Kwame; Schillie, Sarah F.; Murphy, Trudy V.

    2015-01-01

    OBJECTIVE To estimate the cost-effectiveness of testing pregnant women with hepatitis B (hepatitis B surface antigen [HBsAg]-positive) for hepatitis B e antigen (HBeAg) or hepatitis B virus (HBV) DNA, and administering maternal antiviral prophylaxis if indicated, to decrease breakthrough perinatal HBV transmission from the U.S. health care perspective. METHODS A Markov decision model was constructed for a 2010 birth cohort of 4 million neonates to estimate the cost-effectiveness of two strategies: testing HBsAg-positive pregnant women for 1) HBeAg or 2) HBV load. Maternal antiviral prophylaxis is given from 28 weeks of gestation through 4 weeks postpartum when HBeAg is positive or HBV load is high (108 copies/mL or greater). These strategies were compared with the current recommendation. All neonates born to HBsAg-positive women received recommended active-passive immunoprophylaxis. Effects were measured in quality-adjusted life-years (QALYs) and all costs were in 2010 U.S. dollars. RESULTS The HBeAg testing strategy saved $3.3 million and 3,080 QALYs and prevented 486 chronic HBV infections compared with the current recommendation. The HBV load testing strategy cost $3 million more than current recommendation, saved 2,080 QALYs, and prevented 324 chronic infections with an incremental cost-effectiveness ratio of $1,583 per QALY saved compared with the current recommendations. The results remained robust over a wide range of assumptions. CONCLUSION Testing HBsAg-positive pregnant women for HBeAg or HBV load followed by maternal antiviral prophylaxis if HBeAg-positive or high viral load to reduce perinatal hepatitis B transmission in the United States is cost-effective. PMID:24785842

  15. Imaging of testicular tumours.

    PubMed

    Owens, E J; Kabala, J; Goddard, P

    2004-01-01

    This article reviews the diagnosis, pathology and imaging of testicular tumours, predominantly germ cell tumours. It will discuss the imaging techniques used in their diagnosis, staging and surveillance.

  16. The global effect of follicle-stimulating hormone and tumour necrosis factor α on gene expression in cultured bovine ovarian granulosa cells

    PubMed Central

    2014-01-01

    Background Oocytes mature in ovarian follicles surrounded by granulosa cells. During follicle growth, granulosa cells replicate and secrete hormones, particularly steroids close to ovulation. However, most follicles cease growing and undergo atresia or regression instead of ovulating. To investigate the effects of stimulatory (follicle-stimulating hormone; FSH) and inhibitory (tumour necrosis factor alpha; TNFα) factors on the granulosa cell transcriptome, bovine ovaries were obtained from a local abattoir and pools of granulosa cells were cultured in vitro for six days under defined serum-free conditions with treatments present on days 3–6. Initially dose–response experiments (n = 4) were performed to determine the optimal concentrations of FSH (0.33 ng/ml) and TNFα (10 ng/ml) to be used for the microarray experiments. For array experiments cells were cultured under control conditions, with FSH, with TNFα, or with FSH plus TNFα (n = 4 per group) and RNA was harvested for microarray analyses. Results Statistical analysis showed primary clustering of the arrays into two groups, control/FSH and TNFα/TNFα plus FSH. The effect of TNFα on gene expression dominated that of FSH, with substantially more genes differentially regulated, and the pathways and genes regulated by TNFα being similar to those of FSH plus TNFα treatment. TNFα treatment reduced the endocrine activity of granulosa cells with reductions in expression of FST, INHA, INBA and AMH. The top-ranked canonical pathways and GO biological terms for the TNFα treatments included antigen presentation, inflammatory response and other pathways indicative of innate immune function and fibrosis. The two most significant networks also reflect this, containing molecules which are present in the canonical pathways of hepatic fibrosis/hepatic stellate cell activation and transforming growth factor β signalling, and these were up regulated. Upstream regulator analyses also predicted TNF, interferons γ and

  17. Anti-fibrotic effect of thymoquinone on hepatic stellate cells.

    PubMed

    Ghazwani, Mohammed; Zhang, Yifei; Gao, Xiang; Fan, Jie; Li, Jiang; Li, Song

    2014-02-15

    Hepatic stellate cells (HSCs) are the major cell type involved in the production of extracellular matrix in liver. After liver injury, HSCs undergo transdifferentiation process from quiescent state to activated state, which plays an important role in liver fibrosis. Previous studies have shown that thymoquinone (TQ) might have protective effect against liver fibrosis in animal models; however, the underlying mechanism of action is not fully understood. The aim of this study is to examine whether TQ has any direct effect on HSCs. Our results showed that pretreatment of mice with TQ has protective effect against CCl4-induced liver injury compared to control group (untreated), which is consistent with previous studies. Moreover, our in vivo study showed that COL1A1 and α-SMA mRNA levels were significantly downregulated by TQ treatment. Similarly, in vitro study confirmed that TQ downregulated COL1A1, COL3A1 and α-SMA mRNA levels in activated rat HSCs and LX2 cells, an immortalized human hepatic stellate cell line. Pretreatment with TQ also inhibited the LPS-induced proinflammatory response in LX2 cells as demonstrated by reduced mRNA expression of IL-6 and MCP-1. Mechanistically, inactivation of NF-κB pathway is likely to play a role in the TQ-mediated inhibition of proinflammatory response in HSCs. Finally, we have shown that TQ inhibited the culture-triggered transdifferentiation of freshly isolated rat HSCs as shown by significant downregulation of mRNA expression of several fibrosis-related genes. In conclusion, our study suggests that TQ has a direct effect on HSCs, which may contribute to its overall antifibrotic effect. PMID:24182989

  18. Anti-fibrotic effect of thymoquinone on hepatic stellate cells.

    PubMed

    Ghazwani, Mohammed; Zhang, Yifei; Gao, Xiang; Fan, Jie; Li, Jiang; Li, Song

    2014-02-15

    Hepatic stellate cells (HSCs) are the major cell type involved in the production of extracellular matrix in liver. After liver injury, HSCs undergo transdifferentiation process from quiescent state to activated state, which plays an important role in liver fibrosis. Previous studies have shown that thymoquinone (TQ) might have protective effect against liver fibrosis in animal models; however, the underlying mechanism of action is not fully understood. The aim of this study is to examine whether TQ has any direct effect on HSCs. Our results showed that pretreatment of mice with TQ has protective effect against CCl4-induced liver injury compared to control group (untreated), which is consistent with previous studies. Moreover, our in vivo study showed that COL1A1 and α-SMA mRNA levels were significantly downregulated by TQ treatment. Similarly, in vitro study confirmed that TQ downregulated COL1A1, COL3A1 and α-SMA mRNA levels in activated rat HSCs and LX2 cells, an immortalized human hepatic stellate cell line. Pretreatment with TQ also inhibited the LPS-induced proinflammatory response in LX2 cells as demonstrated by reduced mRNA expression of IL-6 and MCP-1. Mechanistically, inactivation of NF-κB pathway is likely to play a role in the TQ-mediated inhibition of proinflammatory response in HSCs. Finally, we have shown that TQ inhibited the culture-triggered transdifferentiation of freshly isolated rat HSCs as shown by significant downregulation of mRNA expression of several fibrosis-related genes. In conclusion, our study suggests that TQ has a direct effect on HSCs, which may contribute to its overall antifibrotic effect.

  19. Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

    PubMed Central

    Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients

  20. Radiation enhances the therapeutic effect of Banoxantrone in hypoxic tumour cells with elevated levels of nitric oxide synthase

    PubMed Central

    MEHIBEL, MANAL; SINGH, SIMENDRA; COWEN, RACHEL L.; WILLIAMS, KAYE J.; STRATFORD, IAN J.

    2016-01-01

    Banoxantrone (AQ4N) is a prototype hypoxia selective cytotoxin that is activated by haem containing reductases such as inducible nitric oxide synthase (iNOS). In the present study, we evaluate whether elevated levels of iNOS in human tumour cells will improve their sensitivity to AQ4N. Further, we examine the potential of radiation to increase cellular toxicity of AQ4N under normoxic (aerobic) and hypoxic conditions. We employed an expression vector containing the cDNA for human iNOS to transfect human fibrosarcoma HT1080 tumour cells. Alternatively, parental cells were exposed to a cytokine cocktail to induce iNOS gene expression and enzymatic activity. The cells were then treated with AQ4N alone and in combination with radiation in the presence or absence of the iNOS inhibitor N-methyl-L-arginine. In parental cells, AQ4N showed little difference in toxicity under hypoxic verses normoxic conditions. Notably, cells with upregulated iNOS activity showed a significant increase in sensitivity to AQ4N, but only under conditions of reduced oxygenation. When these cells were exposed to the combination of AQ4N and radiation, there was much greater cell killing than that observed with either modality alone. In the clinical development of hypoxia selective cytotoxins it is likely they will be used in combination with radiotherapy. In the present study, we demonstrated that AQ4N can selectively kill hypoxic cells via an iNOS-dependent mechanism. This hypoxia-selective effect can be augmented by combining AQ4N with radiation without increasing cytotoxicity to well-oxygenated tissues. Collectively, these results suggest that targeting hypoxic tumours with high levels of iNOS with a combination of AQ4N and radiotherapy could be a useful clinical therapeutic strategy. PMID:26782976

  1. Hepatitis C core antigen testing: a reliable, quick, and potentially cost-effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection.

    PubMed

    Cresswell, Fiona V; Fisher, Martin; Hughes, Daniel J; Shaw, Simon G; Homer, Gary; Hassan-Ibrahim, Mohammed O

    2015-01-15

    Hepatitis C virus (HCV) is increasingly common among human immunodeficiency virus (HIV)-infected men who have sex with men. We evaluated the efficacy of HCV core antigen in diagnosing acute HCV in an HIV-infected cohort. Compared with HCV polymerase chain reaction, core antigen proved sensitive (100%) and specific (97.9%). As a quick, simple, and cost-effective test, it has considerable utility in screening for acute HCV.

  2. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study

    PubMed Central

    2013-01-01

    Background Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. Methods This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Results Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Conclusion Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. Trial registration ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18. PMID:24053191

  3. Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss

    PubMed Central

    Clugston, Robin D.; Huang, Li-Shin; Blaner, William S.

    2015-01-01

    The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol’s effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, ∼15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver.—Clugston, R. D., Huang, L.-S., Blaner, W. S. Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss. PMID:25985802

  4. Electrochemotherapy of Tumours

    PubMed Central

    Sersa, Gregor; Miklavcic, Damijan

    2008-01-01

    Electrochemotherapy is a combined use of certain chemotherapeutic drugs and electric pulses applied to the treated tumour nodule. Local application of electric pulses to the tumour increases drug delivery into cells, specifically at the site of electric pulse application. Drug uptake by delivery of electric pulses is increased for only those chemotherapeutic drugs whose transport through the plasma membrane is impeded. Among many drugs that have been tested so far, bleomycin and cisplatin found their way from preclinical testing to clinical use. Clinical data collected within a number of clinical studies indicate that approximately 80% of the treated cutaneous and subcutaneous tumour nodules of different malignancies are in an objective response, from these, approximately 70% in complete response after a single application of electrochemotherapy. Usually only one treatment is needed, however, electrochemotherapy can be repeated several times every few weeks with equal effectiveness each time. The treatment results in an effective eradication of the treated nodules, with a good cosmetic effect without tissue scarring. PMID:19229171

  5. Comparison of effects of hepatitis E or A viral superinfection in patients with chronic hepatitis B

    PubMed Central

    Ke, Weimin; Xie, Junqiang; Zhao, Zhixin; Xie, Dongying; Gao, Zhiliang

    2010-01-01

    Purpose To compare the demographics, liver function, and prognosis of Chinese patients infected with chronic hepatitis B (CHB) and superinfected with hepatitis E virus (HEV) or hepatitis A virus (HAV). Patients and methods Among 188 patients with CHB, 136 with HEV superinfection and 52 with HAV superinfection were treated at our hospital between March 1999 and October 2007 for clinical features suggestive of acute hepatitis. The patients’ age, sex, incidence of liver failure, and mortality were recorded. The tested biochemical indices and markers of liver function included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), prothrombin activity (PTA), and the serum levels of HBeAg, HBeAb, and HBV DNA. Results There were significant differences between the age and sex distributions of the two groups (P < 0.05). More patients in the CHB + HEV group had complications (94.9 vs. 61.5%, P < 0.001), and hepatic failure (39.7 vs. 11.5%, P = 0.002). Additionally, the mortality among the CHB + HEV group was significantly higher (33.8 vs. 1.9%, P < 0.001). Conclusions The comparison of clinical outcomes revealed that patients with HBV + HEV had more advanced baseline liver disease and a poorer prognosis than those with HBV + HAV. Because there is no vaccine against HEV, patients with CHB should take appropriate precautions against superinfection with HEV, such as consumption of boiled water and well-cooked food, in regions where it is endemic. PMID:21063485

  6. Effect of in vivo activation of natural killer (NK) cells by a tilorone analogue on the survival of mice injected intravenously with different experimental murine tumours

    PubMed Central

    ALGARRA, I.; GONZÁLEZ, A.; PÉREZ, M.; GAFORIO, J J; GARRIDO, F.

    1996-01-01

    We studied the effect of a tilorone analogue (RMI 10,874DA) and anti-asialo GM1 serum on the survival of BALB/c and C57B1/6 mice after i.v. injections of different syngeneic murine tumour cells. Tumour lines used were different clones from chemically (GR9 wild type, GR9.B9, B7.1.B4, B7.1.B5, B7.2.38), and ultraviolet light (GRUV3)-induced sarcomas; B16 melanoma and LSTRA and YC8 lymphomas. Pretreatment of mice with tilorone inhibited metastatic colonization and increased survival significantly in all cases. In some tumour systems, the effect was attenuated when high numbers of cells were injected. Abrogation of NK cells with anti-asialo GM1 serum significantly decreased (in all tumours and at different cell doses) survival in comparison with untreated mice injected with tumours, regardless of cell dose used. These results clearly suggest that NK cell activation in vivo by the tilorone analogue we tested prolongs survival and inhibits metastasis formation in mice, even when pretreatment consists of a single dose of the analogue. PMID:8608652

  7. Effect of ethionine on hepatic mitochondrial and microsomal calcium uptake

    SciTech Connect

    Agarwal, A.K.; Zinermon, W.D.; Latoni, L.

    1988-02-01

    Ethionine, an ethyl analog of methionine, produces a variety of physiological and pathological effects in animals. These range from acute effects in the liver, kidney, pancreas, and other organs to liver carcinogenesis. Female rats when injected with ethionine exhibit a rapid decrease in hepatic adenosine triphosphate levels followed by a marked inhibition of RNA and protein synthesis and accumulation of triglycerides. Since calcium transport in mitochondria and microsomes is ATP dependent, it becomes interesting to find out if ethionine administration has any effect on subcellular calcium transport. Calcium has recently gained an increased controversy regarding its role in chemical induced lethal cell damage. Certain groups believe that influx of extracellular calcium across the damaged plasma membrane might actually mediate the irreversible damage to the cell, whereas according to other, entry of calcium into the cell is secondary to the damage. The present study was carried out to investigate the calcium (/sup 45/Ca) transport in mitochondria and microsomes following ethionine administration. The effect of carbon tetrachloride on calcium uptake in ethionine treated rats was also studied.

  8. Effect of dexamethasone on fetal hepatic glutamine-glutamate exchange.

    PubMed

    Timmerman, M; Teng, C; Wilkening, R B; Fennessey, P; Battaglia, F C; Meschia, G

    2000-05-01

    Intravenous infusion of dexamethasone (Dex) in the fetal lamb causes a two- to threefold increase in plasma glutamine and other glucogenic amino acids and a decrease of plasma glutamate to approximately one-third of normal. To explore the underlying mechanisms, hepatic amino acid uptake and conversion of L-[1-(13)C]glutamine to L-[1-(13)C]glutamate and (13)CO(2) were measured in six sheep fetuses before and in the last 2 h of a 26-h Dex infusion. Dex decreased hepatic glutamine and alanine uptakes (P < 0.01) and hepatic glutamate output (P < 0.001). Hepatic outputs of the glutamate (R(Glu,Gln)) and CO(2) formed from plasma glutamine decreased to 21 (P < 0.001) and 53% (P = 0.009) of control, respectively. R(Glu,Gln), expressed as a fraction of both outputs, decreased (P < 0.001) from 0.36 +/- 0.02 to 0.18 +/- 0.04. Hepatic glucose output remained virtually zero throughout the experiment. We conclude that Dex decreases fetal hepatic glutamate output by increasing the routing of glutamate carbon into the citric acid cycle and by decreasing the hepatic uptake of glucogenic amino acids. PMID:10780940

  9. Tumour biology: Senescence in premalignant tumours

    NASA Astrophysics Data System (ADS)

    Collado, Manuel; Gil, Jesús; Efeyan, Alejo; Guerra, Carmen; Schuhmacher, Alberto J.; Barradas, Marta; Benguría, Alberto; Zaballos, Angel; Flores, Juana M.; Barbacid, Mariano; Beach, David; Serrano, Manuel

    2005-08-01

    Oncogene-induced senescence is a cellular response that may be crucial for protection against cancer development, but its investigation has so far been restricted to cultured cells that have been manipulated to overexpress an oncogene. Here we analyse tumours initiated by an endogenous oncogene, ras, and show that senescent cells exist in premalignant tumours but not in malignant ones. Senescence is therefore a defining feature of premalignant tumours that could prove valuable in the diagnosis and prognosis of cancer.

  10. Effects of petroleum hydrocarbons on hepatic function in the duck

    USGS Publications Warehouse

    Patton, J.F.; Dieter, M.P.

    1980-01-01

    1. The indocyanine green dye clearance test for hepatic function was determined in mallard ducks before and during the chronic ingestion (7 months) of representative paraffinic or aromatic petroleum hydrocarbons (PH). 2. No mortality or visible symptoms of toxicity occured in any of the tests. Ingestion of 4000 ppm aromatic PH produced significant increases in liver (25%), plasma clearance of indocyanine green (33%) and hepatic blood flow (30%). 3. Although the aromatics elicited a greater hepatic stress response than the paraffins, the ducks tolerated high concentrations of PH for extended periods.

  11. Molecular response of 4T1-induced mouse mammary tumours and healthy tissues to zinc treatment.

    PubMed

    Sztalmachova, Marketa; Gumulec, Jaromir; Raudenska, Martina; Polanska, Hana; Holubova, Monika; Balvan, Jan; Hudcova, Kristyna; Knopfova, Lucia; Kizek, Rene; Adam, Vojtech; Babula, Petr; Masarik, Michal

    2015-04-01

    Breast cancer patients negative for the nuclear oestrogen receptor α have a particularly poor prognosis. Therefore, the 4T1 cell line (considered as a triple-negative model) was chosen to induce malignancy in mice. The aim of the present study was to assess if zinc ions, provided in excess, may significantly modify the process of mammary oncogenesis. Zn(II) ions were chosen because of their documented antitumour effects. Zn(II) is also known to induce the expression of metallothioneins (MT) and glutathion (GSH). A total dose of zinc sulphate per one gram of mouse weight used in the experiment was 0.15 mg. We studied the expression of MT1, MT2, TP53 and MTF-1 genes and also examined the effect of the tumour on antioxidant capacity. Tumour-free mice had significantly higher expression levels of the studied genes (p<0.003). Significant differences were also revealed in the gene expression between the tissues (p<0.001). The highest expression levels were observed in the liver. As compared to brain, lung and liver, significantly lower concentrations of MT protein were found in the primary tumour; an inverse trend was observed in the concentration of Zinc(II). In non-tumour mice, the amount of hepatic hydrosulphuryl groups significantly increased by the exposure to Zn(II), but the animals with tumour induction showed no similar trend. The primary tumour size of zinc-treated animals was 20% smaller (p=0.002); however, no significant effect on metastasis progression due to the zinc treatment was discovered. In conclusion, Zn(II) itself may mute the growth of primary breast tumours especially at their early stages.

  12. Hepatitis Vaccines

    PubMed Central

    Ogholikhan, Sina; Schwarz, Kathleen B.

    2016-01-01

    Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID:26978406

  13. Dairy milk fat augments paclitaxel therapy to suppress tumour metastasis in mice, and protects against the side-effects of chemotherapy.

    PubMed

    Sun, Xueying; Zhang, Jie; Gupta, Rita; Macgibbon, Alastair K H; Kuhn-Sherlock, Barbara; Krissansen, Geoffrey W

    2011-10-01

    Milk fat is a natural product containing essential nutrients as well as fatty acids and other food factors with reported anti-cancer potential. Here bovine milk fat was tested for its ability to inhibit the growth of breast and colon cancers and their metastasis to the lung and liver; either alone or in combination with the chemotherapeutic agent paclitaxel. A diet containing 5% typical anhydrous milk fat (representing ~70% of the total dietary fat component) fed to Balb/c mice delayed the appearance of subcutaneous 4T1 breast and CT26 colon cancer tumours and inhibited their metastasis to the lung and liver, when compared to the control diet containing soybean oil as the only fat component. It augmented the inhibitory effects of paclitaxel on tumour growth and metastasis, and reduced the microvessel density of tumours. It displayed no apparent organ toxicity, but instead was beneficial for well-being of tumour-bearing mice by maintaining gastrocnemius muscle and epididymal adipose tissue that were otherwise depleted by cachexia. The milk fat diet ameliorated gut damage caused by paclitaxel in non-tumour-bearing mice, as evidenced by retention of jejunal morphology, villi length and intestinal γ-glutamyl transpeptidase activity, and inhibition of crypt apoptosis. It prevented loss of red and white blood cells due to both cancer-mediated immunosuppression and the cytotoxic effects of chemotherapy. The present study warrants the use of milk fat as an adjuvant to inhibit tumour metastasis during cancer chemotherapy, and to spare patients from the debilitating side-effects of cytotoxic drugs. PMID:21739249

  14. Effects of gentiopicrooside injections on experimental hepatic injury.

    PubMed

    Tong, Li; Chen, Yu-Yao; Liu, Huan-Huan; Li, Ji-Lai; Luo, Jia-Bo

    2001-01-01

    OBJECTIVE: To investigate the protective and jaundice-relieving effects of gentiopicrooside (GPS) injections in mouse and rat models of chemical-induced and immune-mediated hepatic injury. METHODS: Mouse models of chemical-induced liver injury were established by CCl4 injections into the abdominal cavity, mouse models of immune-mediated liver damage by bacillus Calmette-Guerin (BCG) and lipopolysaccharide (LPS) and rat models of jaundice by oral alpha-naphthyliso-thiocyanate (ANIT). Treatment with GPS injections was administered and both of enzyme activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the Serum were measured in the models. The serum level of total bilirubin was determined in the jaundice models. RESULTS: Compared with those of the untreated models, the enzyme activities of ALT and AST were significantly reduced in groups with a 10 day GPS treatment (P<0.001, P<0.05). Higher dosage of GPS showed more conspicuous effects in relieving the jaundice. CONCLUSION: GPS can be administered as the antagonist against CC14-induced liver injury and offers protection against immune-mediated liver damage.

  15. Ophthalmological side effects of interferon therapy of chronic hepatitis C

    PubMed Central

    Medhat, Eman; Esmat, Gamal; Hamza, Eman; Abdel Aziz, Amr; Fouad Fathalah, Waleed; Zakaria, Zeinab; Mostafa, Sameh

    2016-01-01

    Background Egypt has one of the highest prevalence of hepatitis C virus (HCV) worldwide. Ophthalmological side effects are recognized complications of interferon (IFN) therapy. This study aimed to evaluate IFN-induced ophthalmological manifestations in patients receiving PEGylated interferon (PEG IFN) and ribavirin (RBV) and to assess the effect of IFN duration, response and systemic risk factors on the severity. Methods We retrospectively analyzed 100 patients with chronic HCV who were candidates for PEG-IFN and RBV therapy. All patients were subjected to clinical and ophthalmological examination, laboratory investigations, abdominal ultrasound, colored fundus photography and fundus fluorescein angiography, follow up was made at weeks 12, 24, and 48 of treatment. Results IFN-induced retinopathy had been found in (9/100; 9%), 5 (5/9; 55.5%) of them had bilateral lesions, (3/9; 33.3%) were treatment responders and (6/9; 66.6%) non responders. The time of retinopathy appearance was mainly at W12. Retinopathy was asymptomatic in most of the affected patients (7/9; 77.77%) and reversible, cotton wool spots was the major associated sign. Patients with older age, DM and or HTN, and non-responders to antiviral therapy were associated with more severe retinopathy. Conclusions Retinopathy is not a rare complication of IFN therapy for chronic HCV infection, but fortunately it’s asymptomatic and reversible. Ophthalmological assessment at base-line and at follow up during IFN treatment is very important. PMID:27275462

  16. Transmission Model of Hepatitis B Virus with the Migration Effect

    PubMed Central

    Khan, Muhammad Altaf; Islam, Saeed; Arif, Muhammad; ul Haq, Zahoor

    2013-01-01

    Hepatitis B is a globally infectious disease. Mathematical modeling of HBV transmission is an interesting research area. In this paper, we present characteristics of HBV virus transmission in the form of a mathematical model. We analyzed the effect of immigrants in the model to study the effect of immigrants for the host population. We added the following flow parameters: “the transmission between migrated and exposed class” and “the transmission between migrated and acute class.” With these new features, we obtained a compartment model of six differential equations. First, we find the basic threshold quantity Ro and then find the local asymptotic stability of disease-free equilibrium and endemic equilibrium. Furthermore, we find the global stability of the disease-free and endemic equilibria. Previous similar publications have not added the kind of information about the numerical results of the model. In our case, from numerical simulation, a detailed discussion of the parameters and their numerical results is presented. We claim that with these assumptions and by adding the migrated class, the model informs policy for governments, to be aware of the immigrants and subject them to tests about the disease status. Immigrants for short visits and students should be subjected to tests to reduce the number of immigrants with disease. PMID:23984318

  17. Effects of glyphosate on hepatic tissue evaluating melanomacrophages and erythrocytes responses in neotropical anuran Leptodactylus latinasus.

    PubMed

    Pérez-Iglesias, Juan Manuel; Franco-Belussi, Lilian; Moreno, Liliana; Tripole, Susana; de Oliveira, Classius; Natale, Guillermo Sebastián

    2016-05-01

    Glyphosate (GLY) is the most used herbicide worldwide and its effects on anurans are well known. Pollutants can cause physiological and morphological effects. Therefore, this study evaluated the effects of GLY on hepatic melanomacrophages as a response to environmental stressors. Three treatments were exposed to different concentrations of pure GLY (100, 1000, and 10,000 μg g(-1), respectively), and there was also a control group. After the experimental time, liver and blood were analyzed. Melanomacrophages (MMCs) were located between the hepatocyte cordons, close to sinusoids. GLY increased the melanin area in MMCs of Leptodactylus latinasus exposed since lowest concentration until highest concentration. GLY also changed the occurrence of hepatic catabolism pigments into melanomacrophages and erythrocyte nuclear abnormalities; therefore, it can interfere with the hepatic metabolism. In conclusion, GLY promotes alterations in the hepatic tissue and erythrocyte nuclear abnormalities. Furthermore, MMCs may be useful as morphological responses of GLY effects. PMID:26856864

  18. The promoting effect of tumour necrosis factor alpha in radiation-induced cell transformation.

    PubMed Central

    Guo, R. F.; Gong, Y. F.

    1998-01-01

    The ability of tumour necrosis factor alpha (TNF-alpha), a potent endogenous inflammatory agent, to promote malignant transformation of Syrian hamster embryo cells (SHE) initiated by a 0.5-Gy dose of alpha-particles was investigated. Opsonized zymosan particles, which were phagocytosed by a human macrophage-like cell line, triggered TNF-alpha production from U937 cells. This cell supernatant could significantly increase the transformation frequency (TF) of primary SHE cells previously irradiated by a 0.5-Gy dose of alpha-particles. The TF decreased significantly if monoclonal antibody against TNF-alpha was added to the supernatant. Similarly, recombinant human TNF-alpha (rhTNF-alpha) increased the TF of alpha-irradiated primary SHE cells to an even greater extent. Addition of TNF-alpha to subcultures of irradiated SHE cells permitted the continuous propagation of these primary cells. In contrast, both TNF-alpha-treated control and alpha-irradiated cells without subsequent TNF-alpha treatment senesced after 7-15 passages. Irradiated SHE cells treated continuously with TNF-alpha could be subcultured over 40 passages and produced fibrosarcomas upon inoculation into nude mice. Our results provide the first evidence that TNF-alpha released by activated macrophages may contribute to the process of malignant transformation initiated by low-dose alpha-particles. PMID:9579824

  19. Effects of biological drug adalimumab on tumour necrosis factor-alpha-converting enzyme activation.

    PubMed

    Lisi, Sabrina; Sisto, Margherita

    2010-01-01

    Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) is a membrane-bound metalloprotease and disintegrin. It is produced by a number of host cells and is known to shed and release cell-bound cytokines, particularly members of the TNF family. No investigations into the regulation of this enzyme by autoantibodies have been reported. In this study, we tested the hypothesis that anti-Ro/SSA autoantibodies, purified from IgG fractions of patients with primary Sjögren's syndrome, are capable to regulate TACE expression and activation in human salivary gland epithelial cells (SGEC). We also evaluated the potential physiological and therapeutic consequences of TNF-alpha blocking by the biological agent adalimumab, the first fully human (100% human peptide sequences) therapeutic anti-TNF-alpha antibody, on post-translational regulation of TACE. Taken together, our results show a dose-dependent increase in TACE expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein. Adalimumab treatment brought TACE expression to levels than those observed in untreated SGEC. These findings, showing the presence of autoantibodies-dependent mechanisms by which TACE levels are regulated in human SGECs, may have implications in the context of current investigations on the pathological role of autoantibodies.

  20. Protective effect of ajoene on acetaminophen-induced hepatic injury in mice.

    PubMed

    Hattori, A; Yamada, N; Nishikawa, T; Fukuda, H; Fujino, T

    2001-11-01

    Ajoene, a garlic-derived sulfur-containing compound, exhibited a hepatoprotective effect against acetaminophen-induced liver injury in mice. A pretreatment with ajoene suppressed the rise in serum glutamic-pyruvic transaminase activity and the reduction in the hepatic reduced glutathione level. These effects of ajoene were observed dose-dependently (20-100 mg/kg). The pretreatment by ajoene also suppressed the decrease in hepatic protein thiol content resulting from acetaminophen administration.

  1. Hepatic fat accumulation and regulation of FAT/CD36: an effect of hepatic irradiation

    PubMed Central

    Martius, Gesa; Alwahsh, Salamah Mohammad; Rave-Fränk, Margret; Hess, Clemens Friedrich; Christiansen, Hans; Ramadori, Giuliano; Malik, Ihtzaz Ahmed

    2014-01-01

    Irradiation is known to induce inflammation and affect fat metabolic pathways. The current study investigates hepatic fat accumulation and fatty acid transportation in a rat model of single dose liver irradiation (25-Gy). Rat livers were selectively irradiated in-vivo (25-Gy), sham-irradiated rats served as controls. Hepatic lipids were studied by colorimetric assays in liver and serum. Intracellular lipids, protein and mRNA were studied by Nile red staining, immunohistology, Western Blot analysis and RT-PCR in liver, respectively. Changes in FAT/CD36 expression were studied in-vitro in a human monocyte cell line U937 after irradiation in presence or absence of infliximab (IFX). Nile Red staining of liver cryosections showed a quick (12-48 h) increase in fat droplets. Accordingly, hepatic triglycerides (TG) and free fatty acids (FFA) were elevated. An early increase (3-6 h) in the serum level of HDL-C, TG and cholesterol was measured after single dose irradiation followed by a decrease thereafter. Furthermore, expression of the fat transporter protein FAT/CD36 was increased, immunohistochemistry revealed basolateral and cytoplasmic expression in hepatocytes. Moreover, apolipoprotein-B100, -C3 and enzymes (acetyl-CoA carboxylase, lipoprotein-lipase, carnitine-palmitoyltransferase, malonyl-CoA-decarboxylase) involved in fat metabolism were induced at 12-24 h. Early activation of the NFkβ pathway (IκBα) by TNF-α was seen, followed by a significant elevation of serum markers for liver damage (AST and GLDH). TNF-α blockage by anti-TNF-α in cell culture (U937) prevented the increase of FAT/CD36 caused by irradiation. Selective liver irradiation is a model for rapid induction of steatosis hepatis and fat accumulation could be triggered by irradiation-induced inflammatory mediators (e.g. TNF-α). PMID:25197426

  2. Optimization of tumour control probability in hypoxic tumours by radiation dose redistribution: a modelling study.

    PubMed

    Søvik, Aste; Malinen, Eirik; Bruland, Øyvind S; Bentzen, Søren M; Olsen, Dag Rune

    2007-01-21

    Tumour hypoxia is a known cause of clinical resistance to radiation therapy. The purpose of this work was to model the effects on tumour control probability (TCP) of selectively boosting the dose to hypoxic regions in a tumour, while keeping the mean tumour dose constant. A tumour model with a continuous oxygen distribution, incorporating pO(2) histograms published for head and neck patients, was developed. Temporal and spatial variations in the oxygen distribution, non-uniform cell density and cell proliferation during treatment were included in the tumour modelling. Non-uniform dose prescriptions were made based on a segmentation of the tumours into four compartments. The main findings were: (1) Dose redistribution considerably improved TCP for all tumours. (2) The effect on TCP depended on the degree of reoxygenation during treatment, with a maximum relative increase in TCP for tumours with poor or no reoxygenation. (3) Acute hypoxia reduced TCP moderately, while underdosing chronic hypoxic cells gave large reductions in TCP. (4) Restricted dose redistribution still gave a substantial increase in TCP as compared to uniform dose boosts. In conclusion, redistributing dose according to tumour oxygenation status might increase TCP when the tumour response to radiotherapy is limited by chronic hypoxia. This could potentially improve treatment outcome in a subpopulation of patients who respond poorly to conventional radiotherapy. PMID:17202629

  3. Effects of Hydrostatic Pressure Exposure on Hepatic Progenitor Cells.

    PubMed

    Recker, Stephanie; Bukovec, Melani; Sparks, Jessica L

    2015-01-01

    Hepatic progenitor cells (HPCs) have the potential to regenerate healthy tissue in the setting of chronic liver disease. The goal of this study was to characterize the mechanosensitivity of HPCs to sustained hydrostatic pressure (20 mmHg) similar to that observed in liver cirrhosis. Bipotential Murine Oval Liver (BMOL) cells, an HPC-like cell line, were cultured in a hydrostatic pressure controlled chamber at 37°C and 5% CO2 for 4 days (to 90% confluency) or 12 days (superconfluency). Controls were run for each time point in a standard incubator without pressure. Nuclei were stained with DAPI and cells were viewed under a Zeiss 710 laser scanning confocal microscope with 40x objective. Nuclei were measured with Image J software (170 to 398 distinct cell nucleus area measurements per group). Two-way ANOVA was used to examine the influence of pressure and confluency on nuclear size. Cells exposed to pressure (mean nuclear area 126.7µm2, S.D. 56.9) had significantly larger nuclei than control cells (mean nuclear area 102.3µm2, S.D. 84.1), p<.001. The pressure*confluency interaction was also significant (p<.05). Results suggest that HPCs are sensitive to low-level hydrostatic pressure associated with chronic liver disease. Further experiments include analyzing cellular proliferation, morphology, and differentiation effects associated with pressure exposure.

  4. Statins and its hepatic effects: Newer data, implications, and changing recommendations

    PubMed Central

    Jose, Jimmy

    2016-01-01

    Hepatic adverse effects are one of the most commonly known adverse effects reported with statins. Frequently, fear of serious hepatic effects contributes to underutilization of statins as well as unnecessary discontinuation of its use among those indicated. There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders. Based on reviewed literature, statins appear to be associated with a very low risk of true and serious liver injury. Unprecedented fears regarding hepatic adverse effects of statins among prescribers and patients can deny patients of the significant benefits of these agents. Routine periodic monitoring of liver function does not appear to detect or prevent serious liver injury and hence may not be indicated. But the potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice. Statin use need not be avoided in patients with preexisting liver dysfunction such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, compensated cirrhosis, and compensated chronic liver disease if its use is clearly indicated. Physician's judgment based on the risk and benefit for an individual patient does matter when a strategy is chosen regarding the use of statins and monitoring patients while on statins. PMID:26957864

  5. The cost-effectiveness of using hepatitis A/B combined vaccine versus hepatitis B vaccine alone for high-risk heterosexuals.

    PubMed

    Rein, David B; Weinbaum, Cindy M

    2008-10-01

    Previous studies estimated that vaccinating high-risk heterosexuals (HRH) with combination hepatitis A/B vaccine was a cost-effective alternative to vaccinating HRH against hepatitis B alone. Since then, the incidence of hepatitis A has declined dramatically in the United States. We re-estimate the cost-effectiveness of this policy accounting for modern declines in incidence. According to our estimates, vaccinating with combination vaccine resulted in a cost of $120,000 per quality adjusted life year gained (2.79 times the 2005 United States Gross Domestic Product per capita), a ratio that is less favorable than those for most other vaccination strategies.

  6. Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells.

    PubMed

    Filipović, Aleksandra; Lombardo, Ylenia; Faronato, Monica; Fronato, Monica; Abrahams, Joel; Aboagye, Eric; Nguyen, Quang-De; d'Aqua, Barbara Borda; Ridley, Anne; Green, Andrew; Rahka, Emad; Ellis, Ian; Recchi, Chiara; Przulj, Natasa; Sarajlić, Anida; Alattia, Jean-Rene; Fraering, Patrick; Deonarain, Mahendra; Coombes, R Charles

    2014-11-01

    The goal of targeted cancer therapies is to specifically block oncogenic signalling, thus maximising efficacy, while reducing side-effects to patients. The gamma-secretase (GS) complex is an attractive therapeutic target in haematological malignancies and solid tumours with major pharmaceutical activity to identify optimal inhibitors. Within GS, nicastrin (NCSTN) offers an opportunity for therapeutic intervention using blocking monoclonal antibodies (mAbs). Here we explore the role of anti-nicastrin monoclonal antibodies, which we have developed as specific, multi-faceted inhibitors of proliferation and invasive traits of triple-negative breast cancer cells. We use 3D in vitro proliferation and invasion assays as well as an orthotopic and tail vail injection triple-negative breast cancer in vivo xenograft model systems. RNAScope assessed nicastrin in patient samples. Anti-NCSTN mAb clone-2H6 demonstrated a superior anti-tumour efficacy than clone-10C11 and the RO4929097 small molecule GS inhibitor, acting by inhibiting GS enzymatic activity and Notch signalling in vitro and in vivo. Confirming clinical relevance of nicastrin as a target, we report evidence of increased NCSTN mRNA levels by RNA in situ hybridization (RNAScope) in a large cohort of oestrogen receptor negative breast cancers, conferring independent prognostic significance for disease-free survival, in multivariate analysis. We demonstrate here that targeting NCSTN using specific mAbs may represent a novel mode of treatment for invasive triple-negative breast cancer, for which there are few targeted therapeutic options. Furthermore, we propose that measuring NCSTN in patient samples using RNAScope technology may serve as companion diagnostic for anti-NCSTN therapy in the clinic. PMID:25248409

  7. Increased serum concentrations of tumour necrosis factor in beta thalassaemia: effect of bone marrow transplantation.

    PubMed Central

    Meliconi, R; Uguccioni, M; Lalli, E; Nesci, S; Delfini, C; Paradisi, O; Lucarelli, G; Gasbarrini, G; Facchini, A

    1992-01-01

    AIMS: Serum concentrations of tumour necrosis factor-alpha (TNF) were determined in beta thalassemic patients before and after bone marrow transplantation (BMT) to evaluate whether changes in TNF concentrations after BMT were related to immune mediated complications. METHODS: Serum TNF concentrations were determined by enzyme linked immunoassay (EIA) in paired samples from 71 patients with beta thalassemia before and after BMT. Serial samples from 13 patients were also studied for up to six months after BMT. Forty one normal healthy children matched for sex and age were studied as controls. RESULTS: beta thalassemic patients had high serum TNF concentrations before transplantation compared with controls. These were not related to sex, age, duration of disease, number of blood transfusions, transferrin concentrations or splenectomy. DQw1 positive patients showed significantly lower TNF concentrations than non-DQw1 cases. Patients with severe liver fibrosis had significantly higher TNF concentrations. No correlation was found between TNF values and BMT outcome before transplantation but TNF alpha values fell significantly after BMT. The decrease persisted only in patients with successful engraftment. In serial samples studied for up to six months after BMT, TNF values decreased but in four out of five patients with graft rejection and in all five with acute graft versus host disease (GVHD) sharp increases occurred at the time of clinical symptoms. No correlation was found between the degree of GVHD and serum TNF-alpha concentrations nor between TNF-alpha concentrations after BMT and the presence of bacterial, viral, and fungal infections. CONCLUSIONS: About 50% of beta thalassemic patients have increased serum TNF, and the changes after BMT are related to the occurrence of immune mediate complications. The persistence of low TNF concentrations after successful engraftment may be due to the preparative regimen and the lack of adverse immune reactions. PMID:1740519

  8. Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis

    PubMed Central

    Kim, Don-Kyu; Gang, Gil-Tae; Ryu, Dongryeol; Koh, Minseob; Kim, Yo-Na; Kim, Su Sung; Park, Jinyoung; Kim, Yong-Hoon; Sim, Taebo; Lee, In-Kyu; Choi, Cheol Soo; Park, Seung Bum; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

    2013-01-01

    Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder with diverse pathological manifestations and is often associated with abnormal regulation of hepatic glucose production. Many nuclear receptors known to control the hepatic gluconeogenic program are potential targets for the treatment of T2DM and its complications. Nevertheless, the therapeutic potential of the estrogen-related receptor γ (ERRγ) in T2DM remains unknown. In this study, we show that the nuclear receptor ERRγ is a major contributor to hyperglycemia under diabetic conditions by controlling hepatic glucose production. Hepatic ERRγ expression induced by fasting and diabetic conditions resulted in elevated levels of gluconeogenic gene expression and blood glucose in wild-type mice. Conversely, ablation of hepatic ERRγ gene expression reduced the expression of gluconeogenic genes and normalized blood glucose levels in mouse models of T2DM: db/db and diet-induced obesity (DIO) mice. In addition, a hyperinsulinemic-euglycemic clamp study and long-term studies of the antidiabetic effects of GSK5182, the ERRγ-specific inverse agonist, in db/db and DIO mice demonstrated that GSK5182 normalizes hyperglycemia mainly through inhibition of hepatic glucose production. Our findings suggest that the ability of GSK5182 to control hepatic glucose production can be used as a novel therapeutic approach for the treatment of T2DM. PMID:23775767

  9. Effectiveness of ultrasound-guided radiofrequency ablation in the treatment of 36 renal cell carcinoma tumours compared with published results of using computed tomography guidance.

    PubMed

    Davis, Kellie; Kielar, Ania; Jafari, Katayoun

    2012-08-01

    This study aimed to analyse the outcomes of ultrasound (US) guided radiofrequency ablation (RFA) in patients with renal lesions and to compare our outcomes with published results of ablations carried out when using computed tomography (CT) guidance. This retrospective study evaluated RFA of 36 renal tumours in 32 patients (M = 21, F = 11). The mean patient age was 70 years (range, 39-89 years). Ablations were performed by using either multi-tined applicators or cooled and/or cluster applicators under US guidance. Applicator size varied from 2-5 cm, depending on the size of the index tumour. Conscious sedation was administered by an anesthetist. Follow-up imaging by using contrast-enhanced CT was performed 1, 3, 6, and 12 months after RFA, and yearly thereafter. The mean tumour follow-up time was 12 months (range, 1-35 months). The mean tumour size was 2.7 cm (range, 1-5 cm). Primary effectiveness was achieved in 31 cases (86.1%), with patients in 5 cases (11.1%) demonstrating residual disease. Three patients had repeated sessions, which were technically successful. The remaining 2 patients were not re-treated because of patient comorbidities. As a result, secondary effectiveness was achieved in 34 patients (94.4%). In 1 patient, a new lesion developed in the same kidney but remote from the 2 prior areas of treatment. Hydrodissection was performed in 3 patients (8.3%), manipulation or electrode repositioning in 11 patients (30.6%), and ureteric cooling in 1 patient (2.8%). Minor and major complications occurred in 3 (8.3%) and 3 (8.3%) patients, respectively. Correlation coefficients were calculated for distance from skin to tumour and risk of complication as well as compared with primary and secondary effectiveness. This study demonstrates that US-guided RFA is an effective treatment for renal lesions, with rates of effectiveness and complication rates comparable with published CT-guided RFA results.

  10. A dosimetric phantom study of dose accuracy and build-up effects using IMRT and RapidArc in stereotactic irradiation of lung tumours

    PubMed Central

    2012-01-01

    Background and purpose Stereotactic lung radiotherapy (SLRT) has emerged as a curative treatment for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC) and the use of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc treatments (VMAT) have been proposed as the best practical approaches for the delivery of SLRT. However, a large number of narrow field shapes are needed in the dose delivery of intensity-modulated techniques and the probability of underdosing the tumour periphery increases as the effective field size is decreased. The purpose of this study was to evaluate small lung tumour doses irradiated by intensity-modulated techniques to understand the risk for dose calculation errors in precision radiotherapy such as SLRT. Materials and methods The study was executed with two heterogeneous phantoms with targets of Ø1.5 and Ø4.0 cm. Dose distributions in the simulated tumours delivered by small sliding window apertures (SWAs), IMRT and RapidArc treatment plans were measured with radiochromic film. Calculation algorithms of pencil beam convolution (PBC) and anisotropic analytic algorithm (AAA) were used to calculate the corresponding dose distributions. Results Peripheral doses of the tumours were decreased as SWA decreased, which was not modelled by the calculation algorithms. The smallest SWA studied was 2 mm, which reduced the 90% isodose line width by 4.2 mm with the Ø4.0 cm tumour as compared to open field irradiation. PBC was not able to predict the dose accurately as the gamma evaluation failed to meet the criteria of ±3%/±1 mm on average in 61% of the defined volume with the smaller tumour. With AAA the corresponding value was 16%. The dosimetric inaccuracy of AAA was within ±3% with the optimized treatment plans of IMRT and RapidArc. The exception was the clinical RapidArc plan with dose overestimation of 4%. Conclusions Overall, the peripheral doses of the simulated lung tumours were

  11. Protective Effects of N-Acetylcysteine in Concanavalin A-Induced Hepatitis in Mice

    PubMed Central

    Wang, Chengfen; Xia, Yujing; Dai, Weiqi; Wang, Fan; Chen, Kan; Li, Jingjing; Li, Sainan; Zhu, Rong; Yang, Jing; Yin, Qin; Zhang, Huawei; Wang, Junshan; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2015-01-01

    This study was designed to study the protective effects and mechanisms of N-acetylcysteine (NAC) in concanavalin A-induced hepatitis in mice. In this study, pretreatment with NAC ameliorated the histopathological changes and suppressed inflammatory cytokines in ConA-induced hepatitis. The expression of IL-2, IL-6, TNF-α, and IFN-γ was significantly reduced in the NAC-treated groups. NAC activated PI3K/Akt pathway and inhibited the activation of NF-κB. Additionally, NAC reduced autophagosome formation, as assessed by detecting the expression of LC3 and Beclin 1. Our results demonstrate that NAC can alleviate ConA-induced hepatitis by regulating the PI3K/Akt pathway and reducing the late stages of autophagy. Our results described a new pharmaceutical to provide more effective therapies for immune hepatitis. PMID:25821351

  12. Protective Effects of Dracocephalum heterophyllum in ConA-Induced Acute Hepatitis

    PubMed Central

    Wang, Qilan; Lu, Xiaohua; Shi, Qiangqiang; Zou, Junhui

    2016-01-01

    Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. However, the protective effects and pharmacological mechanisms of DH in hepatitis are unknown. In this study, we found that pretreatment with DH extract significantly ameliorated liver injury and suppressed the production of inflammatory cytokines, including tumor necrosis factor (TNF-α) and interferon-γ (IFN-γ) in Concanavalin A- (ConA-) induced hepatitis (CIH). DH recruited more CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) to the liver and suppressed infiltration of macrophages (Kupffer cells) in the liver. The present work explores DH as an effective hepatoprotective medicine to inhibit inflammation and liver injury caused by hepatitis. PMID:27524863

  13. Multiple tumours in survival estimates.

    PubMed

    Rosso, Stefano; De Angelis, Roberta; Ciccolallo, Laura; Carrani, Eugenio; Soerjomataram, Isabelle; Grande, Enrico; Zigon, Giulia; Brenner, Hermann

    2009-04-01

    In international comparisons of cancer registry based survival it is common practice to restrict the analysis to first primary tumours and exclude multiple cancers. The probability of correctly detecting subsequent cancers depends on the registry's running time, which results in different proportions of excluded patients and may lead to biased comparisons. We evaluated the impact on the age-standardised relative survival estimates of also including multiple primary tumours. Data from 2,919,023 malignant cancers from 69 European cancer registries participating in the EUROCARE-4 collaborative study were used. A total of 183,683 multiple primary tumours were found, with an overall proportion of 6.3% over all the considered cancers, ranging from 0.4% (Naples, Italy) to 12.9% (Iceland). The proportion of multiple tumours varied greatly by type of tumour, being higher for those with high incidence and long survival (breast, prostate and colon-rectum). Five-year relative survival was lower when including patients with multiple cancers. For all cancers combined the average difference was -0.4 percentage points in women and -0.7 percentage points in men, and was greater for older registries. Inclusion of multiple tumours led to lower survival in 44 out of 45 cancer sites analysed, with the greatest differences found for larynx (-1.9%), oropharynx (-1.5%), and penis (-1.3%). Including multiple primary tumours in survival estimates for international comparison is advisable because it reduces the bias due to different observation periods, age, registration quality and completeness of registration. The general effect of inclusion is to reduce survival estimates by a variable amount depending on the proportion of multiple primaries and cancer site.

  14. The FGF-1-specific single-chain antibody scFv1C9 effectively inhibits breast cancer tumour growth and metastasis

    PubMed Central

    Shi, Hengliang; Fu, Chunling; Wang, Wei; Li, Yu; Du, Shuang; Cao, Rangjuan; Chen, Jingying; Sun, Dong; Zhang, Zhongyu; Wang, Xingzhi; Zhu, Xiaojuan

    2014-01-01

    Immunotherapy mediated by recombinant antibodies is an effective therapeutic strategy for a variety of cancers. In a previous study, we demonstrated that the fibroblast growth factor 1 (FGF-1)-specific recombinant antibody scFv1C9 arrests the cell cycle at the G0/G1 transition by blocking the intracrine FGF-1 pathway in breast cancer cells. Here, we further show that the overexpression of scFv1C9 in MCF-7 and MDA-MB-231 breast cancer cells by lentiviral infection resulted in decreased tumourigenicity, tumour growth and lung metastasis through FGF-1 neutralization. We found that scFv1C9 resulted in the up-regulation of p21, which in turn inhibited the expression of CDK2 and blocked cell cycle progression. To explore the potential role of scFv1C9 in vivo, we delivered the gene into solid tumours by electroporation, which resulted in significant inhibition of tumour growth. In tumour tissue sections, immunohistochemical staining of the cellular proliferation marker Ki-67 and the microvessel marker CD31 showed a reduction in the proliferative index and microvessel density, respectively, upon expression of scFv1C9 compared with the appropriate controls. Thus, our data indicate a central role for scFv1C9 in blocking the intracrine pathway of FGF-1, therefore, scFv1C9 could be developed in an effective therapeutic for breast cancer. PMID:25124967

  15. Tumour-specific CD4 T cells eradicate melanoma via indirect recognition of tumour-derived antigen.

    PubMed

    Shklovskaya, Elena; Terry, Alexandra M; Guy, Thomas V; Buckley, Adrian; Bolton, Holly A; Zhu, Erhua; Holst, Jeff; Fazekas de St. Groth, Barbara

    2016-07-01

    The importance of CD4 T cells in tumour immunity has been increasingly recognised, with recent reports describing robust CD4 T cell-dependent tumour control in mice whose immune-regulatory mechanisms have been disturbed by irradiation, chemotherapy, immunomodulatory therapy and/or constitutive immunodeficiency. Tumour control in such models has been attributed in large part to direct Major Histocompatibility Complex (MHC) class II-dependent CD4 T cell killing of tumour cells. To test whether CD4 T cells can eradicate tumours without directly killing tumour cells, we developed an animal model in which tumour-derived antigen could be presented to T-cell receptor (TCR)-transgenic CD4 T cells by host but not tumour MHC class II molecules. In I-E(+) mice bearing I-E(null) tumours, naive I-E-restricted CD4 T cells proliferated locally in tumour-draining lymph nodes after recognising tumour-derived antigen on migratory dendritic cells. In lymphopaenic but not immunosufficient hosts, CD4 T cells differentiated into polarised T helper type 1 (Th1) cells expressing interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and interleukin (IL)-2 but little IL-17, and cleared established tumours. Tumour clearance was enhanced by higher TCR affinity for tumour antigen-MHC class II and was critically dependent on IFNγ, as demonstrated by early tumour escape in animals treated with an IFNγ blocking antibody. Thus, CD4 T cells and IFNγ can control tumour growth without direct T-cell killing of tumour cells, and without requiring additional adaptive immune cells such as CD8 T cells and B cells. Our results support a role for effective CD4 T cell-dependent tumour immunity against MHC class II-negative tumours. PMID:26837456

  16. Bronchial mucous gland tumours.

    PubMed

    Spencer, H

    1979-07-27

    Tumours arising in the bronchial mucous glands closely resemble tumours arising in the mixed salivary glands. Bronchial mucous gland tumours account for less than 0.5 per cent of all lung tumours. Twenty six tumours are reviewed and they have been divided into five types, (a) adenoidcystic carcinomas, (b) muco-epidermoid tumors, (c) mixed (pleomorphic) tumors, (d) cystadenomas and (f) oxyphilic adenoma. The clinical features, and postoperative course of the patients are reviewed. Adenocystic carcinomas, arising in the bronchus frequently involve the neighbouring trachea and spread mainly by direct infiltration. Most muco-epidermoid bronchial tumours were confined to young persons, and the only malignant muco-epidermoid tumour occurred in an elderly person. The prognosis in young persons is good provided the tumours are completely excised. The two mixed bronchial tumours resembled their salivary counterparts and one subsequently behaved as a carcinoma and metastasised. Bronchial cystadenomas all proved to be benign tumours but in two cases were associated with surface papillary proliferation. The only example of an oxyphil cell adenoma was discovered at post mortem examination. The histogenesis of the tumours is considered.

  17. An investigation into the effects of temporal resolution on hepatic dynamic contrast-enhanced MRI in volunteers and in patients with hepatocellular carcinoma

    NASA Astrophysics Data System (ADS)

    Gill, Andrew B.; Black, Richard T.; Bowden, David J.; Priest, Andrew N.; Graves, Martin J.; Lomas, David J.

    2014-06-01

    This study investigated the effect of temporal resolution on the dual-input pharmacokinetic (PK) modelling of dynamic contrast-enhanced MRI (DCE-MRI) data from normal volunteer livers and from patients with hepatocellular carcinoma. Eleven volunteers and five patients were examined at 3 T. Two sections, one optimized for the vascular input functions (VIF) and one for the tissue, were imaged within a single heart-beat (HB) using a saturation-recovery fast gradient echo sequence. The data was analysed using a dual-input single-compartment PK model. The VIFs and/or uptake curves were then temporally sub-sampled (at interval ▵t = [2-20] s) before being subject to the same PK analysis. Statistical comparisons of tumour and normal tissue PK parameter values using a 5% significance level gave rise to the same study results when temporally sub-sampling the VIFs to HB < ▵t <4 s. However, sub-sampling to ▵t > 4 s did adversely affect the statistical comparisons. Temporal sub-sampling of just the liver/tumour tissue uptake curves at ▵t ≤ 20 s, whilst using high temporal resolution VIFs, did not substantially affect PK parameter statistical comparisons. In conclusion, there is no practical advantage to be gained from acquiring very high temporal resolution hepatic DCE-MRI data. Instead the high temporal resolution could be usefully traded for increased spatial resolution or SNR.

  18. Therapeutic effects of date fruits (Phoenix dactylifera) in the prevention of diseases via modulation of anti-inflammatory, anti-oxidant and anti-tumour activity

    PubMed Central

    Rahmani, Arshad H; Aly, Salah M; Ali, Habeeb; Babiker, Ali Y; Srikar, Sauda; khan, Amjad A

    2014-01-01

    The current mode of treatment of various diseases based on synthetic drugs is expensive, alters genetic and metabolic pathways and also shows adverse side effects. Thus, safe and effective approach is needed to prevent the diseases development and progression. In this vista, Natural products are good remedy in the treatment/management of diseases and they are affordable and effective without any adverse effects. Dates are main fruit in the Arabian Peninsula and are considered to be one of the most significant commercial crops and also have been documented in Holy Quran and modern scientific literatures. Earlier studies have shown that constituents of dates act as potent antioxidant, anti-tumour as well as anti-inflammatory, provide a suitable alternative therapy in various diseases cure. In this review, dates fruits has medicinal value are summarized in terms of therapeutic implications in the diseases control through anti-oxidant, anti-inflammatory, anti-tumour and ant-diabetic effect. PMID:24753740

  19. Cimicifuga foetida L. plus adefovir effectively inhibits the replication of hepatitis B virus in patients with chronic hepatitis B

    PubMed Central

    DAI, XIUFANG; YI, XIANFU; SUN, ZEQUN; RUAN, PENG

    2016-01-01

    The aim of the present study was to assess the anti-hepatitis B virus (HBV) effect of Cimicifuga foetida L. (C. foetida) in the patients with chronic hepatitis B (CHB). A total of 60 randomly selected patients with CHB were recruited and divided into groups I and II. The patients in group I received a monotherapy of adefovir (ADV), and the patients in group II received a combination therapy of ADV and C. foetida for >48 weeks. Intrahepatic (IH) HBV covalently closed circular DNA (cccDNA), serum HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase levels and serum interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels were quantified during the test. Following the treatment, a significant reduction of the median IH cccDNA level was identified in group II (P=0.017), but not in group I (P=0.05, and P=0.01 between the 2 groups), and a significant reduction of log10 HBsAg was identified in groups I (P=0.012) and II (P<0.0001, and P=0.20 between the 2 groups). A significant increase of the median serum IFN-γ level was found in group II (P=0.0005), but not in group I (P=0.06, and P=0.004 between the 2 groups), and a significant reduction of the median TGF-β level was identified in groups I (P<0.0001) and II (P<0.0001, and P=0.002 between the 2 groups). A total of 24 patients in group I, and 27 patients in group II achieved a sustained virological response (P=0.0386), and 20 patients in group I and 24 in group II achieved hepatitis B e antigen seroclearance (P=0.0442). In conclusion, C. foetida can effectively inhibit HBV transcription and replication in the patients by stimulating the release of the inflammatory cytokines, such as IFN-γ. PMID:27073640

  20. LASERS IN MEDICINE: Light-oxygen effect in cells and its potential applications in tumour therapy (review)

    NASA Astrophysics Data System (ADS)

    Zakharov, S. D.; Ivanov, Andrei V.

    1999-12-01

    The light-oxygen effect (POE) represents damage (and at low optical doses, activation) of cells by photogeneration of molecular singlet oxygen from O2 dissolved in cells, in accordance with the reaction: 3O2+hν→1O2→ biological effect. The phases of evolution of the LOE are similar to the phases, observed in cell experiments, of the photodynamic effect (PDE) the mechanism of which is the basis of the familiar method of photodynamic cancer therapy. The reported proofs of the occurrence of the LOE are in the form of detailed spectra of the biological action of optical radiation on cells recorded in four spectral intervals with the aid of tunable lasers. Allowances are made for the relationships governing a new type of cell excitation, associated with reversible structural transitions in the biomembrane. A demonstration is reported of the same efficiency of cw and pulsed irradiation. An analysis is made of the reasons why the optical doses initiating the PDE and the LOE are comparable. The results are given of the first experimental applications of the LOE in tumour therapy. Identification of the primary photoacceptor (O2) in cell biostimulation and photodestruction provides a scientific basis for the development of low-intensity laser light-oxygen cancer therapy methods.

  1. Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4.

    PubMed

    Stephenson, Sally-Anne; Douglas, Evelyn L; Mertens-Walker, Inga; Lisle, Jessica E; Maharaj, Mohanan S N; Herington, Adrian C

    2015-04-10

    EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand-independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies. PMID:25831049

  2. Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4

    PubMed Central

    Stephenson, Sally-Anne; Douglas, Evelyn L.; Mertens-Walker, Inga; Lisle, Jessica E.; Maharaj, Mohanan S.N.; Herington, Adrian C.

    2015-01-01

    EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand-independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies. PMID:25831049

  3. Effects of butylated hydroxyanisole and butylated hydroxytoluene on DNA adduct formation and arylamine N-acetyltransferase activity in human bladder tumour cells.

    PubMed

    Lu, Hsueh-Fu; Wu, Hsi-Chin; Hsia, Te-Chun; Chen, Wen-Chi; Hung, Chi-Fu; Chung, Jing-Gung

    2002-01-01

    In this study, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) were used to determine the inhibition of arylamine N-acetyltransferase (NAT) activity and DNA adduct formation in human bladder tumour cell line T-24. The activity of NAT was measured by high-performance liquid chromatography, assaying for the amounts of N-acetyl-2-aminofluorene and N-acetyl-p-aminobenzoic acid and remaining 2-aminofluorene and p-aminobenzoic acid. Human bladder tumour cell line T-24 cytosols and intact cells were used for examining NAT activity and carcinogen-DNA adduct formation. The results demonstrated that NAT activity and 2-aminofluorene-DNA adduct formation in human bladder tumour cells were inhibited and decreased by BHA and BHT in a dose-dependent manner. The effects of BHA and BHT on the values of the apparent K(m) and V(max) also were determined in both systems examined. The results indicated that BHA and BHT decreased the apparent values of K(m) and V(max) from human bladder tumour cells in both cytosol and intact cells.

  4. Long-Term Effectiveness of Accelerated Hepatitis B Vaccination Schedule in Drug Users

    PubMed Central

    Shah, Dimpy P.; Grimes, Carolyn Z.; Nguyen, Anh T.; Lai, Dejian

    2015-01-01

    Objectives. We demonstrated the effectiveness of an accelerated hepatitis B vaccination schedule in drug users. Methods. We compared the long-term effectiveness of accelerated (0–1–2 months) and standard (0–1–6 months) hepatitis B vaccination schedules in preventing hepatitis B virus (HBV) infections and anti-hepatitis B (anti-HBs) antibody loss during 2-year follow-up in 707 drug users (HIV and HBV negative at enrollment and completed 3 vaccine doses) from February 2004 to October 2009. Results. Drug users in the accelerated schedule group had significantly lower HBV infection rates, but had a similar rate of anti-HBs antibody loss compared with the standard schedule group over 2 years of follow-up. No chronic HBV infections were observed. Hepatitis C positivity at enrollment and age younger than 40 years were independent risk factors for HBV infection and antibody loss, respectively. Conclusions. An accelerated vaccination schedule was more preferable than a standard vaccination schedule in preventing HBV infections in drug users. To overcome the disadvantages of a standard vaccination schedule, an accelerated vaccination schedule should be considered in drug users with low adherence. Our study should be repeated in different cohorts to validate our findings and establish the role of an accelerated schedule in hepatitis B vaccination guidelines for drug users. PMID:25880946

  5. Duplex/colour Doppler sonography: measurement of changes in hepatic arterial haemodynamics following intra-arterial angiotensin II infusion.

    PubMed

    Leen, E; Angerson, W J; Warren, H W; Goldberg, J A; Sutherland, G R; Cooke, T G; McArdle, C S

    1993-06-01

    Angiotensin II (AT-II) has been used to target regionally-administered cytotoxic microspheres in patients with intrahepatic tumours. The optimisation of vasoconstrictor targeting requires a knowledge of the blood flow changes induced by agents such as AT-II. We therefore assessed duplex/colour Doppler sonography (DCDS) as a means of evaluating the effects of AT-II infusion on hepatic arterial blood flow (HABF) and arterial resistance in patients with intrahepatic tumours. HABF was measured continuously in nine patients using DCDS before, during and after an infusion of AT-II (15 micrograms in 3 ml of saline over 90 s) via a hepatic artery catheter. In seven patients with less than 30% hepatic replacement by tumour, the baseline level of HABF was 331 +/- 85 ml min-1 (mean +/- s.d.), and this was reduced by 75-80% within 30 s of the start of AT-II infusion. HABF recovered rapidly from the end of the infusion, and increased by up to 20% above the baseline for approximately 2 min. In two patients with greater than 50% hepatic replacement, HABF showed no reduction but rose continuously from the start of AT-II infusion, increasing by a factor of 2-2.5 after 3-4 min. Arterial resistance showed reciprocal changes in all cases. We conclude that DCDS is effective in assessing the temporal changes in hepatic arterial blood flow caused by AT-II. In order to optimise tumour targeting, the injection of microspheres loaded with cytotoxic drugs should be completed before the end of the AT-II infusion. The targeting advantage of AT-II in patients with a high percentage hepatic replacement by tumour should be re-assessed.

  6. Antiproliferative effect of methyl-beta-cyclodextrin in vitro and in human tumour xenografted athymic nude mice.

    PubMed Central

    Grosse, P. Y.; Bressolle, F.; Pinguet, F.

    1998-01-01

    The anti-tumour activity of methyl-beta-cyclodextrin (MEBCD), a cyclic oligosaccharide known for its interaction with the plasma membrane, was investigated in vitro and in vivo and compared with that of doxorubicin (DOX) in the human tumour models MCF7 breast carcinoma and A2780 ovarian carcinoma. In vitro proliferation was assessed using the MTT assay. In vivo studies were carried out using xenografted Swiss nude mice injected weekly i.p. with MEBCD at 300 or 800 mg kg(-1) or DOX at 2 mg kg(-1), during 2 months. Under these conditions, MEBCD was active against MCF7 and A2780 cell lines and tumour xenografts. For each tumour model, the tumoral volume of the xenografted mice treated with MEBCD was at least twofold reduced compared with the control group. In the MCF7 model, MEBCD (800 mg kg(-1)) was more active than DOX (2 mg kg(-1)). After 56 days of treatment with MEBCD, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared with controls. The accumulation of MEBCD in normal and tumour tissues was also assessed using a chromatographic method. Results indicated that after a single injection of MEBCD, tumour, liver and kidneys accumulated the highest concentrations of MEBCD. These results provided a basis for the potential therapeutic application of MEBCD in cancer therapy. PMID:9820174

  7. Circulating tumour cells: insights into tumour heterogeneity.

    PubMed

    Hayes, D F; Paoletti, C

    2013-08-01

    Tumour heterogeneity is a major barrier to cure breast cancer. It can exist between patients with different intrinsic subtypes of breast cancer or within an individual patient with breast cancer. In the latter case, heterogeneity has been observed between different metastatic sites, between metastatic sites and the original primary tumour, and even within a single tumour at either a metastatic or a primary site. Tumour heterogeneity is a function of two separate, although linked, processes. First, genetic instability is a hallmark of malignancy, and results in 'fixed' genetic changes that are almost certainly carried forward through progression of the cancer over time, with increasingly complex additional genetic changes in new metastases as they arise. The second type of heterogeneity is due to differential but 'plastic' expression of various genes important in the biology and response to various therapies. Together, these processes result in highly variable cancers with differential response, and resistance, to both targeted (e.g. endocrine or anti-human epithelial growth receptor type 2 (HER2) agents) and nontargeted therapies (e.g. chemotherapy). Ideally, tumour heterogeneity would be monitored over time, especially in relation to therapeutic strategies. However, biopsies of metastases require invasive and costly procedures, and biopsies of multiple metastases, or serially over time, are impractical. Circulating tumour cells (CTCs) represent a potential surrogate for tissue-based cancer and therefore might provide the opportunity to monitor serial changes in tumour biology. Recent advances have enabled accurate and reliable quantification and molecular characterization of CTCs with regard to a number of important biomarkers including oestrogen receptor alpha and HER2. Preliminary data have demonstrated that expression of these markers between CTCs in individual patients with metastatic breast cancer reflects the heterogeneity of the underlying tumours. Future

  8. Immunomodulatory effect of arctigenin, a lignan compound, on tumour necrosis factor-alpha and nitric oxide production, and lymphocyte proliferation.

    PubMed

    Cho, J Y; Kim, A R; Yoo, E S; Baik, K U; Park, M H

    1999-11-01

    We have investigated the immunomodulatory effects of arctigenin, a dibenzyl butyrolactone lignan compound, on tumour necrosis factor (TNF)-alpha and nitric oxide (NO) production, and lymphocyte proliferation. Arctigenin inhibited strongly TNF-alpha production by lipopolysaccharide-stimulated murine macrophage RAW264.7 and differentiated human macrophage U937 with IC50 values of 5.0 and 3.9 microM, respectively, without displaying cytotoxicity. The TNF-alpha inhibitory effect of arctigenin in lipopolysaccharide-triggered RAW264.7 cells was increased by co-treatment with several known TNF-alpha inhibitors. It also potently attenuated T and B cell proliferation stimulated by concanavalin A and lipopolysaccharide in a dose-dependent manner with IC50 values of 2.9 and 14.6 microM, respectively. In contrast, the compound showed a different pattern in lipopolysaccharide- and interferon (IFN)-gamma-induced NO production from RAW264.7 cells. Arctigenin inhibited NO release by IFN-gamma signal, whereas it significantly enhanced lipopolysaccharide-triggered NO production in RAW264.7 cells. The results suggested that arctigenin may regulate immune responses in activated macrophages and lymphocytes including TNF-alpha and NO production and lymphocyte proliferation.

  9. Prooxidative effect of copper--metallothionein in the acute cytotoxicity of hydrogen peroxide in Ehrlich ascites tumour cells.

    PubMed

    Suntres, Zacharias E; Lui, Edmund M K

    2006-01-16

    This study was concerned with the role of copper (Cu) and Cu-metallothionein (Cu-MT) in oxidative stress. Hydrogen peroxide (H(2)O(2))-induced oxidative injury was examined in Ehrlich ascites tumour cells isolated from host mice pretreated with 0, 1 or 2mg of CuSO(4) (ip) 24h earlier. Control Ehrlich cells contained low levels of Cu and Cu treatment produced dose-related increases in cellular Cu and Cu-MT levels and corresponding increases in sensitivity to oxidative toxicity of H(2)O(2) (LC(50), cell blebbing, lipid peroxidation, GSH depletion, and increase in intracellular free [Ca(2+)](i)). Hydrogen peroxide treatment also resulted in the oxidation of MT thiolates, reduction in the binding of Cu to MT resulting in translocation of Cu to other subcellular sites. d-penicillamine, a Cu-chelating agent, obliterated the sensitization effect of Cu-pretreatment and reduced the redistribution of MT-bound Cu, suggesting the participation of Cu ions derived from MT in promoting oxidant stress. Additional experiments with desferoxamine and mannitol have revealed the involvement of a Cu-dependent Fenton reaction in the mediation of the prooxidative effect of Cu-MT. These data suggest that cells with high levels of Cu-MT may be particularly susceptible to oxidative stress. PMID:16221516

  10. Tumour progression and metastasis.

    PubMed

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible.

  11. High mitomycin C concentration in tumour tissue can be achieved by isolated liver perfusion in rats.

    PubMed

    Marinelli, A; Pons, D H; Vreeken, J A; Nagesser, S K; Kuppen, P J; Tjaden, U R; van de Velde, C J

    1991-01-01

    To enable the treatment of hepatic metastasis with higher, theoretically more effective, doses of systemically toxic anticancer drugs, an isolated liver perfusion (ILP) technique was developed in WAG/Ola rats. First, in a toxicity study the maximally tolerated dose (MTD) of mitomycin C (MMC) was determined for a 25-min ILP and for hepatic artery infusion (HAI) after the administration of a bolus dose. The MTD in the ILP setting (4.8 mg/kg) was 4 times that using HAI (1.2 mg/kg). Subsequently, in a rat colorectal hepatic-metastasis model, concentrations of MMC in tumour, liver, plasma and perfusate were measured during a 25-min ILP to investigate the expected pharmacokinetic advantage of ILP. The mean plasma level determined after ILP (1.2 as well as 4.8 mg/kg MMC) was significantly lower (P less than 0.001) than that obtained following HAI. This may explain both the absence of severe systemic toxicity and the higher MTD in ILP-treated groups. No significant difference in mean tumour and liver tissue concentrations of MMC were found when the groups treated with 1.2 mg/kg drug via HAI vs ILP were compared. The mean MMC concentration in tumour tissue was significantly higher (almost 5 times; P less than 0.05) in rats treated by ILP with the MTD (4.8 mg/kg) than in those treated via HAI with the MTD (1.2 mg/kg). ILP of MMC can be safely performed using a dose 4 times higher than the MTD in the HAI setting, leading to an almost 5-fold concentration of MMC in hepatic metastasis. ILP of MMC may therefore represent a promising therapy for metastasis confined to the liver. PMID:1905590

  12. Beneficial effect of glatiramer acetate (Copaxone) on immune modulation of experimental hepatic fibrosis.

    PubMed

    Horani, Amjad; Muhanna, Nidal; Pappo, Orit; Melhem, Alaa; Alvarez, Carlos E; Doron, Sarit; Wehbi, Wehbi; Dimitrios, Karussis; Friedman, Scott L; Safadi, Rifaat

    2007-02-01

    While CD8 subsets activate hepatic fibrosis, natural killer (NK) cells exhibit antifibrotic activity. Glatiramer acetate (GA) is an immune modulator for multiple sclerosis. We assessed the potential impact of GA on mouse hepatic fibrogenesis. Hepatic fibrosis was induced in C57BL/6 mice by intraperitoneal administration of carbon tetrachloride (CCl(4)) for 6 wk. During the last 2 wk, animals were also treated with either GA (200 mu/day ip) or medium and compared with naive and fibrotic mice (8 animals/group). GA markedly attenuated fibrosis without altering reactive oxygen species production. By morphometric measurement of Sirius red-stained tissue sections, the relative fibrosis area decreased from 5.28 +/- 0.32% (mean +/- SE) in the untreated CCl(4) group to 2.01 +/- 0.28% in CCl(4)+GA-treated animals, compared with 0.38 +/- 0.07% in naive mice. alpha-Smooth muscle actin immunoblotting and mRNA expression revealed a similar pattern. Serum aminotransferase and Ishak-Knodell necroinflammatory score were markedly elevated, to the same extent, in both CCl(4)-treated groups. Fibrosis induction was associated with significant increase in CD8 subsets and decrease in CD4 T cells. After GA treatment, however, NK content, CD4(+)CD25(+)FoxP3(+) cells, hepatic expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and apoptosis of hepatic stellate cells were all increased. Serum interleukin (IL)-10 levels markedly rose, whereas IL-4 fell. In vitro activation of human hepatic stellate cells cocultured with hepatitis C virus-derived peripheral blood lymphocytes decreased when lymphocytes were preincubated with GA before coculture. In an animal model of hepatic fibrosis, GA has an antifibrotic effect associated with decreased CD8 cells and reduced serum IL-4 levels and increased NK cells, CD4(+)CD25(+)FoxP3(+) cells, TRAIL, and elevated serum IL-10 levels.

  13. Effects of dietary carbohydrate on hepatic de novo lipogenesis in European seabass (Dicentrarchus labrax L.).

    PubMed

    Viegas, Ivan; Jarak, Ivana; Rito, João; Carvalho, Rui A; Metón, Isidoro; Pardal, Miguel A; Baanante, Isabel V; Jones, John G

    2016-07-01

    Farmed seabass have higher adiposity than their wild counterparts and this is often attributed to carbohydrate (CHO) feeding. Whether this reflects a reduction in fat oxidation, increased de novo lipogenesis (DNL), or both, is not known. To study the effects of high CHO diets on hepatic TG biosynthesis, hepatic TG deuterium ((2)H) enrichment was determined following 6 days in (2)H-enriched tank water for fish fed with a no-CHO control diet (CTRL), and diets with digestible starch (DS) and raw starch (RS). Hepatic fractional synthetic rates (FSRs, percent per day(-1)) were calculated for hepatic TG-glyceryl and FA moieties through (2)H NMR analysis. Glyceryl FSRs exceeded FA FSRs in all cases, indicating active cycling. DS fish did not show increased lipogenic potential compared to CTRL. RS fish had lower glyceryl FSRs compared with the other diets and negligible levels of FA FSRs despite similar hepatic TG levels to CTRL. DS-fed fish showed higher activity for enzymes that can provide NADPH for lipogenesis, relative to CTRL in the case of glucose-6-phosphate dehydrogenase (G6PDH) and relative to RS for both G6PDH and 6-phosphogluconate dehydrogenase. This approach indicated that elevated hepatic adiposity from DS feeding was not attributable to increased DNL. PMID:27247346

  14. Effects of aluminum chloride on serum proteins, bilirubin, and hepatic trace elements in chickens.

    PubMed

    Wang, Ben; Zhu, Yanzhu; Zhang, Hongling; Liu, Liming; Li, Guojiang; Song, Yongli; Li, Yanfei

    2016-09-01

    The aim of this study was to reveal the effects of aluminum chloride (AlCl3) on the hepatic metabolism function and trace elements' distribution. Two hundred healthy male chickens (1 day old) were intraperitoneally administered with AlCl3 (0, 18.31, 27.47, and 36.62 mg kg(-1) day(-1) of Al(3+)) consecutively for 3 days. Then the chickens were allowed to rest for 1 day. The cycle lasted four days. The cycle was repeated 15 times (60 days). The contents of serum total protein (TP), albumin (ALB), total bilirubin (TBI), direct bilirubin (DBI), hepatic aluminum (Al), copper (Cu), iron (Fe), and zinc (Zn) were examined. The results showed that the contents of serum TP and ALB and hepatic Fe and Zn decreased and the contents of serum TBI and DBI and hepatic Al and Cu increased in the chickens with AlCl3 This indicates that chronic administration of AlCl3 impairs the hepatic metabolism function and disorders the hepatic trace elements' distribution. PMID:25896954

  15. The effects of tramadol on hepatic ischemia/reperfusion injury in rats

    PubMed Central

    Mahmoud, Mona F.; Gamal, Samar; Shaheen, Mohamed A.; El-Fayoumi, Hassan M.

    2016-01-01

    Objectives: Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Materials and Methods: Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Results: Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. Conclusion: The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects. PMID:27298497

  16. Estimations of intra- and extracellular volume and pH by 31P magnetic resonance spectroscopy: effect of therapy on RIF-1 tumours.

    PubMed Central

    Bhujwalla, Z. M.; McCoy, C. L.; Glickson, J. D.; Gillies, R. J.; Stubbs, M.

    1998-01-01

    Quantification of metabolite or drug concentrations in living tissues requires determination of intra- and extracellular volumes. This study demonstrates how this can be achieved non-invasively by 31P magnetic resonance spectroscopy (MRS) employing dimethyl methylphosphonate (DMMP) as a marker of total water space, 3-aminopropylphosphonate (3-APP) as a marker of extracellular space and P and 3-APP as markers of intracellular pH (pH) and extracellular pH (pHe) respectively. The MRS measurements of the tumour volumes were validated by classic radiolabelling methods using 3H2O and [14C]inulin as markers of total and extracellular space respectively. The extracellular volume fraction measured by radiolabelling of RIF-1 tumours was 23 +/- 0.83% (mean +/- s.e.m. n = 9), not significantly different (P > 0.1) from that found by MRS (27 +/- 2.9%, n = 9, London, and 35 +/- 6.7, n = 14, Baltimore). In untreated RIF-1 tumours, pH was about 0.2 units higher than pHe (P < 0.01). 5-Fluorouracil (5FU) treatment (165 mg kg(-1)) caused no significant changes in either pHe or per cent extracellular volume. However significant increases in pH, 48 h after treatment (P < 0.01) correlated with decreased tumour size and improved bioenergetic status [NTP/inorganic phosphate (Pi) ratio]. This study shows the feasibility of an MR method (verified by a 'gold standard') for studying the effects of drug treatment on intra- and extracellular spaces and pH in solid tumours in vivo. PMID:9744499

  17. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.

    PubMed

    Colegio, Oscar R; Chu, Ngoc-Quynh; Szabo, Alison L; Chu, Thach; Rhebergen, Anne Marie; Jairam, Vikram; Cyrus, Nika; Brokowski, Carolyn E; Eisenbarth, Stephanie C; Phillips, Gillian M; Cline, Gary W; Phillips, Andrew J; Medzhitov, Ruslan

    2014-09-25

    Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

  18. Purification of glutathione S-transferase isoenzymes from tumour and nontumour human stomach and inhibitory effects of some heavy metals on enzymes activities.

    PubMed

    Demirdag, Ramazan; Yerlikaya, Emrah; Kufrevioglu, Omer Irfan; Gundogdu, Cemal

    2013-10-01

    In this study, glutathione S-transferase (GST) enzyme was purified from nontumour and tumour human gastric tissue and in vitro effects of heavy metals on the enzyme were examined. GST was purified 3089 fold with a specific activity of 20 U/mg and a yield of 78% from gastric tumour tissue; and 1185 fold with a specific activity of 5.69 U/mg and a yield of 50% from nontumour tissue by using glutathione-agarose affinity column, respectively. Enzyme purity was verified by SDS-PAGE and subunit molecular mass was calculated around 26 kDa. The molecular weight of the enzyme was calculated as 52 kDa by using Sephadex G-75 gel filtration column. Then, inhibitory effects of metal ions on the enzymes were investigated. Mg(2+) and Cd(2+) had inhibitory effect on the enzymes activities. Other kinetic properties of the enzymes were also determined.

  19. Hepatitis A outbreaks: the effect of a mass vaccination programme.

    PubMed

    Torner, N; Broner, S; Martinez, A; Godoy, P; Batalla, J; Dominguez, A

    2011-04-01

    A Hepatitis A vaccination programme of people belonging to risk groups begun in Catalonia in 1995 and a universal vaccination programme of pre-adolescents 12 years of age with the hepatitis A + B vaccine was added in 1998. The aim of the study was to investigate the characteristics of hepatitis A outbreaks occurring in Catalonia between 1991 and 2007 to determine the associated risk factors and optimize the use of vaccination. Incidence rates of outbreaks, cases and hospitalizations associated with outbreaks and the rate ratios (RR) of person-to-person transmission outbreaks between the periods before and after mass vaccination and their 95% confidence intervals (CI) were calculated. A rate of 2.45 outbreaks per million persons per year was found. The rate of cases affected in these outbreaks was 1.28 per 10(5) persons per year and the rate of hospitalizations was 0.45 per million persons per year. In person-to-person outbreaks, the highest incidence rate (5.26 and 6.33 per million persons per year) of outbreaks according to the age of the index case was in the 5 to 14 year age group in both periods (RR:0.83; 95% CI:0.48-1.43). A significant increase was observed in the 25 to 44 year age group (RR: 0.35; 95% CI 0.14-0.77). Hepatitis A vaccination has made an important impact on burden and characteristics of outbreaks and could provide greater benefits to the community if the vaccine was administrated to children during their first years of life.

  20. Cytotoxicity of alpha-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia.

    PubMed Central

    Hauck, M. L.; Larsen, R. H.; Welsh, P. C.; Zalutsky, M. R.

    1998-01-01

    The high linear energy transfer, alpha-particle-emitting radionuclide astatine-211 (211At) is of interest for certain therapeutic applications; however, because of the 55- to 70-microm path length of its alpha-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of alpha-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 211At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 microm) greater than the range of 211At alpha-particles. Hyperthermia for 1 h at 42 degrees C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml(-1). A significant regrowth delay was observed at 125 and 250 kBq ml(-1) in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 42 degrees C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids. Images Figure 4 Figure 5 PMID:9514054

  1. Effects of tumour necrosis factor-alpha synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis.

    PubMed

    Bobin-Dubigeon, C; Collin, X; Grimaud, N; Robert, J M; Le Baut, G; Petit, J Y

    2001-11-01

    The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation. PMID:11716848

  2. Cytotoxicity of alpha-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia.

    PubMed

    Hauck, M L; Larsen, R H; Welsh, P C; Zalutsky, M R

    1998-03-01

    The high linear energy transfer, alpha-particle-emitting radionuclide astatine-211 (211At) is of interest for certain therapeutic applications; however, because of the 55- to 70-microm path length of its alpha-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of alpha-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 211At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 microm) greater than the range of 211At alpha-particles. Hyperthermia for 1 h at 42 degrees C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml(-1). A significant regrowth delay was observed at 125 and 250 kBq ml(-1) in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 42 degrees C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids.

  3. Effect of chronic excess of tumour necrosis factor-alpha on contractile proteins in rat skeletal muscle.

    PubMed

    Cheema, I R; Hermann, C; Postell, S; Barnes, P

    2000-01-01

    The effect of chronic tumour necrosis factor-alpha (TNF-alpha) treatment on the synthesis of specific myofibrillar proteins such as heavy chain myosin, light chain myosin and G-actin in rat diaphragm were evaluated. Muscles (diaphragm) from control and experimental groups (TNF-alpha i.v. at 50 microg/kg body wt for 5 days) were incubated in the presence of 35S-methionine for 2 h. Myofibrillar protein extracts were prepared and protein was electrophoresed on sodium dodecyl sulphate-polyacrylamide gels. Heavy chain myosin, light chain myosin and G-actin were identified by Western blot analysis using specific monoclonal antibodies. Polyacrylamide gel electrophoresis (PAGE) followed by Western blot analysis revealed two types of heavy chain myosin (206 and 212 kD), all four types of light chain myosin (15, 16.5, 18 and 20 kD) and a single type of G-actin (42 kD). Chronic TNF-alpha treatment produced a significant decline in the synthesis of all types of myofibrillar proteins, namely heavy chain myosin, light chain myosin and G-actin. TNF-alpha impaired peptide-chain initiation in diaphragm muscle which was reversed by the branched-chain amino acids (BCAA) therapy of TNF-alpha treated rats. These findings indicate a significant role for TNF-alpha in the translational regulation of protein synthesis in skeletal muscle.

  4. Tailored nanoparticles for tumour therapy.

    PubMed

    Jiang, Pei-Shin; Drake, Philip; Cho, Hui-Ju; Kao, Chao-Hung; Lee, Kun-Feng; Kuo, Chien-Hung; Lin, Xi-Zhang; Lin, Yuh-Jiuan

    2012-06-01

    Gd doped iron-oxide nanoparticles were developed for use in tumour therapy via magnetic fluid hyperthermia (MFH). The effect of the Gd3+ dopant on the particle size and magnetic properties was investigated. The final particle composition varied from Gd0.01Fe2.99O4 to Gd0.04Fe2.96O4 as determined by Inductively coupled plasma atomic emission spectroscopy (ICP-AES). TEM image analysis showed the average magnetic core diameters to be 12 nm and 33 nm for the lowest and highest Gd levels respectively. The specific power adsorption rate (SAR) determined with a field strength of 246 Oe and 52 kHz had a maximum of 38Wg(-1) [Fe] for the Gd0.03Fe2.97O4 sample. This value is about 4 times higher than the reported SAR values for Fe3O4. The potential for in vivo tumour therapy was investigated using a mouse model. The mouse models treated with Gd0.02Fe2.98O4 displayed much slower tumour growth after the first treatment cycle, the tumour had increased its mass by 25% after 7 days post treatment compared to a 79% mass increase over the same period for those models treated with standard iron-oxide or saline solution. After a second treatment cycle the mouse treated with Gd0.02Fe2.98O4 showed complete tumour regression with no tumour found for at least 5 days post treatment. PMID:22905580

  5. Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients.

    PubMed Central

    Dellian, M.; Helmlinger, G.; Yuan, F.; Jain, R. K.

    1996-01-01

    Tumour pH plays a significant role in cancer treatment. However, because of the limitations of the current measurement techniques, spatially and temporally resolved pH data, obtained non-invasively in solid tumours, are not available. Fluorescence ratio imaging microscopy (FRIM) has been used previously for noninvasive, dynamic evaluation of pH in neoplastic tissue in vivo (Martin GR, Jain RK 1994, Cancer Res., 54, 5670-5674). However, owing to problems associated with quantitative fluorescence in thick biological tissues, these studies were limited to thin (50 microns) tumours. We, therefore, adapted the FRIM technique for pH determination in thick (approximately 2 mm) solid tumours in vivo using a pinhole illumination-optical sectioning (PIOS) method. Results show that (1) steep interstitial pH gradients (5 microns resolution), with different spatial patterns, exist between tumour blood vessels; (2) pH decreased by an average of 0.10 pH units over a distance of 40 microns away from the blood vessel wall, and by 0.33 pH units over a 70 microns distance; (3) the maximum pH drop, defined as the pH difference between the intervessel midpoint and the vessel wall, was positively correlated with the intervessel distance; (4) 45 min following a systemic glucose injection (6 g kg-1 i.v), interstitial pH gradients were shifted to lower pH values by an average of 0.15 pH units, while the spatial gradient (slope) was maintained, when compared with preglucose values. This pH decrease was not accompanied by significant changes in local blood flow. pH gradients returned to near-baseline values 90 min after glucose injection; (5) interstitial tumour pH before hyperglycaemia and the glucose-induced pH drop strongly depended on the local vessel density; and (6) sodium bicarbonate treatment, either acute (1 M, 0.119 ml h-1 for 3 h i.v.) or chronic (1% in drinking water for 8 days), did not significantly change interstitial tumour pH. Modified FRIM may be combined with other optical

  6. Antiviral therapy effects upon hepatitis C cholestatic syndrome.

    PubMed

    Vere, C C; Gofiţă, Eliza; Forţofoiu, C; Streba, Letiţia Adela Maria; Genunche, Amelia

    2007-01-01

    Cholestasis includes, as a syndrome, all clinical and biological manifestations caused by the deficient or simply absent biliar secretion or caused by the obstruction of the biliary ducts. The hepatic cholestasis from the chronic hepatitis C (HC VHC) is a result of the altered interlobular biliary canalicules, caused by the modified cellular transport mechanisms and it is associated with a medium to severe degree of fibrosis. The aim of this study was to evaluate the efficiency of antiviral therapy in HC VHC patients. The study included a number of 37 HC VHC patients admitted at the Medical Department no. 1 of the Emergency County Hospital of Craiova; they were treated with Pegasys, 180 microg/week and Copegus, 1000 or 1200 mg/day, taking in consideration their weight, for 48 weeks and they were monitored for 24 weeks after the treatment. The following parameters were analyzed: direct bilirubine, total cholesterol, alkaline phosphatase, gamma-glutamiltranspeptidase and leucin-aminopeptidase. Under treatment, the clinical status caused by the cholestasis (pruritus, icteric syndrome, hemoragipary syndrome) was improved in six of the given cases (16.22%). Before therapy, the hepatic cholestasis was present in 20 patients (54.05%), and after treatment in 14 patients (37.83%). During therapy, the average values for all the monitored parameters decreased: direct bilirubine (0.38 +/- 0.18 mg/dl vs. 0.34 +/- 0.24 mg/dl, p = 0.0867), total cholesterol (198.53 md/dl vs. 183.16 mg/dl, p = 0.0808), alkaline phosphatase (236.99 +/- 79.09 iu/l vs. 227.82 +/- 87.59 iu/l, p = 0.0845), gamma-glutamiltranspeptidase (47 +/- 32.89 iu/l vs. 43.91 +/- 29.66 iu/l, p = 0.1509), and leucin-aminopeptidase (32.33 +/- 13.22 iu/l vs. 28.95 +/- 14.22 iu/l, p = 0.0038). Under antiviral treatment there was noticed an improvement of the cholestasis clinical status in a small number of cases. Antiviral therapy favorably influenced the liver cholestasis associated in patients with chronic hepatitis

  7. Cost effectiveness of vaccinating food service workers against hepatitis A infection.

    PubMed

    Jacobs, R J; Grover, S F; Meyerhoff, A S; Paivana, T A

    2000-06-01

    Foodborne transmission is an important means of hepatitis A infection that may be reduced through vaccination of food service workers (FSWs). Several states are considering actions to encourage or mandate FSW vaccination, but the cost effectiveness of such policies has not been assessed. We estimated the clinical and economic consequences of vaccinating FSWs from the 10 states with the highest reported rates of hepatitis A. A decision analytic model was used to predict the effects of vaccinating FSWs at age 20 years. It was assumed all FSWs would receive one dose of inactivated hepatitis A vaccine, and 50% would receive the second recommended dose. Parameter estimates were obtained from published reports and Centers for Disease Control and Prevention databases. The primary endpoint was cost per year of life saved (YOLS). Secondary endpoints were symptomatic infections, days of illness, deaths, and costs of hepatitis A treatment, public health intervention, and work loss. Each endpoint was considered separately for FSWs and patrons. We estimate vaccination of 100,000 FSWs would cost $8.1 million but reduce the costs of hepatitis A treatment, public health intervention, and work loss by $3.0 million, $2.3 million, and $3.1 million, respectively. Vaccination would prevent approximately 2,500 symptomatic infections, 93,000 days of illness, and 8 deaths. A vaccination policy would reduce societal costs while costing the health system $13,969 per YOLS, a ratio that exceeds generally accepted standards of cost effectiveness. PMID:10852572

  8. Tumour progression and metastasis

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour’s survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  9. PET imaging for the quantification of biologically heterogeneous tumours: measuring the effect of relative position on image-based quantification of dose-painting targets

    NASA Astrophysics Data System (ADS)

    McCall, Keisha C.; Barbee, David L.; Kissick, Michael W.; Jeraj, Robert

    2010-05-01

    Quantitative imaging of tumours represents the foundation of customized therapies and adaptive patient care. As such, we have investigated the effect of patient positioning errors on the reproducibility of images of biologically heterogeneous tumours generated by a clinical PET/CT system. A commercial multi-slice PET/CT system was used to acquire 2D and 3D PET images of a phantom containing multiple spheres of known volumes and known radioactivity concentrations and suspended in an aqueous medium. The spheres served as surrogates for sub-tumour regions of biological heterogeneities with dimensions of 5-15 mm. Between image acquisitions, a motorized-arm was used to reposition the spheres in 1 mm intervals along either the radial or the axial direction. Images of the phantom were reconstructed using typical diagnostic reconstruction techniques, and these images were analysed to characterize and model the position-dependent changes in contrast recovery. A simulation study was also conducted to investigate the effect of patient position on the reproducibility of PET imaging of biologically heterogeneous head and neck (HN) tumours. For this simulation study, we calculated the changes in image intensity values that would occur with changes in the relative position of the patients at the time of imaging. PET images of two HN patients were used to simulate an imaging study that incorporated set-up errors that are typical for HN patients. One thousand randomized positioning errors were investigated for each patient. As a result of the phantom study, a position-dependent trend was identified for measurements of contrast recovery of small objects. The peak contrast recovery occurred at radial and axial positions that coincide with the centre of the image voxel. Conversely, the minimum contrast recovery occurred when the object was positioned at the edges of the image voxel. Changing the position of high contrast spheres by one-half the voxel dimension lead to errors in the

  10. Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With Ribavirin.

    PubMed

    Dao Thi, Viet Loan; Debing, Yannick; Wu, Xianfang; Rice, Charles M; Neyts, Johan; Moradpour, Darius; Gouttenoire, Jérôme

    2016-01-01

    Infection with hepatitis E virus genotype 3 may result in chronic hepatitis in immunocompromised patients. Reduction of immunosuppression or treatment with ribavirin or pegylated interferon-α can result in viral clearance. However, safer and more effective treatment options are needed. Here, we show that sofosbuvir inhibits the replication of hepatitis E virus genotype 3 both in subgenomic replicon systems as well as a full-length infectious clone. Moreover, the combination of sofosbuvir and ribavirin results in an additive antiviral effect. Sofosbuvir may be considered as an add-on therapy to ribavirin for the treatment of chronic hepatitis E in immunocompromised patients.

  11. Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21

    PubMed Central

    Mei, Liufeng; Chen, Yicheng; Wang, Zhimeng; Wang, Jian; Wan, Jiali; Yu, Chunrong; Liu, Xin; Li, Wenhua

    2015-01-01

    Background and Purpose Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. Experimental Approach Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. Key Results Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21−/− HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. Conclusions and Implications The combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment. PMID:25521075

  12. Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels

    PubMed Central

    Rittling, S R; Wejse, P L; Yagiz, K; Warot, G A; Hui, T

    2014-01-01

    Background: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Methods: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α9 integrin was determined. Results: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α9 integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α9 binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. Conclusions: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α9 integrin are likely involved. PMID:24473400

  13. Acute and chronic effect of ethanol on hepatic albumin synthesis in rat liver in vitro

    SciTech Connect

    Ohtake, H.; Kato, S.; Murawaki, Y.; Kishimoto, Y.; Wakushima, T.; Hirayama, C.

    1986-08-01

    To study the effects of ethanol and its metabolite on albumin metabolism, we examined the hepatic albumin synthesis and secretion in male Wistar rats in vitro, following acute and chronic ethanol administration. After acute ethanol administration, proalbumin synthesis in rat liver in vitro, declined to 47% of the control level at 4 hrs, the lowest level, and increased thereafter to slightly higher than the control level at 16 hrs. On the other hand, chronic ethanol administration for 4 weeks, increased proalbumin synthesis to 1.5 times that of the control level. In the acute ethanol group, a significant negative correlation was observed between proalbumin radioactivity and the concentration of hepatic ethanol and acetaldehyde. The variation between proalbumin radioactivity and hepatic ethanol concentration was wider than the variation between proalbumin and hepatic acetaldehyde. In the chronic ethanol group, ethanol was not detected in the liver. No significant differences from the proalbumin/albumin ratio were seen at any time point after acute or chronic ethanol administration. These findings suggest that the effects of ethanol on hepatic albumin synthesis differ with the method of ethanol administration, and acetaldehyde and/or ethanol is involved in the reduction in albumin synthesis, however, proalbumin-albumin conversion is not disturbed.

  14. Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

    PubMed Central

    Winnick, J. J.; Ramnanan, C. J.; Saraswathi, V.; Roop, J.; Scott, M.; Jacobson, P.; Jung, P.; Basu, R.; Cherrington, A. D.

    2013-01-01

    The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition (P < 0.05) due to a reduction in net hepatic glycogenolysis (P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P < 0.05) and the suppression of lipolysis were increased (P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production. PMID:23403942

  15. The Effects of Physiological and Environmental Factors on Hepatic Perfusion and First-Pass Metabolism.

    NASA Astrophysics Data System (ADS)

    Modi, Marlene Woodruff

    The interaction of three important parameters; hepatic blood flow (Q_{rm H} ), plasma protein binding (f), and hepatic intrinsic clearance (CL_{rm int}) determines the disposition of agents undergoing extensive first-pass metabolism. This collection of studies focuses on the interaction of these parameters in man and the rat in the presence and absence of a given physiological and environmental perturbation. Potential mechanisms implicated in the "Food Effect" phenomenon whereby concomitant food intake increases the bioavailability a basic lipophilic drug are examined. These investigations provide insight as to the physiological response of the liver in the face of nutritional, pharmacological and physiological perturbations. The measurement of hepatic blood flow is a necessary endeavor before and understanding of the hepatic circulation or hepatic clearance concepts can be realized. Preliminary studies were performed to improve our understanding of the factors affecting the interpretation of hepatic blood flow estimates. It has been postulated that this food effect is caused at least in part by a transient increase in Q _{rm H} with its associated decrease in hepatic first-pass metabolism. Posture was manipulated in such a manner as to simulate the hepatic blood flow pattern observed in postprandial subjects. Although transient changes in Q_{rm H } comparable in magnitude and duration to those encountered after food consumption were observed, the AUC _{rm oral} for propanolol was not affected. It is important to assess the free concentration being presented to the organ which is highly extracting the drug. Single macronutrient feedings of glucose and vitamin-free casein to male Sprague-Dawley rats did not produce significant changes in the serum protein binding of a model basic lipophilic drug (quinidine) in systemic or hepatic blood. It has been postulated that food intake may have a greater influence on the bioavailability of metoprolol (a high clearance drug

  16. A study on the protective effect of Silybum marianum extract on hepatic ischemia-reperfusion injury.

    PubMed

    Liu, Shaojun; Chen, Zhiheng; Cao, Dongbo; Liu, Fen; Wang, Xiaoyan; Zhao, Lian; Liu, Rui; Xiao, Zhiming

    2013-01-01

    The objective of the study was to study the protective effect of Silybum marianum extract on hepatic ischemia-reperfusion injury. Rats were randomly divided into five groups; namely Silybum marianum extract high-, medium-, and low-dose protection groups, model group and control group. Hepatic ischemia-reperfusion injury model was prepared. Serum or plasma AST, ALT, MDA, TNF-α, IL-1β, IL-6 levels were measured. The results revealed that after liver injury, AST, ALT, MDA, TNF-α, IL-1β, and IL-6 levels significantly increased in succession, showing significant differences. We concluded that inflammatory cytokines participate in liver injury and that Silybum marianum extract can reduce the production of inflammatory cytokines, and thus can have a protective effect on hepatic ischemia and reperfusion.

  17. The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome

    PubMed Central

    Robinson, S M; Mann, D A; Manas, D M; Oakley, F; Mann, J; White, S A

    2013-01-01

    Background: Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury. Methods: We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI. Results: In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury. Conclusion: It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors. PMID:24113143

  18. The anti-tumour effects of the prodrugs N-l-leucyl-doxorubicin and vinblastine-isoleucinate in human ovarian cancer xenografts.

    PubMed Central

    Boven, E.; Hendriks, H. R.; Erkelens, C. A.; Pinedo, H. M.

    1992-01-01

    N-l-leucyl-doxorubicin and vinblastine-isoleucinate can be considered as relatively non-toxic prodrugs from doxorubicin and vinblastine, respectively. A comparative analysis was carried out of the anti-tumour activity of the four compounds as well as vintriptol in four human ovarian cancer xenografts different in histology, growth rate and chemosensitivity. Injections were given i.v. weekly twice into mice bearing well-established s.c. tumours. At equitoxic doses, the amount of drug administered for N-l-leucyl-doxorubicin and vinblastine-isoleucinate was respectively 3-fold and 2-fold higher than the doses of the parent compound. N-l-leucyl-doxorubicin induced a growth inhibition > 50% in three out of four human ovarian cancer lines. The anti-tumour effects obtained were significantly better (P < 0.01) than in the case of doxorubicin. Vinblastine-isoleucinate studied in two of these lines could induce a growth inhibition of > 50%. This prodrug appeared slightly less effective than vinblastine. Insignificant growth inhibition (< 50%) was obtained by vintriptol. PMID:1457343

  19. Mediated effect of endotoxin and lead upon hepatic metabolism

    SciTech Connect

    Kuttner, R.E.; Ebata, T.; Schumer, W.

    1984-10-01

    A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after a systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.

  20. The Laser Treatment of Experimental Malignant Tumours

    PubMed Central

    McGuff, Paul E.; Deterling, Ralph A.; Gottlieb, Leonard S.; Fahimi, H. Dariush; Bushnell, David; Roeber, Fred

    1964-01-01

    Some of the results of experiments performed during the past two years to assess effects of laser energy on experimental malignant tumours are reviewed. Twenty types of malignant tumours (most in the cheek pouch and 11 of human origin) were treated in over 700 Syrian hamsters. Results of laser treatment of malignant melanomas and thyroidal carcinomas are presented. A human patient with malignant melanoma treated by laser energy is described. Investigation of thermal effect revealed that the laser-treated tumour remained warm for about one minute, while the cautery-treated tumour cooled to normal temperature in five seconds. Direct action of laser on superficial tumours is possible; deeper lesions must be exposed surgically. Laser energy has a selective effect on certain malignant tumours, resulting in their progressive regression and ultimate dissolution. All hamsters with implanted malignant melanomas and carcinomas of human origin, after completion of a course of laser treatment, showed no gross or histologic evidence of tumour up to the date of last observation. ImagesFig. 1Fig. 2aFig. 2bFig. 2cFig. 2dFig. 2eFig. 2fFig. 3Fig. 4aFig. 4bFig. 4cFig. 4dFig. 4eFig. 4fFig. 4gFig. 6 PMID:14229757

  1. Protective effects of fish oil, allopurinol, and verapamil on hepatic ischemia-reperfusion injury in rats

    PubMed Central

    Messiha, Basim Anwar Shehata; Abo-Youssef, Amira M.

    2015-01-01

    Background: The major aim of this work was to study the protective effects of fish oil (FO), allopurinol, and verapamil on hepatic ischemia-reperfusion (IR)-induced injury in experimental rats. Materials and Methods: Sixty male Wistar albino rats were randomly assigned to six groups of 10 rats each. Group 1 served as a negative control. Group 2 served as hepatic IR control injury. Groups 3, 4, 5, and 6 received N-acetylcysteine (standard), FO, allopurinol, and verapamil, respectively, for 3 consecutive days prior to ischemia. All animals were fasted for 12 h, anesthetized and underwent midline laparotomy. The portal triads were clamped by mini-artery clamp for 30 min followed by reperfusion for 30 min. Blood samples were withdrawn for estimation of serum alanine transaminase (ALT) and aspartate transaminase (AST) activities as well as hepatic thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, and total nitrate/nitrite levels, in addition to histopathological examination. Results: Fish oil, allopurinol, and verapamil reduced hepatic IR injury as evidenced by significant reduction in serum ALT and AST enzyme activities. FO and verapamil markedly reduced oxidative stress as compared to control IR injury. Levels of inflammatory biomarkers in liver were also reduced after treatment with FO, allopurinol, or verapamil. In accordance, a marked improvement of histopathological findings was observed with all of the three treatments. Conclusion: The findings of this study prove the benefits of FO, allopurinol, and verapamil on hepatic IR-induced liver injury and are promising for further clinical trials. PMID:26283828

  2. Effect of Trichlorfon on Hepatic Lipid Accumulation in Crucian Carp Carassius auratus gibelio

    PubMed Central

    Xu, WeiNa; Liu, WenBin; Shao, XianPing; Jiang, GuangZhen; Li, XianngFei

    2012-01-01

    This study evaluated the toxic effects of the organophosphate pesticide trichlorfon on hepatic lipid accumulation in crucian carp Carassius auratus gibelio. Seventy-five fish were divided into five groups (each group in triplicate), and then exposed to 0, 0.5, 1.0, 2.0, and 4.0 mg/L of trichlorfon and fed with commercial feed for 30 d. At the end of the experiment, plasma and hepatic lipid metabolic biochemical status were analyzed. Triglyceride contents were significantly (P < 0.05) increased in liver but decreased in plasma after 1.0, 2.0, and 4.0 mg/L trichlorfon treatments. Plasma insulin contents were markedly (P < 0.05) increased when trichlorfon concentrations were 0.5, 1.0, and 4.0 mg/L. There were no significant differences in hepatic hormone-sensitive lipase contents between the trichlorfon-treated fish and the controls. Hepatic cyclic adenosine 3′, 5′-monophosphate, very-low-density lipoprotein, and apolipoprotein B100 contents were decreased in the fish when trichlorfon concentration was 2.0 mg/L. Furthermore, electron microscope observations showed rough endoplasmic reticulum dilatation and mitochondrial vacuolization in hepatocytes with trichlorfon exposure. On the basis of morphological and physiological evidence, trichlorfon influenced crucian carp hepatic pathways of lipid metabolism and hepatocellular ultrastructure, which resulted in lipid accumulation in the liver. PMID:22897202

  3. Effects of a cloned cell line with NK activity on bone marrow transplants, tumour development and metastasis in vivo

    NASA Astrophysics Data System (ADS)

    Warner, John F.; Dennert, Gunther

    1982-11-01

    Natural killer (NK) cells cloned in vitro have been transferred into NK-deficient hosts. These cells have been shown to have a role in the rejection of allogeneic bone marrow grafts, resistance to both radiation-induced thymic leukaemia and challenge with melanoma tumour cells. It appears that NK cells have an important role in immune surveillance.

  4. Comparison of metabolic effects of vegetables and teas with colorectal proliferation and with tumour development in DMH-treated F344 rats.

    PubMed

    O'Neill, I K; Loktionov, A; Manson, M M; Ball, H; Bandaletova, T; Bingham, S A

    1997-03-19

    The aim of this study was to screen potentially chemopreventive vegetables and teas for their effects as human dietary components for the colorectal epithelium and also to seek biomarkers of preventive efficacy. Groups of F344 rats were adapted to a human basal diet supplemented with vegetables or teas, having known contents of glucosinolates, polyphenols and anti-oxidants. Both inductions and suppressions were found for overall glutathione S-transferase (GST) and quinone reductase activities. The mitotic index (MI) showed a three-fold range between groups, with substantial reductions by black tea, spinach, petit pois and peppers. Changes to PCNA labelling index and proliferation zone were marginal. No correlation was found between colonic and hepatic enzyme activities, nor with glucosinolate intake. Colonic MI was associated with the activity ratio GST(hepatic)/GST(colonic) (r = 0.49, P < 0.002), possibly reflecting a need for direct induction rather than exposure to products of hepatic conjugation.

  5. Effect of methionine deprivation on S-adenosylmethionine decarboxylase of tumour cells.

    PubMed

    Tisdale, M J

    1981-07-17

    Transference of Walker carcinoma and TLX5 lymphoma from normal L-methionine-containing medium to medium containing limiting amounts of L-methionine, or L-homocysteine only, caused a 2-fold increase of S-adenosylmethionine decarboxylase activity. Kinetic analysis showed an increase in the V value of the enzyme from 22 to 53 pmol/min per mg protein in media containing only 0.1 mM L-homocysteine, without any alteration in the Km value (0.1 mM). The increase in enzyme activity does not result from (a) a reduction of the intracellular level of S-adenosylmethionine, since cycloleucine, an inhibitor of methionine adenosyltransferase, had no effect on enzyme activity; (b) an increase in intracellular adenosine 3',5' monophosphate (cyclic AMP), since high extracellular concentrations of N6-monobutyryl cyclic AMP had no effect on enzyme activity; (c) an alteration of polyamine levels, since addition of micromolar concentrations of exogenous putrescine, spermidine and spermine did not prevent the induction of S-adenosylmethionine decarboxylase activity in methionine-free media containing 0.1 mM L-homocysteine. The increased enzyme activity appears to be mainly due to enhanced stabilization, since the half-life was increased from 2.45 to 5.0 h in media containing only 0.1 mM L-homocysteine. Induction of enzyme activity is specific to the removal of L-methionine, since no increase occurred in the absence of L-serine or L-glycine, or both, or by reduction of the serum concentrations in the medium.

  6. [Effects of repeated sevoflurane anesthesia on hepatic and renal function in a pediatric patient].

    PubMed

    Tanikawa, M; Mitsuhata, H; Shimizu, R; Akazawa, S; Fukuda, H; Saitoh, K; Hirabayashi, Y; Togashi, H

    1994-10-01

    A 10-yr-old boy with an injured lower extremity received sevoflurane anesthesia 5 times within 40 days. Laboratory tests for hepatic and renal function i.e., serum transaminase (glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, gamma-glutamyl transpeptidase), serum cholinesterase, plasma protein, serum cholinesterase, serum bilirubine, serum lactic dehydrogenase, serum prothrombin time, blood urea nitrogen, serum creatinine, beta 2-microglobulin, N-acetyl-D-glucosamidase and 24 hr-creatinine clearance remained within normal ranges throughout his perioperative period. Repeated sevoflurane anesthesia did not exert any adverse effect on hepatic and renal function in this patient.

  7. [Effectiveness and tolerance of genetically engineered vaccines for hepatitis B--a comparative study].

    PubMed

    Schmid, K; Strebl, H; Heck, K J; Weltle, D; Raithel, H J

    1992-05-01

    The two hepatitis B vaccines produced by gene technology that are presently available in Germany, were compared in respect of efficacy and tolerance in 80 nurses (female and male) who were under training. Both vaccines proved to be highly effective and well tolerated. In respect of the achieved anti-HBs titer, however, the two vaccines differed significantly from each other. Using the 20 micrograms HBs antigen, the antibody titers obtained were higher by a factor of 1.8. The article gives update recommendations in respect of hepatitis B vaccination as a preventive measure in risk groups. PMID:1535816

  8. In vitro radiosensitizing effects of ultrasmall gadolinium based particles on tumour cells.

    PubMed

    Mowat, P; Mignot, A; Rima, W; Lux, F; Tillement, O; Roulin, C; Dutreix, M; Bechet, D; Huger, S; Humbert, L; Barberi-Heyob, M; Aloy, M T; Armandy, E; Rodriguez-Lafrasse, C; Le Duc, G; Roux, S; Perriat, P

    2011-09-01

    Since radiotherapy is widely used in cancer treatment, it is essential to develop strategies which lower the irradiation burden while increasing efficacy and become efficient even in radio resistant tumors. Our new strategy is relying on the development of solid hybrid nanoparticles based on rare-earth such as gadolinium. In this paper, we then evidenced that gadolinium-based particles can be designed to enter efficiently into the human glioblastoma cell line U87 in quantities that can be tuned by modifying the incubation conditions. These sub-5 nm particles consist in a core of gadolinium oxide, a shell of polysiloxane and are functionalized by diethylenetriaminepentaacetic acid (DTPA). Although photoelectric effect is maximal in the [10-100 keV] range, such particles were found to possess efficient in-vitro radiosensitizing properties at an energy of 660 keV by using the "single-cell gel electrophoresis comet assay," an assay that measures the number of DNA damage that occurs during irradiation. Even more interesting, the particles have been evidenced by MTT assays to be also efficient radiosensitizers at an energy of 6 MeV for doses comprised between 2 and 8 Gy. The properties of the gadolinium-based particles give promising opening to a particle-assisted radio-therapy by using irradiation systems already installed in the majority of hospitals.

  9. Protective effect of Acanthopanax gracilistylus-extracted Acankoreanogenin A on mice with fulminant hepatitis.

    PubMed

    Zhang, Bao-Xin; Li, Ning; Zhang, Zu-Ping; Liu, Hong-Bo; Zhou, Rong-Rong; Zhong, Bai-Yun; Zou, Ming-Xiang; Dai, Xia-Hong; Xiao, Mei-Fang; Liu, Xiang-Qian; Fan, Xue-Gong

    2011-08-01

    The release of pro-inflammatory cytokines in both acute (IL-1β and TNF-α) and chronic [high mobility group box 1 protein (HMGB1)] phases, is thought to play important roles in the development of fulminant hepatitis (FH). Triterpenoid Acankoreanogenin A (AA) which is extracted from the leaves of the Acanthopanax gracilistylus W.W. Smith (AGS) has shown its inhibiting effect on TNF-α, IL-1β and HMGB1 release in vitro in our preliminary experiments. In present study, we investigated the effect of AA on mice with fulminant hepatitis in vivo. Fulminant hepatitis mice model was established by intraperitoneally injecting galactosamine (GalN) and lipopolysaccharide (LPS). The levels of serum of TNF-α, IL-1β, ALT, AST and HMGB1 from AA-treated mice were measured at different time points. Our results demonstrated that pre-treatment of mice with AA markedly reduced the serum levels of TNF-α, IL-1β, HMGB1, ALT and AST with the improvement in histological features. And the survival rate from AA-treated fulminant hepatitis mice was increased. Furthermore, delayed administration of AA after peak occurrence of the early pro-inflammatory cytokines still endowed significant protection against GalN/LPS-induced lethality. The post-treatment of AA could significantly attenuate the release of HMGB1, but not the TNF-α and IL-1β. These results indicate that AA inhibits the systemic release of pro-inflammatory cytokine HMGB1, and dose-dependently rescue the mice from lethal GalN/LPS-induced fulminant hepatitis, which suggests this component as a candidate therapy for fulminant hepatitis. PMID:21356341

  10. Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

    PubMed Central

    Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. PMID:22866165

  11. Effects of tumour necrosis factor-α on BrdU incorporation in cultured human enterocytes

    PubMed Central

    McDevitt, J.; Feighery, C.; O'Farrelly, C.; Martin, G.; Weir, D. G.

    1995-01-01

    Bromodeoxyuridine incorporation is a useful method for studying the pattern of DNA synthesis in proliferating cells. The distribution pattern of incorporated BrdU in villus enterocytes of duodenal explants was analysed after exposure to TNFα in organ culture. TNFα caused a consistent, low level uptake of BrdU in the portion of the nucleus close to the nuclear membrane, this pattern was absent from the control cultures. As these epithelial cells are terminally arrested in G0, the BrdU incorporation was thought not to be due to S phase DNA synthesis, but rather a response to the cytotoxic influence of TNFα. Microtitre plate proliferation assays of cell density and DNA synthesis were devised to study the effects of TNFα on confluent monolayers of the human foetal jejunal cell line I407 and the mouse fibrosarcoma cell line L929. Both cell lines showed a similar response to TNFα. Exposure to TNFα alone did not reduce cell numbers but did cause a significant increase in DNA synthesis (p < 0.05). When cycloheximtde was added in tandem with TNFα there was a significant reduction in cell number (p < 0.001) and level of DNA synthesis (p < 0.01) indicative of cell death. The DNA of cells exposed to TNFα and cycloheximide was fragmented when viewed on an electrophoresis gel. The results show that BrdU incorporation might be a good indicator of damage to the DNA of cells after cytotoxic insult. TNFα may be responsible for villus enterocyte damage in enteropathies such as coeliac disease and GVHR of the small bowel. PMID:18475613

  12. Heavy ion tumour therapy

    NASA Astrophysics Data System (ADS)

    Scholz, M.

    2000-03-01

    Ion beams represent a promising radiotherapy modality for the treatment of deep seated tumours. Compared to conventional photon beams, in particular beams of heavier ions like e.g. carbon show several advantages which are related to their different physical and radiobiological properties: The dose increases with penetration depth and shows a sharp distal fall off at the end of the particle range, i.e., the depth dose profile is inverted compared to photon beams. They exhibit an increased biological effectiveness in particular at the end of their range and thus in the target volume. The spatial distribution of stopping particles can be monitored by means of PET-techniques making use of the small amount of radioactive projectile fragments. Ion beams were first used for medical applications in 1954 in Berkeley. Since then, several treatment facilities for tumour therapy have been established worldwide, and approximately 25 000 patients have been treated with protons and 3000 patients with heavier ions successfully. As an example, the specific advantages of the heavy ion therapy facility at GSI Darmstadt established in cooperation with the Radiological Clinics and DKFZ Heidelberg and FZ Rossendorf will be described. In contrast to most existing facilities, it is based on an active beam delivery system, using magnetic deflection of a pencil beam (raster scan) and accelerator energy variation to adjust the penetration depth. Thus, an optimal conformation of the dose to the target volume is achieved. PET-measurements allow for a quasi on-line monitoring of the 3D distribution of stopping particles and in particular of the position of the distal edge of the dose distribution. Furthermore, in the treatment planning procedure the radiobiological properties of ion beams are taken into account in great detail. In December 1997, patient treatments started at GSI, and up to now 42 patients were treated with carbon ions alone or in a mixed carbon/photon beam regime.

  13. Hepatitis C virus replication in hepatocellular carcinoma.

    PubMed Central

    Niu, J; Kumar, U; Monjardino, J; Goldin, R; Rosin, D; Thomas, H C

    1995-01-01

    Hepatitis C virus (HCV) replication is reported in both tumour and non-tumour tissue in a case of hepatocellular carcinoma. Viral replication was established by showing the presence of minus strand HCV RNA by PCR amplification, after excluding residual reverse transcriptase activity of Taq polymerase. No minus strand was found in serum derived virion RNA. PCR amplified products from both tumour and non-tumour parenchyma were sequenced in the 5' non-coding region and shown to be identical. The genotype of this Indonesian patient was found to be 1b (or II), the most prevalent type in the Far East. Images PMID:7490330

  14. OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION

    EPA Science Inventory

    Evaluating the Effects of Methapyrilene and Clofibrate on Hepatic Gene Expression: A Collaboration Between Laboratories and a Comparison of Platform and Analytical Approaches

    Roger G. Ulrich1, John C. Rockett2, G. Gordon Gibson3 and Syril Pettit4

    1 Rosetta Inpharmat...

  15. [Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure].

    PubMed

    Yamanishi, A; Ishibashi, Y; Kuriyama, K; Tachiiri, T; Kusajima, H; Kojima, E; Momo, K

    1999-01-01

    To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction.

  16. Monte Carlo study of the dose enhancement effect of gold nanoparticles during X-ray therapies and evaluation of the anti-angiogenic effect on tumour capillary vessels.

    PubMed

    Amato, Ernesto; Italiano, Antonio; Leotta, Salvatore; Pergolizzi, Stefano; Torrisi, Lorenzo

    2013-01-01

    Gold nanoparticles (GNPs) are a promising radiosensitizer agent in radiotherapy. Through a simulation performed with the Geant4 Monte Carlo code, we evaluated the dose enhancement effect of GNPs during therapies with an x-ray tube operating at 150 kV (E = 55 keV and E(max) = 150 keV) and we studied the impact of GNP diffusion out of the tumour vessels, in terms of antiangiogenic and cytotoxic effects. Firstly, a single x-ray beam was assumed to irradiate a parallelepiped volume of soft tissue, in which a GNP-doped "target" volume was placed at different depths. Average dose enhancement factors (DEF) in presence of GNPs were obtained as a function of the target depth and GNP concentration, uniformly distributed; values ranging between 1.6 for 10 mg Au/g at 0 cm and 7.2 for 200 mg Au/g at 5 cm were determined. Furtherly, a second geometry was adopted, in which a blood capillary vessel (10 μm thick and 10 μm of inner radius) was placed at the centre of a cubic volume of soft tissue; doses and DEFs to the capillary endothelium as well as to the surrounding viable tumour were evaluated, for different models of GNP diffusion. Our results indicate that the radial DEF profiles around the vessel are in close relationship with the radial profiles of GNP concentration assumed, except for at sharp gradients of concentration. DEFs at the endothelium ranged from 1.6 to 6.5, for GNP concentrations in the blood of 10 and 200 mg/ml, respectively. These data can be helpful for the development of new and more specific GNP-based radiosensitizers of potential interest in radiotherapy, exploiting the combined benefit of anti-angiogenic and cytotoxic dose enhancement effects. PMID:23694913

  17. Ionone Derivatives from the Mycelium of Phellinus linteus and the Inhibitory Effect on Activated Rat Hepatic Stellate Cells

    PubMed Central

    Huang, Shiow-Chyn; Kuo, Ping-Chung; Hung, Hsin-Yi; Pan, Tai-Long; Chen, Fu-An; Wu, Tian-Shung

    2016-01-01

    Three new γ-ionylideneacetic acid derivatives, phellinulins A–C (1–3), were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1) was subjected to the examination of effects on activated rat hepatic stellate cells and exhibited significant inhibition of hepatic fibrosis. PMID:27164091

  18. Safe and cost-effective control of post-transplantation recurrence of hepatitis B

    PubMed Central

    Takaki, Akinobu; Yagi, Takahito; Yamamoto, Kazuhide

    2015-01-01

    A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence. PMID:24905970

  19. Safe and cost-effective control of post-transplantation recurrence of hepatitis B.

    PubMed

    Takaki, Akinobu; Yagi, Takahito; Yamamoto, Kazuhide

    2015-01-01

    A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence.

  20. Costs and cost-effectiveness of a universal, school-based hepatitis B vaccination program.

    PubMed Central

    Krahn, M; Guasparini, R; Sherman, M; Detsky, A S

    1998-01-01

    OBJECTIVES: This study evaluated the costs and cost-effectiveness of a school-based grade 6 universal vaccination program against hepatitis B. METHODS: We performed a descriptive cost study and cost-effectiveness analysis of British Columbia's vaccination program for 1994 and 1995. Since 1992, public health nurses have administered hepatitis B vaccine to grade 6 students in schools. We measured costs of vaccine, vaccine administration, and net program costs and used a validated Markov model to calculate the cost-effectiveness of the program. RESULTS: Vaccinating each student cost $44, $24 of which was the cost of vaccine administration. The net cost was $9 per person; considering productivity costs, net savings were $75 per person. Marginal cost per life year gained was $2100. Universal adolescent vaccination is also economically attractive in the United States but less attractive in regions with incidence rates below 3 cases per 100,000 per year. CONCLUSIONS: Hepatitis B vaccine can be delivered in North American schools at a reasonable cost. Adolescent vaccination is economically attractive in North American regions of high and average incidence rates. Our analysis supports vaccination in adolescents who remain at risk for hepatitis B virus infection. PMID:9807529

  1. Induction of hepatic enzymes by methaqualone and effect on warfarin-induced hypoprothrombinemia.

    PubMed

    Mathur, P P; Smyth, R D; Herczeg, T; Reavey-Cantwell, N H

    1976-01-01

    The effect of methaqualone on the induction of hepatic enzymes was evaluated in rats and compared with that of phenobarbital by measuring effects on hexobarbital and methaqualone hypnosis, plasma and tissue levels of methaqualone, hepatic aniline hydroxylase and aminopyrine demethylase activity and warfarin-induced hypoprothrombinemia. Maximal reductions in hexobarbital hypnosis occurred 3 days after daily administration of 60 mg of methaqualone per kg per day. At this time, the activities of aniline hydroxylase and aminopyrine demethylase were increased 60 and 139%, respectively, and hepatic microsomal proteins increased 15% above controls in methaqualone-pretreated animals. Methaqualone altered its own metabolism as demonstrated by a 48% reduction in methaqualone hypnosis in pretreated animals. The extent and duration of induction by phenobarbital was considerably greater than methaqualone in all experiments. Methaqualone pretreatment did not affect warfarin-induced hypoprothrombinemia, whereas phenobarbital-pretreated animals showed a 32 to 64% reduction in response to the anticoagulant. These studies indicate that methaqualone is a relatively weak inducer of hepatic drug-metabolizing enzymes and has no effect on the anticoagulant acitivty of warfarin.

  2. Effect of embolic microspheres in the treatment of primary hepatic carcinoma.

    PubMed

    Wang, K B; Sui, H; Li, W; Cui, L M; Bai, B

    2016-01-01

    The purpose of this study was to evaluate the clinical effect of embolic microspheres in the treatment of primary hepatic carcinoma. Fifty-eight patients who were confirmed with primary hepatic carcinoma by imaging were retrospectively analyzed. They were firstly perfused with 50 mg of oxaliplatin and 40 mg of epirubicin. Embolic microspheres were then injected into the distal end of targeted blood vessels. After this procedure, dynamic observation was carried out until tumor stain disappeared. Liver function and blood indexes were reexamined on days 5, 6, 7 and 28 after treatment, and moreover, the liver was examined with Magnetic Resonance Imaging (MRI) or computed tomography (CT). Compared to traditional lipiodol embolization, embolic microspheres did not aggregate the damage on liver function and the imaging examination suggested necrosis of some tumor tissues. Embolic microspheres proved to be effective in treating primary hepatic carcinoma. It produces no damage on liver function and can lead to significant shrinkage of hepatic carcinoma and necrosis of some tumor tissues. Embolic microspheres, which merely block distal branches of tumor-feeding artery, can avoid collateral circulation induced by permanent blocking, thus achieve a good treatment effect.

  3. Protective Effects of Alisma orientale Extract against Hepatic Steatosis via Inhibition of Endoplasmic Reticulum Stress.

    PubMed

    Jang, Min-Kyung; Han, Yu-Ran; Nam, Jeong Soo; Han, Chang Woo; Kim, Byung Joo; Jeong, Han-Sol; Ha, Ki-Tae; Jung, Myeong Ho

    2015-01-01

    Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. Alisma orientale Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of Alisma orientale (MEAO) against ER stress-induced hepatic steatosis in vitro and in vivo. MEAO inhibited the tunicamycin-induced increase in luciferase activity of ER stress-reporter constructs containing ER stress response element and ATF6 response element. MEAO significantly inhibited tunicamycin-induced ER stress marker expression including GRP78, CHOP, and XBP-1 in tunicamycin-treated Human hepatocellular carcinoma (HepG2) cells and the livers of tunicamycin-injected mice. It also inhibited tunicamycin-induced accumulation of cellular triglyceride. Similar observations were made under physiological ER stress conditions such as in palmitate (PA)-treated HepG2 cells and the livers of high-fat diet (HFD)-induced obese mice. MEAO repressed hepatic lipogenic gene expression in PA-treated HepG2 cells and the livers of HFD obese mice. Furthermore, MEAO repressed very low-density lipoprotein receptor (VLDLR) expression and improved ApoB secretion in the livers of tunicamycin-injected mice or HFD obese mice as well as in tunicamycin or PA-treated HepG2 cells. Alismol, a guaiane-type sesquiterpenes in Alisma orientale, inhibited GRP78 expression in tunicamycin-treated HepG2 cells. In conclusion, MEAO attenuates ER stress and prevents hepatic steatosis pathogenesis via inhibition of expression of the hepatic lipogenic genes and VLDLR, and enhancement of ApoB secretion. PMID:26540043

  4. Protective Effects of Alisma orientale Extract against Hepatic Steatosis via Inhibition of Endoplasmic Reticulum Stress.

    PubMed

    Jang, Min-Kyung; Han, Yu-Ran; Nam, Jeong Soo; Han, Chang Woo; Kim, Byung Joo; Jeong, Han-Sol; Ha, Ki-Tae; Jung, Myeong Ho

    2015-11-02

    Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. Alisma orientale Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of Alisma orientale (MEAO) against ER stress-induced hepatic steatosis in vitro and in vivo. MEAO inhibited the tunicamycin-induced increase in luciferase activity of ER stress-reporter constructs containing ER stress response element and ATF6 response element. MEAO significantly inhibited tunicamycin-induced ER stress marker expression including GRP78, CHOP, and XBP-1 in tunicamycin-treated Human hepatocellular carcinoma (HepG2) cells and the livers of tunicamycin-injected mice. It also inhibited tunicamycin-induced accumulation of cellular triglyceride. Similar observations were made under physiological ER stress conditions such as in palmitate (PA)-treated HepG2 cells and the livers of high-fat diet (HFD)-induced obese mice. MEAO repressed hepatic lipogenic gene expression in PA-treated HepG2 cells and the livers of HFD obese mice. Furthermore, MEAO repressed very low-density lipoprotein receptor (VLDLR) expression and improved ApoB secretion in the livers of tunicamycin-injected mice or HFD obese mice as well as in tunicamycin or PA-treated HepG2 cells. Alismol, a guaiane-type sesquiterpenes in Alisma orientale, inhibited GRP78 expression in tunicamycin-treated HepG2 cells. In conclusion, MEAO attenuates ER stress and prevents hepatic steatosis pathogenesis via inhibition of expression of the hepatic lipogenic genes and VLDLR, and enhancement of ApoB secretion.

  5. Protective Effects of Alisma orientale Extract against Hepatic Steatosis via Inhibition of Endoplasmic Reticulum Stress

    PubMed Central

    Jang, Min-Kyung; Han, Yu-Ran; Nam, Jeong Soo; Han, Chang Woo; Kim, Byung Joo; Jeong, Han-Sol; Ha, Ki-Tae; Jung, Myeong Ho

    2015-01-01

    Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. Alisma orientale Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of Alisma orientale (MEAO) against ER stress-induced hepatic steatosis in vitro and in vivo. MEAO inhibited the tunicamycin-induced increase in luciferase activity of ER stress-reporter constructs containing ER stress response element and ATF6 response element. MEAO significantly inhibited tunicamycin-induced ER stress marker expression including GRP78, CHOP, and XBP-1 in tunicamycin-treated Human hepatocellular carcinoma (HepG2) cells and the livers of tunicamycin-injected mice. It also inhibited tunicamycin-induced accumulation of cellular triglyceride. Similar observations were made under physiological ER stress conditions such as in palmitate (PA)-treated HepG2 cells and the livers of high-fat diet (HFD)-induced obese mice. MEAO repressed hepatic lipogenic gene expression in PA-treated HepG2 cells and the livers of HFD obese mice. Furthermore, MEAO repressed very low-density lipoprotein receptor (VLDLR) expression and improved ApoB secretion in the livers of tunicamycin-injected mice or HFD obese mice as well as in tunicamycin or PA-treated HepG2 cells. Alismol, a guaiane-type sesquiterpenes in Alisma orientale, inhibited GRP78 expression in tunicamycin-treated HepG2 cells. In conclusion, MEAO attenuates ER stress and prevents hepatic steatosis pathogenesis via inhibition of expression of the hepatic lipogenic genes and VLDLR, and enhancement of ApoB secretion. PMID:26540043

  6. Effect of tomato extract supplementation against high-fat diet-induced hepatic lesions.

    PubMed

    Melendez-Martinez, Antonio J; Nascimento, Andre F; Wang, Yan; Liu, Chun; Mao, Yilei; Wang, Xiang-Dong

    2013-08-01

    Higher intake of tomatoes or tomato-based products has been associated with lower risk for liver cancer. In this study, we investigated the effects of supplementing tomato extract (TE), which contains mainly lycopene (LY) and less amounts of its precursors, phytoene (PT) and phytofluene (PTF) against high-fat-diet related hepatic inflammation and lipid profiles, and carcinogenesis. Four groups of rats were injected with a hepatic carcinogen, diethylnitrosamine (DEN) and then fed either Lieber-DeCarli control diet (35% fat, CD) or high fat diet (71% fat, HFD) with or without TE supplementation for 6 weeks. Results showed that the supplementation of TE significantly decreased the multiplicity of both inflammatory foci and altered hepatic foci (AHF) expressing placental form glutathione-S transferase (p-GST) in the liver of HFD-fed rats. High-performance liquid chromatography (HPLC) analysis showed that TE supplementation results in a significantly higher accumulation of both PT and PTF than LY in livers of rats. In addition, the TE supplementation led to a decrease of plasma cholesterol levels but an overall increase in hepatic lipids which is associated with changes in the genes on lipid metabolism, including the peroxisome proliferator-activated receptor gamma (PPARγ) and the sterol-regulatory element binding protein (SREBP-1). These data suggest that TE supplementation decreases hepatic inflammation and plasma total cholesterol associated with high dietary fat intake. Moreover, TE supplementation results in an accumulation of hepatic PT and PTF as well as increased lipogenesis suggesting further investigation into their biological function(s). PMID:24273751

  7. Paediatric extracranial germ-cell tumours.

    PubMed

    Shaikh, Furqan; Murray, Matthew J; Amatruda, James F; Coleman, Nicholas; Nicholson, James C; Hale, Juliet P; Pashankar, Farzana; Stoneham, Sara J; Poynter, Jenny N; Olson, Thomas A; Billmire, Deborah F; Stark, Daniel; Rodriguez-Galindo, Carlos; Frazier, A Lindsay

    2016-04-01

    Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups. PMID:27300675

  8. Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment

    PubMed Central

    Venkatakrishnan, Karthik; Liu, Yi; Noe, Dennis; Mertz, Jaime; Bargfrede, Michael; Marbury, Thomas; Farbakhsh, Kambiz; Oliva, Cristina; Milton, Ashley

    2014-01-01

    Aims To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT®) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. Methods Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). Results Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6–132%) and 119% (90% confidence interval, 94.1–151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg). Conclusions These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations. PMID:24134216

  9. Uveal tumour resection

    PubMed Central

    Char, D.; Miller, T.; Crawford, J

    2001-01-01

    AIM—To review the ocular retention rates, visual results, and metastases in uveal tumours managed with eye wall resection techniques.
METHODS—This was a retrospective analysis of consecutive local uveal tumour resections performed by a single surgeon. All enucleation specimens were reviewed by one author. Both parametric and non-parametric analysis of data were performed.
RESULTS—138 eyes were scheduled for eye wall resection surgery. The mean age was 52 years (range 11-86 years). Tumours involved predominantly the iris in 14 cases, iris-ciliary body in 57, ciliary body alone in 18 patients, and in 49 cases the choroid was involved (ciliochoroidal, iris-ciliary body-choroid, or choroid). 125 eyes harboured melanomas; posterior tumours were more likely to have epithelioid cells (p<0.05). The mean follow up was 6 years. The mean clock hours in iris and iris-ciliary body tumours was 3.5. In tumours that involved the choroid the mean largest diameter was 12.9 mm and the mean thickness 8.5 mm. 105 of 138 (76%) eyes were retained. Histological assessment of surgical margins did not correlate evidence of tumour in enucleated eyes or metastatic disease. Surgical margins of more anterior tumours were more likely to be clear on histological evaluation (p<0.05). Approximately 53% of retained eyes had a final visual acuity of ⩾20/40; visual results were significantly better in more anteriorly located tumours (p<0.05). All retained iris tumour cases had ⩾20/40 final visual acuity. In tumours that involved the choroid nine of 31 retained eyes kept that level of visual acuity. Eight patients developed metastases; all metastatic events developed in patients with tumours that involved the choroid, and seven of eight were mixed cell melanomas.
CONCLUSIONS—76% of eyes were retained and 53% of these had a final visual acuity of ⩾20/40. Only 7% of uveal melanoma patients developed metastatic disease with a mean follow up of 6 years. Survival did not

  10. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight

    PubMed Central

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-01-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. PMID:25648860

  11. Tumour nuclear oestrogen receptor beta 1 correlates inversely with parathyroid tumour weight.

    PubMed

    Haglund, Felix; Rosin, Gustaf; Nilsson, Inga-Lena; Juhlin, C Christofer; Pernow, Ylva; Norenstedt, Sophie; Dinets, Andrii; Larsson, Catharina; Hartman, Johan; Höög, Anders

    2015-03-01

    Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness. PMID:25648860

  12. Effect of maternal ethanol consumption on foetal and neonatal rat hepatic protein synthesis.

    PubMed Central

    Rawat, A K

    1976-01-01

    Effects of maternal ethanol consumption were investigated on the rates of protein synthehsis by livers of foetal and neonatal rats both in vivo and in vitro, and on the activities of enzymes involved in protein synthesis and degradation. The rates of general protein synthesis by ribosomes in vitro studied by measuring the incorporation of [14C]leucine into ribosomal protein showed that maternal ethanol consumption resulted in an inhibition of the rates of protein synthesis by both foetal and neonatal livers from the ethanol-fed group. The rates of incorporation of intravenously injected [14C]leucine into hepatic proteins were also significantly lower in the foetal, neonatal and adult livers from the ethanol-fed group. Incubation of adult-rat liver slices with ethanol resulted in an inhibition of the incorporation of [14C]leucine into hepatic proteins; however, this effect was not observed in the foetal liver slices. This effect of externally added ethanol was at least partially prevented by the addition of pyrazole to the adult liver slices. Pyrazole addition to foetal liver slices was without significant effect on the rates of protein synthesis. Cross-mixing experiments showed that the capacity of both hepatic ribosomes and pH5 enzyme fractions to synthesize proteins was decreased in the foetal liver from the ethanol-fed group. Maternal ethanol consumption resulted in a decrease in hepatic total RNA content, RNA/DNA ratio and ribosomal protein content in the foetal liver. Foetal hepatic DNA content was not significantly affected. Ethanol consumption resulted in a significant decrease in proteolytic activity and the activity of tryptophan oxygenase in the foetal, neonatal and adult livers. It is possible that the mechanisms of inhibition of protein synthesis observed here in the foetal liver after maternal ethanol consumption may be responsible for at least some of the changes observed in 'foetal alcohol syndrome'. PMID:1016246

  13. Attenuated Effects of Deep-Sea Water on Hepatic Apoptosis in STZ-Induced Diabetic Rats.

    PubMed

    Hsu, Tsai-Ching; Chiu, Chun-Ching; Lin, Hsou-Lin; Kao, Tseng-Wei; Chen, Li-Jeng; Wu, Li-Yi; Huang, Chih-Yang; Tzang, Bor-Show

    2015-06-30

    Diabetes mellitus (DM) is a metabolic disorder and increasing evidences have indicated a connection between DM and hepatic abnormality. Deep-sea water (DSW) has been applied in many fields, especially in medicine; herein, we investigated the influence of DSW on hepatic apoptosis in streptozocin (STZ)-induced diabetes rats. Our experimental results firstly demonstrated the beneficial effects of 1×DSW, 2×DSW and 3×DSW in alleviating hepatic apoptosis in STZ-induced diabetic rats. We demonstrated that 1×DSW, 2×DSW and 3×DSW significantly suppressed the caspase-3 activity and TUNEL-positive cells in livers of STZ-induced diabetic rats. Significant reductions of both Fas-dependent and mitochondrial-dependent apoptotic molecules were also detected in livers of STZ-induced diabetic rats receiving DSW. Additionally, apoptotic signaling molecules such as phosphorylated IκB-α and NF-κB were significantly reduced in livers of DSW-treated STZ-induced diabetic rats. These findings indicate hepatic protective effects of DSW on DM and suggest DSW as a possible ingredient for health food. PMID:26014125

  14. Attenuated Effects of Deep-Sea Water on Hepatic Apoptosis in STZ-Induced Diabetic Rats.

    PubMed

    Hsu, Tsai-Ching; Chiu, Chun-Ching; Lin, Hsou-Lin; Kao, Tseng-Wei; Chen, Li-Jeng; Wu, Li-Yi; Huang, Chih-Yang; Tzang, Bor-Show

    2015-06-30

    Diabetes mellitus (DM) is a metabolic disorder and increasing evidences have indicated a connection between DM and hepatic abnormality. Deep-sea water (DSW) has been applied in many fields, especially in medicine; herein, we investigated the influence of DSW on hepatic apoptosis in streptozocin (STZ)-induced diabetes rats. Our experimental results firstly demonstrated the beneficial effects of 1×DSW, 2×DSW and 3×DSW in alleviating hepatic apoptosis in STZ-induced diabetic rats. We demonstrated that 1×DSW, 2×DSW and 3×DSW significantly suppressed the caspase-3 activity and TUNEL-positive cells in livers of STZ-induced diabetic rats. Significant reductions of both Fas-dependent and mitochondrial-dependent apoptotic molecules were also detected in livers of STZ-induced diabetic rats receiving DSW. Additionally, apoptotic signaling molecules such as phosphorylated IκB-α and NF-κB were significantly reduced in livers of DSW-treated STZ-induced diabetic rats. These findings indicate hepatic protective effects of DSW on DM and suggest DSW as a possible ingredient for health food.

  15. The therapeutic effect of TNFR1-selective antagonistic mutant TNF-alpha in murine hepatitis models.

    PubMed

    Shibata, Hiroko; Yoshioka, Yasuo; Ohkawa, Akiko; Abe, Yasuhiro; Nomura, Tetsuya; Mukai, Yohei; Nakagawa, Shinsaku; Taniai, Madoka; Ohta, Tsunetaka; Mayumi, Tadanori; Kamada, Haruhiko; Tsunoda, Shin-ichi; Tsutsumi, Yasuo

    2008-11-01

    Tumor necrosis factor-alpha (TNF-alpha) is critically involved in a wide variety of inflammatory pathologies, such as hepatitis, via the TNF receptor-1 (TNFR1). To develop TNFR1-targeted anti-inflammatory drugs, we have already succeeded in creating a TNFR1-selective antagonistic mutant TNF-alpha (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-alpha/TNFR1-mediated biological activity in vitro. In this study, we examined the therapeutic effect of R1antTNF in acute hepatitis using two independent experimental models, induced by carbon tetrachloride (CCl(4)) or concanavalin A (ConA). In a CCl(4)-induced model, treatment with R1antTNF significantly inhibited elevation in the serum level of ALT (alanine aminotransferase), a marker for liver damage. In a ConA-induced T-cell-mediated hepatitis model, R1antTNF also inhibited the production of serum immune activated markers such as IL-2 and IL-6. These R1antTNF-mediated therapeutic effects were as good as or better than those obtained using conventional anti-TNF-alpha antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-alpha antagonist in hepatitis.

  16. Gland-preserving surgery can effectively preserve gland function without increased recurrence in treatment of benign submandibular gland tumour.

    PubMed

    Min, Ruan; Zun, Zhang; Siyi, Li; Wenjun, Yang; Jian, Sun; Chenping, Zhang

    2013-10-01

    The most widely accepted treatment for neoplasms of the submandibular gland usually involves excision of the entire gland. Our aim was to establish a gland-preserving operation for benign tumours of the submandibular gland and evaluate its efficacy. We treated 40 patients from January 2007 to December 2008 with benign submandibular gland tumours who were listed to have an operation that either preserved the gland or sacrificed it. Duration of operation, extent of injury to the nerve, postoperative function of the gland, aesthetic appearance, and recurrence were assessed. We found no significant difference in baseline characteristics among the 20 patients in each group (19 men; 21 women, mean (SD) age of 34 (33.8 ± 5.72) years. The extent of injury to the lingual nerve and submandibular branch, together with deformities of the facial contour, were significantly less in the group in which the gland was preserved. Postoperative salivary production and overall patients' satisfaction were also better in that group. There was no recurrence in either group during the follow up period of 38 months-5 years. The gland-preserving procedure has advantages over the typical approach in which the gland is sacrificed. There is less risk of injury to the nerve, less deformity of the facial contour, better preservation of function, and patients are more satisfied. The gland-preserving technique should therefore be the first choice for management of benign submandibular tumours.

  17. Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response

    PubMed Central

    Habets, Thomas H. P. M.; Oth, Tammy; Houben, Ans W.; Huijskens, Mirelle J. A. J.; Senden-Gijsbers, Birgit L. M. G.; Schnijderberg, Melanie C. A.; Brans, Boudewijn; Dubois, Ludwig J.; Lambin, Philippe; De Saint-Hubert, Marijke; Germeraad, Wilfred T. V.; Tilanus, Marcel G. J.; Mottaghy, Felix M.

    2016-01-01

    Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isotypes. Likewise, we demonstrated that treatment of tumour-bearing Balb/C mice with DC stimulating growth factor Flt3-L did neither modulate the magnitude nor the composition of the humoral immune response. Finally, we evaluated the immune infiltrate and Ig isotype content of the tumour tissue using flow cytometry and found no differences between treatment groups that were indicative for local antibody production. In conclusion, we demonstrate that the 67NR mammary carcinoma in Balb/C mice is associated with a pre-existing antibody response. And, we show that in tumour-bearing Balb/C mice with abscopal tumour regression such pre-existing antibody responses are not altered upon fractionated RT and/or DC stimulation with Flt3-L. Our research indicates that evaluating the humoral immune response in the setting of abscopal tumour regression is not invariably associated with therapeutic effects. PMID:27427766

  18. Effects of recombinant human adenovirus-p53 on the regression of hepatic fibrosis

    PubMed Central

    Liu, Yehong; Yang, Puye; Chen, Na; Lin, Shumei; Liu, Min

    2016-01-01

    Hepatic fibrosis is a scarring process that may progress to hepatic cirrhosis and even hepatic carcinoma if left untreated. Hepatic stellate cells (HSCs) play essential roles in the development of hepatic fibrosis. The tumor suppressor protein p53 is a transcription factor that is involved in cell proliferation, cell cycle regulation, apoptosis and DNA repair. Recombinant human adenovirus-p53 (Ad-p53) has been demonstrated to act as a promising antitumor gene therapy in various types of cancer. However, there is limited infomration regarding the therapeutic effect of Ad-p53 on the regression of hepatic fibrosis. In order to examine the underlying molecular mechanism responsible for the effects of Ad-p53 on HSCs, a rat model of hepatic fibrosis was established and HSC-T6 cells were cultured under different conditions. The expression of p53, transforming growth factor (TGF-β1) and α-smooth muscle actin (α-SMA), which is a marker of activated HSCs, was detected by immunohistochemical assays and RT-qPCR. In vitro, five different concentrations (1×106, 5×106, 1×107, 2×107 and 5×107 PFU/ml) of Ad-p53 were selected for use in the MTT assay to analyze the proliferation of HSCs at 0, 24, 48 and 72 h. Flow cytometric analysis was applied to determine the effect of three different concentrations of Ad-p53 (5×106, 1×107 and 2×107 PFU/ml) on the cell cycle and the apoptosis of HSC-T6 cells at 24 and 48 h. The results of immunohistochemical studies and RT-qPCR showed that Ad-p53 upregulated the expression of p53, and downregulated the expression of TGF-β1 and α-SMA. The MTT assay revealed that when treated with various doses of Ad-p53, the proliferation of HSCs was inhibited within a certain range of concentrations and time periods. Analysis of flow cytometric data showed that Ad-p53 arrested the cell cycle in G1 phase and significantly induced apoptosis. Taken together, these findings suggest that Ad-p53 promotes apoptosis and inhibits the proliferation of HSCs in

  19. Adult thymus transplantation with allogeneic intra-bone marrow–bone marrow transplantation from same donor induces high thymopoiesis, mild graft-versus-host reaction and strong graft-versus-tumour effects

    PubMed Central

    Miyake, Takashi; Hosaka, Naoki; Cui, Wenhao; Nishida, Teruhisa; Takaki, Takashi; Inaba, Muneo; Kamiyama, Yasuo; Ikehara, Susumu

    2009-01-01

    Although allogeneic bone marrow transplantation (BMT) plus donor lymphocyte infusion (DLI) is performed for solid tumours to enhance graft-versus-tumour (GVT) effects, a graft-versus-host reaction (GVHR) is also elicited. We carried out intra-bone marrow–bone marrow transplantation (IBM-BMT) plus adult thymus transplantation (ATT) from the same donor to supply alloreactive T cells continually. Normal mice treated with IBM-BMT + ATT survived for a long time with high donor-derived thymopoiesis and mild GVHR. The percentage of CD4+ FoxP3+ regulatory T cells in the spleen of the mice treated with IBM-BMT + ATT was lower than in normal B6 mice or mice treated with IBM-BMT alone, but higher than in mice treated with IBM-BMT + DLI; the mice treated with IBM-BMT + DLI showed severe GVHR. In tumour-bearing mice, tumour growth was more strongly inhibited by IBM-BMT + ATT than by IBM-BMT alone. Mice treated with IBM-BMT + a high dose of DLI also showed tumour regression comparable to that of mice treated with IBM-BMT + ATT but died early of GVHD. By contrast, mice treated with IBM-BMT + a low dose of DLI showed longer survival but less tumour regression than the mice treated with IBM-BMT + ATT. Histologically, significant numbers of CD8+ T cells were found to have infiltrated the tumour in the mice treated with IBM-BMT + ATT. The number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling (TUNEL)-positive apoptotic tumour cells also significantly increased in the mice treated with IBM-BMT + ATT. Allogeneic IBM-BMT + ATT thus can induce high thymopoiesis, preserving strong GVT effects without severe GVHR. PMID:18778285

  20. Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach

    PubMed Central

    Lolas, Georgios; Bianchi, Arianna; Syrigos, Konstantinos N.

    2016-01-01

    It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination. PMID:26861829

  1. Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach.

    PubMed

    Lolas, Georgios; Bianchi, Arianna; Syrigos, Konstantinos N

    2016-01-01

    It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination. PMID:26861829

  2. Tumour-induced neoneurogenesis and perineural tumour growth: a mathematical approach

    NASA Astrophysics Data System (ADS)

    Lolas, Georgios; Bianchi, Arianna; Syrigos, Konstantinos N.

    2016-02-01

    It is well-known that tumours induce the formation of a lymphatic and a blood vasculature around themselves. A similar but far less studied process occurs in relation to the nervous system and is referred to as neoneurogenesis. The relationship between tumour progression and the nervous system is still poorly understood and is likely to involve a multitude of factors. It is therefore relevant to study tumour-nerve interactions through mathematical modelling: this may reveal the most significant factors of the plethora of interacting elements regulating neoneurogenesis. The present work is a first attempt to model the neurobiological aspect of cancer development through a system of differential equations. The model confirms the experimental observations that a tumour is able to promote nerve formation/elongation around itself, and that high levels of nerve growth factor and axon guidance molecules are recorded in the presence of a tumour. Our results also reflect the observation that high stress levels (represented by higher norepinephrine release by sympathetic nerves) contribute to tumour development and spread, indicating a mutually beneficial relationship between tumour cells and neurons. The model predictions suggest novel therapeutic strategies, aimed at blocking the stress effects on tumour growth and dissemination.

  3. The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of chemotherapy effects in some major tumour types--summary and conclusions.

    PubMed

    Glimelius, B; Bergh, J; Brandt, L; Brorsson, B; Gunnars, B; Hafström, L; Haglund, U; Högberg, T; Janunger, K G; Jönsson, P E; Karlsson, G; Kimby, E; Lamnevik, G; Nilsson, S; Permert, J; Ragnhammar, P; Sörenson, S; Nygren, P

    2001-01-01

    This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent

  4. Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells.

    PubMed

    García-Rivera, Dagmar; Delgado, René; Bougarne, Nadia; Haegeman, Guy; Berghe, Wim Vanden

    2011-06-01

    Vimang is a standardized extract derived from Mango bark (Mangifera Indica L.), commonly used as anti-inflammatory phytomedicine, which has recently been used to complement cancer therapies in cancer patients. We have further investigated potential anti-tumour effects of glucosylxanthone mangiferin and indanone gallic acid, which are both present in Vimang extract. We observed significant anti-tumour effects of both Vimang constituents in the highly aggressive and metastatic breast cancer cell type MDA-MB231. At the molecular level, mangiferin and gallic acid both inhibit classical NFκB activation by IKKα/β kinases, which results in impaired IκB degradation, NFκB translocation and NFκB/DNA binding. In contrast to the xanthone mangiferin, gallic acid further inhibits additional NFκB pathways involved in cancer cell survival and therapy resistance, such as MEK1, JNK1/2, MSK1, and p90RSK. This results in combinatorial inhibition of NFκB activity by gallic acid, which results in potent inhibition of NFκB target genes involved in inflammation, metastasis, anti-apoptosis and angiogenesis, such as IL-6, IL-8, COX2, CXCR4, XIAP, bcl2, VEGF. The cumulative NFκB inhibition by gallic acid, but not mangiferin, is also reflected at the level of cell survival, which reveals significant tumour cytotoxic effects in MDA-MB231 cells. Altogether, we identify gallic acid, besides mangiferin, as an essential anti-cancer component in Vimang extract, which demonstrates multifocal inhibition of NFκB activity in the cancer-inflammation network.

  5. Transient effects of empty liposomes on hepatic macrophage populations in rats

    PubMed Central

    Pervin, Munmun; Golbar, Hossain M.; Bondoc, Alexandra; Izawa, Takeshi; Kuwamura, Mitsuru; Yamate, Jyoji

    2016-01-01

    Liposomes have been used as a vehicle for encapsulating chemicals or toxins in toxicological studies. We investigated the transient effects of empty liposomes on hepatic macrophages by applying a single intravenous injection at a dose of 10 ml/kg body weight in 6-week-old male F344 rats. One day after injection, the numbers of hepatic macrophages reacting to CD163, CD68, Iba-1, MHC class II, Gal-3 and CD204 were significantly increased in liposome-treated rats. CD163+ Kupffer cells and CD68+ macrophages with increased phagocytic activity in hepatic lobules were most sensitive. The histological architecture of the liver was not changed following liposome injection; however, hepatocytes showed increased proliferating activity, demonstrable with proliferation marker immunostaining and by an increase in gene profiles related to the cell cycle. In the liposome-treated rats, interestingly, AST and ALT values were significantly decreased, and MCP-1, IL-1β and TGF-β1 mRNAs were significantly increased. Collectively, the present study found that hepatic macrophages activated by liposomes can influence liver homeostasis. This information would be useful for background studies on liposomes. PMID:27182120

  6. Hepatoprotective effect of Caesalpinia gilliesii and Cajanus cajan proteins against acetoaminophen overdose-induced hepatic damage.

    PubMed

    Rizk, Maha Z; Aly, Hanan F; Abo-Elmatty, Dina M; Desoky, M M; Ibrahim, N; Younis, Eman A

    2016-05-01

    This study aims to evaluate two proteins derived from the seeds of the plants Cajanus cajan (Leguminosae) and Caesalpinia gilliesii (Leguminosae) for their abilities to ameliorate the toxic effects of chronic doses of acetoaminphen (APAP) through the determination of certain biochemical parameters including liver marker enzymes: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin. Also, total protein content and hepatic marker enzyme, lactate dehydrogenase were studied. Moreover, liver antioxidants, glutathione (GSH), nitric oxide, and lipid peroxides were determined in this study. Hepatic adenosine triphosphatase (ATPase), adenylate energy charge (ATP, adenosine diphosphate, adenosine monophosphate, and inorganic phosphate), and phosphate potential, serum interleukin-6, tumor necrosis factor-α, and myeloperoxidase were also examined in the present study. On the other hand, histopathological examination of intoxicated and liver treated with both proteins was taken into consideration. The present results show disturbances in all biochemical parameters and hepatic toxicity signs including mild vascular congestion, moderate inflammatory changes with moderate congested sinusoids, moderate nuclear changes (pyknosis), moderate centrilobular necrosis, fatty changes, nuclear pyknosis vascular congestion, and change in fatty centrilobular necrosis liver. Improvement in all biochemical parameters studied was noticed as a result of treatment intoxicated liver with C. gilliesii and C. cajan proteins either paracetamol with or post paracetamol treatment. These results were documented by the amelioration signs in rat's hepatic architecture. Thus, both plant protein extracts can upregulate and counteract the inflammatory process, minimize damage of the liver, delay disease progression, and reduce its complications. PMID:24414985

  7. Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats.

    PubMed

    Mershiba, Sam Daniel; Dassprakash, M Velayutham; Saraswathy, Sundara Dhakshinamurthy

    2013-05-01

    Arsenic has a long history as a potent human poison, chronic exposure over a period of time may result in the manifestation of toxicity in practically all systems of the body. In the present investigation the efficacy of naringenin (NRG), a naturally occurring citrus flavanone against arsenic-induced hepatotoxic and nephrotoxic manifestations have been studied in rats. Arsenic trioxide was administered orally at the dose of 2 mg/kg/day with or without combination of NRG (20 or 50 mg/kg/day) for 28 days. At the end of the experimental period the hepatic and renal dysfunction was evaluated by histological examination, serum biomarkers and markers of oxidative stress; lipid peroxidation (LPO), reduced glutathione (GSH) and antioxidant enzymes. Arsenic intoxication increased serum bilirubin, urea, uric acid and creatinine levels, additionally enhanced the activities of hepatic marker enzymes aspartate transaminase, alanine transaminase and alkaline phosphatase. Also, the hepatic and renal tissues showed a marked elevation in LPO levels with a decrease in GSH content and the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase on arsenic treatment. Simultaneous treatment with NRG restored the activities of serum biomarkers and antioxidant enzymes in the tissues in a dose-dependent manner. Furthermore, the histopathological studies confirmed the protective effect of NRG co-treatment by reducing the pathological changes due to arsenic intoxication in both liver and kidney. Thus, our present study demonstrates that NRG has a potential to protect arsenic-induced oxidative hepatic and renal dysfunction.

  8. Hepatotherapeutic effect of Aloe vera in alcohol-induced hepatic damage.

    PubMed

    Saka, W A; Akhigbe, R E; Ishola, O S; Ashamu, E A; Olayemi, O T; Adeleke, G E

    2011-07-15

    There is a lack of reliable hepatotherapeutic drugs in modern medicine in the management of alcohol/drug-induced liver damage. Aloe vera extract has been used in folklore medicine for its medicinal values. This study evaluates the hepatotherapeutic activity of aqueous extract of Aloe vera gel in rats. Sprague-Dawley rats were divided into three groups; the negative control, positive control and the extract-treated groups. The negative control received only distilled water daily. The positive control received alcohol, while the extract-treated group received aqueous extract of Aloe vera and alcohol. Hepatotoxicity was induced in the positive control and extract-treated rats with alcohol. The hepatotherapeutic effect was evaluated by performing an assay of the serum total bilirubin, alkaline phosphatase, aspartate and alanine transaminases and liver histopathology. Alanine transaminase activities were comparable in all groups. Alcohol treatment alone significantly (p < 0.05) increased total serum bilirubin, alkaline phosphatase and aspartate transaminase activities. Alcohol-induced hepatic dysfunction was abrogated by Aloe vera extract. Histopathological examination revealed that alcohol induced hepatic damage. Aloe vera treatment maintained hepatic architecture similar to that seen in the control. This study shows that aqueous extract of Aloe vera gel is hepatotherapeutic and thus lends credence to the use of the plant in folklore medicine in the management of alcohol-induced hepatic dysfunction.

  9. Viral Hepatitis

    MedlinePlus

    ... Public Home » For Veterans and the Public Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... the Public Veterans and Public Home How is Hepatitis C Treated? Find the facts about the newest ...

  10. Mesenchymal phosphaturic tumour: early detection of recurrence

    PubMed Central

    Allevi, Fabiana; Rabbiosi, Dimitri; Mandalà, Marco; Colletti, Giacomo

    2014-01-01

    The case of a recurrent phosphaturic mesenchymal tumour of the maxillary sinus 10 years after the first surgical excision is reported. The neoplasm first presented with paraneoplastic osteomalacia causing a pathological femur fracture. A right maxillary sinus tumour was identified and treated thereafter. The patient had no local symptoms and serum electrolytes returned to normal after surgical removal of the tumour. However, 10 years later, the patient's urine Ca and P levels increased and an octreoscan detected a new tumour in the right maxillary sinus. Early diagnosis prevented the effects of the paraneoplastic activity of the neoplasm. This case emphasises the importance of specific, close follow-up, because the neoplasm rarely produces local signs indicating its position. To our knowledge, this is the first reported case of a late relapse presenting without relevant symptoms (local pain or swelling or pathological fractures). PMID:24827649

  11. Hepatitis delta virus mutant: effect on RNA editing.

    PubMed

    Wu, T T; Bichko, V V; Ryu, W S; Lemon, S M; Taylor, J M

    1995-11-01

    During the replication cycle of hepatitis delta virus (HDV), RNA editing occurs at position 1012 on the 1679-nucleotide RNA genome. This changes an A to G in the amber termination codon, UAG, of the small form of the delta antigen (delta Ag). The resultant UGG codon, tryptophan, allows the translation of a larger form of the delta Ag with a 19-amino-acid C-terminal extension. Using HDV cDNA-transfected cells, we examined the editing potential of HDV RNA mutated from G to A at 1011 on the antigenome, adjacent to normal editing site at 1012. Four procedures were used to study not only the editing of the A at 1012, but also that of the new A at 1011: (i) nucleotide sequencing, (ii) a PCR-based RNA-editing assay, (iii) immunoblot assays, and (iv) immunofluorescence. Five findings are reported. (i) Even after the mutation at 1011, editing still occurred at 1012. (ii) Site 1011 itself now acted as a novel RNA-editing site. (iii) Sites 1011 and 1012 were edited independently. (iv) At later times, both sites became edited, thereby allowing the synthesis of the large form of the delta Ag (delta Ag-L). (v) Via immunofluorescence, such double editing became apparent as a stochastic event, in that groups of cells arose in which the changes had taken place. Evaluation of these findings and of those from previous studies of the stability of the HDV genomic sequence (H.J. Netter et al., J. Virol. 69:1687-1692, 1995) supports both the recent reevaluation of HDV RNA editing as occurring on antigenomic RNA (Casey and Gerin, personal communication) and the interpretation that editing occurs via the RNA-modifying enzyme known as DRADA.

  12. The Effect of Policy Changes on Hepatitis A Vaccine Uptake in Arizona Children, 1995–2008

    PubMed Central

    Ernst, Kacey C.; Pogreba-Brown, Kristen; Rasmussen, Lisa; Erhart, Laura M.

    2011-01-01

    Objective In 1995, the first hepatitis A vaccines became available for use. At that time, Arizona had the highest hepatitis A incidence of all 50 states. During that same time period, the Arizona State Immunization Information System (ASIIS) was created to collect information on all immunizations given in the state. Four state-level hepatitis A vaccination policies were enacted according to Centers for Disease Control and Prevention recommendations and local initiatives from 1996 to 2005. Our primary objective was to assess the impact of these policies on vaccine uptake in children. Methods Immunization records from ASIIS were used to calculate yearly coverage of children with at least one reported hepatitis A vaccination between 1995 and 2008. Proportions vaccinated were calculated by age group (12–23 months, 24–59 months, 5–9 years, 10–14 years, and 15–19 years) for three regions: Maricopa County; Apache and Navajo counties; and the remaining 12 Arizona counties, which were grouped as one to reflect different target groups for the four policies examined. We calculated percent changes from before and after each policy implementation. Results Significantly different percent changes were detected among the three regions that related to the four policies implemented. Percent change in uptake was consistently higher in the regions that were targeted for that specific policy. Conclusions Analysis of ASIIS data revealed a major effect of hepatitis A policy recommendations on vaccine uptake in Arizona. Targeting high-risk populations through vaccine recommendations and child care entry requirements was highly successful in achieving higher vaccination coverage. PMID:21812173

  13. Viral Hepatitis

    MedlinePlus

    ... with hepatitis? How does a pregnant woman pass hepatitis B virus to her baby? If I have hepatitis B, what does my baby need so that she ... Can I breastfeed my baby if I have hepatitis B? More information on viral hepatitis What is hepatitis? ...

  14. Inhibition of Lysyl Oxidase and Lysyl Oxidase-Like Enzymes Has Tumour-Promoting and Tumour-Suppressing Roles in Experimental Prostate Cancer

    PubMed Central

    Nilsson, Maria; Adamo, Hanibal; Bergh, Anders; Halin Bergström, Sofia

    2016-01-01

    Lysyl oxidase (LOX) and LOX-like (LOXL) enzymes are key players in extracellular matrix deposition and maturation. LOX promote tumour progression and metastasis, but it may also have tumour-inhibitory effects. Here we show that orthotopic implantation of rat prostate AT-1 tumour cells increased LOX and LOXLs mRNA expressions in the tumour and in the surrounding non-malignant prostate tissue. Inhibition of LOX enzymes, using Beta-aminopropionitrile (BAPN), initiated before implantation of AT-1 cells, reduced tumour growth. Conversely, treatment that was started after the tumours were established resulted in unaffected or increased tumour growth. Moreover, treatment with BAPN did not suppress the formation of spontaneous lymph node metastases, or lung tumour burden, when tumour cells were injected intravenously. A temporal decrease in collagen fibre content, which is a target for LOX, was observed in tumours and in the tumour-adjacent prostate tissue. This may explain why early BAPN treatment is more effective in inhibiting tumour growth compared to treatment initiated later. Our data suggest that the enzymatic function of the LOX family is context-dependent, with both tumour-suppressing and tumour-promoting properties in prostate cancer. Further investigations are needed to understand the circumstances under which LOX inhibition may be used as a therapeutic target for cancer patients. PMID:26804196

  15. Enzymic degradation of plasma arginine using arginine deiminase inhibits nitric oxide production and protects mice from the lethal effects of tumour necrosis factor alpha and endotoxin.

    PubMed Central

    Thomas, J Brandon; Holtsberg, Frederick W; Ensor, C Mark; Bomalaski, John S; Clark, Mike A

    2002-01-01

    Septic shock is mediated in part by nitric oxide (NO) and tumour necrosis factor alpha (TNFalpha). NO is synthesized primarily from extracellular arginine. We tested the ability of an arginine-degrading enzyme to inhibit NO production in mice and to protect mice from the hypotension and lethality that occur after the administration of TNFalpha or endotoxin. Treatment of BALB/c mice with arginine deiminase (ADI) formulated with succinimidyl succinimide polyethylene glycol of M(r) 20000 (ADI-SS PEG(20000)) eliminated all measurable plasma arginine (from normal levels of approximately 155 microM arginine to 2 microM). In addition, ADI-SS PEG(20000) also inhibited the production of NO, as quantified by plasma nitrate+nitrite. Treatment of mice with TNFalpha or endotoxin resulted in a dose-dependent increase in NO production and lethality. Pretreatment of mice with ADI-SS PEG(20000) resulted in increased resistance to the lethal effects of TNFalpha and endotoxin. These observations are consistent with NO production resulting, to some extent, from the metabolism of extracellular arginine. The toxic effects of TNFalpha and endotoxin may be partially inhibited by enzymic degradation of plasma arginine by ADI-SS PEG(20000). Interestingly, pretreatment with ADI-SS PEG(20000) did not inhibit the anti-tumour activity of TNFalpha in vitro or in vivo. This treatment may allow greater amounts of TNFalpha, as well as other cytokines, to be administered while abrogating side effects such as hypotension and death. PMID:11964159

  16. Late preventive effects of trifluoperazine on carbon tetrachloride-induced hepatic necrosis

    SciTech Connect

    Villarruel, M.C.; Fernandez, G.; de Ferreyra, E.C.; de Fenos, O.M.; Castro, J.A.

    1986-04-01

    As a very preliminary test for a possible role of calmodulin in CCl/sub 4/-induced hepatic injury, we studied the effects of the anticalmodulin drug trifluoperazine (TFP) on several deleterious actions of CCl/sub 4/ on the liver. TFP administrated 30 min before or 6 or 10 hr after CCl/sub 4/ significantly prevented hepatic necrosis induced by the hepatotoxin at 24 hr but not at 72 hr. TFP did not modify the CCl/sub 4/ concentrations reaching the liver, or the intensity of the covalent binding of CCl/sub 4/-reactive metabolites to hepatic microsomal proteins or lipids or the CCl/sub 4/-induced cytochrome P-450 and glucose 6 phosphatase destruction. TFP administration decreased body temperature between 0 and 1 degree C in controls and between 1.2 and 3.5 degrees C in CCl/sub 4/-treated animals during the 24-hr observation period. When TFP-treated CCl/sub 4/-poisoned animals were kept normothermic, protective effects were eliminated. One possibility is that the protective effect of TFP might be due to a nonspecific action related to decreased body temperature. Alternatively, prevention might result from TFP inhibition of a late-occurring process critical for CCl/sub 4/-induced cell necrosis requiring calmodulin participation. If this alternative were in operation, protective consequences of this inhibitory effect of TFP should be either canceled or counteracted in the normothermic TFP + CCl/sub 4/-treated animal.

  17. Cost-effectiveness of sofosbuvir in the treatment of patients with hepatitis C.

    PubMed

    Leleu, H; Blachier, M; Rosa, I

    2015-04-01

    In France, 190,306 patients were suffering from chronic hepatitis C in 2012. These patients have a decreased life expectancy and are susceptible to complications associated with chronic hepatitis. Current treatments are poorly tolerated and their effectiveness varies depending on the genotype of the virus. Sofosbuvir, a new class of treatment, has demonstrated in five phase III trials sustained viral response (SVR) rates of over 90% across genotypes, higher than current treatments and has a tolerance profile similar to placebo. The objective was to determine the cost-effectiveness of using sofosbuvir in the treatment of chronic HCV infection. A Markov model was used to compare treatment strategies with and without sofosbuvir. The model simulated the natural history of HCV infection. SVR rates were based on data from clinical trials. Utilities associated with different stages of disease were based on data from the literature. French direct medical costs were used. Price for sofosbuvir was the price used in the early access program for severe fibrosis stages. The incremental cost-effectiveness ratio for sofosbuvir versus current reference treatments was € 16,278/QALY and varied from 40,000 €/QALY for F0 stages to 12,080 €/QALY for F4 stages. The sensitivity analyses carried out confirmed the robustness of this result. Sofosbuvir is a cost-effective treatment option for patients with hepatitis C.

  18. Local tumour hyperthermia as immunotherapy for metastatic cancer

    PubMed Central

    Toraya-Brown, Seiko; Fiering, Steven

    2014-01-01

    Abstract Local tumour hyperthermia for cancer treatment is currently used either for ablation purposes as an alternative to surgery or less frequently, in combination with chemotherapy and/or radiation therapy to enhance the effects of those traditional therapies. As it has become apparent that activating the immune system is crucial to successfully treat metastatic cancer, the potential of boosting anti-tumour immunity by heating tumours has become a growing area of cancer research. After reviewing the history of hyperthermia therapy for cancer and introducing methods for inducing local hyperthermia, this review describes different mechanisms by which heating tumours can elicit anti-tumour immune responses, including tumour cell damage, tumour surface molecule changes, heat shock proteins, exosomes, direct effects on immune cells, and changes in the tumour vasculature. We then go over in vivo studies that provide promising results showing that local hyperthermia therapy indeed activates various systemic anti-tumour immune responses that slow growth of untreated tumours. Finally, future research questions that will help bring the use of local hyperthermia as systemic immunotherapy closer to clinical application are discussed. PMID:25430985

  19. The Role of Liver Transplantation in the Management of Paediatric Liver Tumours

    PubMed Central

    Stringer, Mark D

    2007-01-01

    In recent years, considerable progress has been made in the treatment of children with hepatoblastoma largely due to effective pre-operative chemotherapy. Total hepatectomy and liver transplantation has emerged as an effective treatment for the small proportion of children with unresectable hepatoblastoma limited to the liver. A 5-year survival of 70% can be achieved in such cases. In contrast, the results of liver transplantation in children with hepatocellular cancer remain poor because these tumours are usually advanced with evidence of major vascular invasion and/or extrahepatic spread at the time of presentation. An exception is those children in whom the hepatocellular carcinoma is detected during surveillance of chronic liver disease – they typically have smaller tumours and frequently have a good prognosis after liver transplantation. The role of liver transplantation in children with other primary hepatic malignancies remains uncertain because experience is very limited. Liver transplantation is rarely needed in the management of children with benign liver tumours but, if other treatments have failed, it can be a life-saving intervention. PMID:17316514

  20. Protective effect of Indigofera aspalathoides against CCl4-induced hepatic damage in rats.

    PubMed

    Rajkapoor, B; Jayakar, B; Kavimani, S; Murugesh, N

    2006-01-01

    The alcoholic extract of stem of Indigofera aspalathoides was evaluated for its antihepatotoxic activity against CCl(4)-induced hepatic damage in rats. The activity was evaluated by using biochemical parameters, such as serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin and gama glutamate transpeptidase (GGTP). The histopathological changes of liver sample were compared with respective control. The extract showed remarkable hepatoprotective effect.

  1. Tumours of the thymus

    PubMed Central

    Sellors, T. Holmes; Thackray, A. C.; Thomson, A. D.

    1967-01-01

    Eighty-eight cases of thymoma are discussed with the object of trying to co-ordinate the histological and clinical features. The pathological specimens were in all cases obtained at operation. The pathology classification introduced by Thomson and Thackray in 1957 has been found to correspond adequately with the clinical pattern. The most common groups of tumours are basically epithelial and can be separated into five or six subdivisions, each of which has a separate pattern of behaviour. Lymphoid and teratomatous tumours also occur, but there were only two examples in this series. Clinically, separation of patients who suffered from myasthenia (38) and those who did not (50) affords the first main grouping. The majority of patients who had myasthenia gravis had tumours classified as epidermoid (19) and lymphoepithelial (14), the former with a more malignant appearance and behaviour than the latter. Removal of the tumour with or without radiation gave considerable and sometimes complete relief from myasthenic symptoms. Non-myasthenic thymoma (50) was usually discovered as a result of pressure signs or in the course of routine radiography. Spindle or oval celled tumours followed a benign pattern whereas undifferentiated thymoma was in every sense malignant, as also were teratomatous growths. Granulomatous or Hodgkin-like thymomas were of special interest and had an unpredictable course, some patients surviving many years after what was regarded as inadequate treatment. The place of radiotherapy as a pre- or post-operative agent complementary to surgery is discussed. Images PMID:6033387

  2. Salivary gland tumours.

    PubMed

    Speight, P M; Barrett, A W

    2002-09-01

    Salivary gland tumours are a relatively rare and morphologically diverse group of lesions. Although most clinicians and pathologists will have encountered the more common benign neoplasms, few have experience of the full range of salivary cancers, which are best managed in specialist centres. This review considers some current areas of difficulty and controversy in the diagnosis and management of these neoplasms. The classification of these lesions is complex, encompassing nearly 40 different entities, but precise classification and terminology is essential for an accurate diagnosis and for the allocation of tumours to prognostic groups. For many salivary tumours diagnosis is straightforward but the wide range of morphological diversity between and within tumour types means that a diagnosis may not be possible on small incisional biopsies and careful consideration of the clinical and pathological features together is essential. Although tumour grading is important and helpful, it is not an independent prognostic indicator and must be considered in the context of stage. Large malignancies tend to have a poor prognosis regardless of grade and even high-grade neoplasms may do well when they are small. A helpful guide to management of salivary cancers is the '4 cm rule'.

  3. Hepatic encephalopathy.

    PubMed

    Córdoba, Juan; Mínguez, Beatriz

    2008-02-01

    Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices. PMID:18293278

  4. Consensus on biomarkers for neuroendocrine tumour disease

    PubMed Central

    Oberg, Kjell; Modlin, Irvin M; De Herder, Wouter; Pavel, Marianne; Klimstra, David; Frilling, Andrea; Metz, David C; Heaney, Anthony; Kwekkeboom, Dik; Strosberg, Jonathan; Meyer, Timothy; Moss, Steven F; Washington, Kay; Wolin, Edward; Liu, Eric; Goldenring, James

    2016-01-01

    Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours. PMID:26370353

  5. Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours.

    PubMed

    Zaffryar-Eilot, Shelly; Marshall, Derek; Voloshin, Tali; Bar-Zion, Avinoam; Spangler, Rhyannon; Kessler, Ofra; Ghermazien, Haben; Brekhman, Vera; Suss-Toby, Edith; Adam, Dan; Shaked, Yuval; Smith, Victoria; Neufeld, Gera

    2013-10-01

    Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.

  6. Effect of human, bovine and ovine prolactin on DNA synthesis by organ cultures of benign human breast tumours.

    PubMed Central

    Welsch, C. W.; Dombroske, S. E.; McManus, M. J.; Calaf, G.

    1979-01-01

    Ten benign breast tumours from 9 female patients (8 with fibrocystic disease and 1 with fibroadenoma) and 1 male patient (with gynaecomastia) were processed into slices and individually cultured for 2 days in serum-free Medium 199. [3H]-TdR was added to the culture medium to assess DNA synthesis. The addition of human prolactin to the culture medium (500 ng/ml) significantly (0.05 greater than P greater than 0.01) increased DNA synthesis; all 9 biopsy specimens from the 9 female patients responded positively to this hormone. Ovine prolactin (500 ng/ml) and bovine prolactin (500 ng/ml) increased the mean incorporation of [3H]-TdR into extracted DNA and increased the mean number of [3H]-TdR-labelled cells, but this increase did not reach the 5% level of probability. The sole case of male breast dysplasia analysed in this study did not respond to either human, ovine or bovine prolactin. These results provide evidence that human prolactin and, to a lesser degree, ovine and bovine prolactin are direct mitogenic stimulants to the epithelium in human (female) benign breast tumours. PMID:575047

  7. In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model.

    PubMed

    Bergamo, A; Masi, A; Peacock, A F A; Habtemariam, A; Sadler, P J; Sava, G

    2010-01-01

    We have compared the organometallic arene complexes [(eta(6)-biphenyl)M(ethylenediamine)Cl](+) RM175 (M=Ru(II)) and its isostructural osmium(II) analogue AFAP51 (M=Os(II)) for their ability to induce cell detachment resistance from fibronectin, collagen IV and poly-l-lysine, and cell re-adhesion after treatment, their effects on cell migration and cell viability, on matrix metalloproteinases production, and on primary tumour growth of MCa mammary carcinoma, the effect of human serum albumin on their cytotoxicity. There are differences between ruthenium and osmium. The Os complex is up to 6x more potent than RM175 towards highly-invasive breast MDA-MB-231, human breast MCF-7 and human epithelial HBL-100 cancer cells, but whereas RM175 was active against MCa mammary carcinoma in vivo and caused metastasis reduction, AFAP51 was not. Intriguingly the presence of human serum albumin in the growth medium enhanced the cytotoxicity of both compounds. RM175 increased the resistance of MDA-MB-231 cells to detachment from substrates and both compounds inhibited the production of MMP-2. These data confirm the key role of ruthenium itself in anti-metastatic activity. It will be interesting to explore the activity of osmium arene complexes in other tumour models and the possibility of changing the non-arene ligands to tune the anticancer activity of osmium in vivo.

  8. Effects of atrazine on hepatic metabolism and endocrine homeostasis in rainbow trout (Oncorhynchus mykiss)

    SciTech Connect

    Salaberria, Iurgi Hansen, Bjorn Henrik; Asensio, Vega; Olsvik, Pal A.; Andersen, Rolf A.; Jenssen, Bjorn Munro

    2009-01-01

    The herbicide atrazine (ATZ) is one of the most widely used pesticides in the world and is now under scrutiny for its alleged capacity to disrupt the endocrine system. Exhibiting negligible interaction with the estrogen receptor (ER), ATZ's mode of action remains to be elucidated. ATZ may act as an inducer of the enzyme aromatase, which converts androgens to estrogens, although other mechanisms should also be taken into consideration such as impairment of hepatic metabolism. Therefore we administered juvenile rainbow trout (Oncorhynchus mykiss) a dose of either 2 or 200 {mu}g ATZ/kg, or of carrier control phosphate buffered saline (PBS) and we measured plasma concentrations of testosterone (T), 17beta-estradiol (E2) and vitellogenin (Vtg) 6 days after exposure. Simultaneously we analyzed hepatic gene expression of cytochrome P450 (CYP) 1A and pi-class glutathione S-transferase (GST-P), and catalase (CAT) activity. Although sex steroid levels showed no significant alterations, we found a dose-dependent increase in Vtg and a concomitant decrease in CYP1A. There was no effect of ATZ on GST-P mRNA levels but GST-P was positively correlated with CYP1A. Also, CYP1A was negatively correlated with liver CAT and E2, and varied with T concentrations in a hormetic manner. The results showed that ATZ can alter hepatic metabolism, induce estrogenic effects and oxidative stress in vivo, and that these effects are linked.

  9. Protective effect of thymoquinone against lead-induced hepatic toxicity in rats.

    PubMed

    Mabrouk, Aymen; Bel Hadj Salah, Imen; Chaieb, Wafa; Ben Cheikh, Hassen

    2016-06-01

    Lead (Pb) intoxication is a worldwide health problem which frequently affects the liver. This study was carried out to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver damage. Adult male rats were randomized into four groups: Control group received no treatment, Pb group was exposed to 2000 ppm Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per orally), and TQ group receiving only TQ. All treatments were applied for 5 weeks. Results indicated that Pb exposure increased hepatic Pb content, damaged hepatic histological structure (necrotic foci, hepatic strands disorganization, hypertrophied hepatocytes, cytoplasmic vacuolization, cytoplasmic loss, chromatin condensation, mononuclear cell infiltration, congestion, centrilobular swelling), and changed liver function investigated by plasma biochemical parameters (AST, ALT, ALP, γ-GT, LDH). Pb treatment also decreased total antioxidant status level and increased lipid peroxidation in the liver. Supplementation with TQ remarkably improved the Pb-induced adverse effects without significantly reducing the metal accumulation in the liver. In conclusion, our results indicate, for the first time, a protective effect of TQ against Pb-induced hepatotoxicity and suggest that this component might be clinically useful in Pb intoxication. PMID:26971798

  10. Hop bitter acids exhibit anti-fibrogenic effects on hepatic stellate cells in vitro.

    PubMed

    Saugspier, Michael; Dorn, Christoph; Thasler, Wolfgang E; Gehrig, Manfred; Heilmann, Jörg; Hellerbrand, Claus

    2012-04-01

    Female inflorescences of the hop plant Humulus lupulus L. contain a variety of secondary metabolites with bitter acids (BA) as quantitatively dominating secondary metabolites. The use of hops in beer brewing has a long history due to the antibacterial effects of the BA and their typical bitter taste. Furthermore, hop cones are used in traditional medicine and for pharmaceutical purposes. Recent studies indicate that BA may affect activity of the transcription factor NFκB. NFκB plays a key role in the activation process of hepatic stellate cells (HSC), which is the key event of hepatic fibrosis. The aim of this study was to investigate the effect of BA on HSC (activation) and their potential to inhibit molecular processes involved in the pathogenesis of hepatic fibrosis. HSC were isolated from murine and human liver tissue and incubated with a characterized fraction of bitter acids purified from a CO(2) hop extract. At a concentration of 25μg/ml BA started to induce LDH leakage. Already at lower concentrations BA lead to a dose dependent inhibition of HSC proliferation and inhibited IκB-α-phosphorylation, nuclear p65 translocation and binding activity in a dose dependent way (up to 10μg/ml). Accordingly, the same BA-doses inhibited the expression of pro-inflammatory and NFκB regulated genes as MCP-1 and RANTES, but did not affect expression of genes not related to NFκB signaling. In addition to the effect on activated HSC, BA inhibited the in vitro activation process of freshly isolated HSC as evidenced by delayed expression of collagen I and α-SMA mRNA and protein. Together, these findings indicate that BA inhibit NFκB activation, and herewith the activation and development of profibrogenic phenotype of HSC. Thus, bitter acids appear as potential functional nutrients for the prevention or treatment hepatic fibrosis in chronic liver disease.

  11. Simulation Shows That Early Treatment of Chronic Hepatitis B Infection Can Cut Deaths and Be Cost-Effective

    PubMed Central

    Post, Sarah E.; Sodhi, Neetu Khurana; Peng, Chia-hui; Wan, Kejia; Pollack, Henry J.

    2014-01-01

    Chronic hepatitis B affects more than a million people in the U.S. and causes 4,000 deaths each year, yet the costs and benefits of treatment have not been fully evaluated. Using a model that simulates disease progression, we compare treatment programs for hepatitis B that start at an early versus late stage of disease. Early care is shown to improve health, reduce premature deaths, and prevent expensive complications, making it highly cost-effective. Our results demonstrate the importance of linking hepatitis B screening to treatment, and illustrate how predictive models can be used to evaluate strategies for improving access to care. PMID:21289356

  12. A comparison of the inductive effects of phenobarbital, methaqualone, and methyprylon on hepatic mixed function oxidase enzymes in the rat.

    PubMed

    Reinke, L A; O'Connor, M F; Piepho, R W; Stohs, S J

    1975-05-01

    The effects of equal doses of three sedative-hypnotics, phenobarbital, methaqualone, and methyprylon, on the hepatic mixed function oxidase enzymes of the rat were investigated and compared. After 5 days of pretreatment, phenobarbital and methyprylon significantly increased aminopyrine demethylation, aniline hydroxylation, and cytochrome P-450 content in hepatic microsomes. Methaqualone pretreatment only increased hepatic aminopyrine demethylase activity and wet liver weights. After 29 days of pretreatment, phenobarbital significantly increases aminopyrine demethylase, aniline hydroxylase activity, liver weight and cytochrome P-450 content. Methaqualone only produced a significant increase in wet liver weight.

  13. Combined therapy of transcatheter hepatic arterial embolization with intratumoral dendritic cell infusion for hepatocellular carcinoma: clinical safety

    PubMed Central

    Nakamoto, Y; Mizukoshi, E; Tsuji, H; Sakai, Y; Kitahara, M; Arai, K; Yamashita, T; Yokoyama, K; Mukaida, N; Matsushima, K; Matsui, O; Kaneko, S

    2007-01-01

    The curative treatments for hepatocellular carcinoma (HCC), including surgical resection and radiofrequency ablation (RFA), do not prevent tumour recurrence effectively. Dendritic cell (DC)-based immunotherapies are believed to contribute to the eradication of the residual and recurrent tumour cells. The current study was designed to assess the safety and bioactivity of DC infusion into tumour tissues following transcatheter hepatic arterial embolization (TAE) for patients with cirrhosis and HCC. Peripheral blood mononuclear cells (PBMCs) were differentiated into phenotypically confirmed DCs. Ten patients were administered autologous DCs through an arterial catheter during TAE treatment. Shortly thereafter, some HCC nodules were treated additionally to achieve the curative local therapeutic effects. There was no clinical or serological evidence of adverse events, including hepatic failure or autoimmune responses in any patients, in addition to those due to TAE. Following the infusion of 111Indium-labelled DCs, DCs were detectable inside and around the HCC nodules for up to 17 days, and were associated with lymphocyte and monocyte infiltration. Interestingly, T lymphocyte responses were induced against peptides derived from the tumour antigens, Her-2/neu, MRP3, hTERT and AFP, 4 weeks after the infusion in some patients. The cumulative survival rates were not significantly changed by this strategy. These results demonstrate that transcatheter arterial DC infusion into tumour tissues following TAE treatment is feasible and safe for patients with cirrhosis and HCC. Furthermore, the antigen-non-specific, immature DC infusion may induce immune responses to unprimed tumour antigens, providing a plausible strategy to enhance tumour immunity. PMID:17223971

  14. Photodynamic therapy effect in an intraocular retinoblastoma-like tumour assessed by an in vivo to in vitro colony forming assay.

    PubMed Central

    Winther, J.

    1989-01-01

    Cell survival was investigated in an intraocular retinoblastoma-like tumour 30 min to 48 h after photodynamic therapy. The survival of the cells was assessed by an in vivo to in vitro colony forming assay, estimated by either the plating efficiency of the treated tumour cells compared to non-treated cells or the number of clonogenic cells per mg excised tumour. Curves showing cell survival as a function of the time between light irradiation and excision of the intraocular tumours were biphasic. This suggests more than one PDT tissue destruction mechanism in vivo (i.e. an early direct cell damage plus a subsequent late damage occurring in the tumour tissue left in situ after treatment). The delayed mechanism may be due to changes in the environment of the tumours probably caused by vascular damage. Tumour cells sensitised by Photofrin II in vivo and excised from the eyes were damaged by light when irradiated in vitro and this was dependent on the light energy dose. This showed that cellular Photofrin II uptake in the eye tumours was sufficient for direct cell damage and thus supports the suggestion that direct and indirect tumour destruction occurs in this eye tumour after photodynamic therapy. PMID:2525401

  15. Long Term Effect of Curcumin in Restoration of Tumour Suppressor p53 and Phase-II Antioxidant Enzymes via Activation of Nrf2 Signalling and Modulation of Inflammation in Prevention of Cancer

    PubMed Central

    Das, Laxmidhar; Vinayak, Manjula

    2015-01-01

    Inhibition of carcinogenesis may be a consequence of attenuation of oxidative stress via activation of antioxidant defence system, restoration and stabilization of tumour suppressor proteins along with modulation of inflammatory mediators. Previously we have delineated significant role of curcumin during its long term effect in regulation of glycolytic pathway and angiogenesis, which in turn results in prevention of cancer via modulation of stress activated genes. Present study was designed to investigate long term effect of curcumin in regulation of Nrf2 mediated phase-II antioxidant enzymes, tumour suppressor p53 and inflammation under oxidative tumour microenvironment in liver of T-cell lymphoma bearing mice. Inhibition of Nrf2 signalling observed during lymphoma progression, resulted in down regulation of phase II antioxidant enzymes, p53 as well as activation of inflammatory signals. Curcumin potentiated significant increase in Nrf2 activation. It restored activity of phase-II antioxidant enzymes like GST, GR, NQO1, and tumour suppressor p53 level. In addition, curcumin modulated inflammation via upregulation of TGF-β and reciprocal regulation of iNOS and COX2. The study suggests that during long term effect, curcumin leads to prevention of cancer by inducing phase-II antioxidant enzymes via activation of Nrf2 signalling, restoration of tumour suppressor p53 and modulation of inflammatory mediators like iNOS and COX2 in liver of lymphoma bearing mice. PMID:25860911

  16. Immunology of naturally transmissible tumours

    PubMed Central

    Siddle, Hannah V; Kaufman, Jim

    2015-01-01

    Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution. PMID:25187312

  17. Calcium sensing receptor effects in adipocytes and liver cells: Implications for an adipose-hepatic crosstalk.

    PubMed

    Villarroel, Pia; Mattar, Pamela; D'Espessailles, Amanda; Arrese, Marco; Arreguin, Andrea; Fuentes, Cecilia; Reyes, Marcela; Cifuentes, Mariana

    2016-10-01

    The calcium sensing receptor (CaSR) is expressed in human adipose cells, and its activation may associate with adipose tissue (AT) dysfunction. We evaluated whether CaSR stimulation influences adipocyte triglyceride (TG) and fatty acid binding protein 4 (aP2) content, and hepatocyte TGs and proinflammatory cytokine expression. The effect of the calcimimetic cinacalcet on TGs (fluorimetry), lipogenic genes (qPCR) and aP2 (immunoblot) was evaluated in LS14 adipocytes or AT. In the human HepG2 hepatic cell line, we assessed CaSR expression and cinacalcet effect on TGs and lipogenic and proinflammatory genes. CaSR activation decreased adipocyte TG content by 20% and the expression of GPD and LPL by 34% and 20%, respectively. Cinacalcet increased aP2 protein expression by 60%. CaSR expression was shown in HepG2 cells and human liver samples. Cinacalcet-treated HepG2 cells in the presence of oleic acid exhibited a19% increased TG content. No changes were observed in the expression of lipogenic genes in HepG2 cells, however there was a 50%-300% elevation in the expression of proinflammatory cytokines. CaSR activation in adipocytes may associate with decreased TG storage ability and increased aP2. Hepatic CaSR stimulation may elevate steatosis and proinflammatory factors. We propose that CaSR may contribute to obesity-associated hepatic metabolic consequences. PMID:27565442

  18. Anti-fibrotic effects of the Masson pine pollen aqueous extract on hepatic fibrosis rat model

    PubMed Central

    Cong, Tao; Jin, Xue-Yuan; Zhao, Lin; Ma, Long; Li, Rui-Sheng; Zhao, Ping; Guo, Chang-Jiang

    2015-01-01

    Aim: To observe the antifibrotic effects of Masson Pine Pollen aqueous extract. Methods: Adult Sprague-Dawley rats were randomly divided into control (CG), hepatic fibrosis model (MG), MPPAE low dose (LG), MPPAE high dose (HG), and MPP original powder (MPPOP; OG) groups. Each group was treated with specific protocols and sacrificed 8 weeks later. Multiple indicators such as serum transaminase, HE staining of the liver tissue, and relevant indexes to fibrosis were determined. Results: Severe hyperplasia of fibrous connective tissues was observed in livers of the MG group rats, while aspartate transaminase and alanine transaminase levels and collagen content obviously increased, superoxide dismutase and glutathione peroxidase activities and MMPs expression decreased, malondialdehyde (MDA) and 8-hydroxy-2’-deoxyguanosine concentrations increased, while mRNA expressions of hepatic stellate cell (HSC)-related cytokines such as transforming growth factor-β1 and platelet-derived growth factor, transcription factors such as nuclear factor-κB p65, and signaling protein α-smooth muscle actin were all increased significantly. Conclusions: MPPAE effectively inhibited the fibrotic process in this CCl4-induced hepatic fibrosis rat model. It may be associated with synergic functions of antioxidant activity, inhibitory activity on HSC proliferation, collagen synthesis, and MMPs expression induction. PMID:26191155

  19. Anti-inflammatory effect of recombinant thrombomodulin for fulminant hepatic failure.

    PubMed

    Kurokohchi, Kazutaka; Imataki, Osamu; Kubo, Fumiyoshi

    2015-07-14

    Fulminant hepatic failure (FHF) is a critical illness that can be comorbid to primary liver damage. FHF shows a high mortality rate, and patients with FHF require intensive therapy, including plasma apheresis. However, intensive care at the present is not enough to restore the severe liver damage or promote hepatocellular reproduction, and a standard therapy for the treatment of FHF has not been established. An 86-year-old female with FHF was admitted to our hospital. Her manifestation demonstrated a clinical situation of systemic inflammatory response syndrome (SIRS) and disseminated intravascular coagulation. A diagnosis of fulminant hepatitis was made according to the definition given in the position paper of the American Association for the Study of Liver Diseases. Her serum hepatocyte growth factor (HGF) level had increased to 11.84 ng/mL. The HGF level indicated massive liver damage as seen in FHF. Recombinant thrombomodulin (rTM) was administered daily from the admission day for 1 wk at 380 U/kg. The patient's white blood cells and C-reactive protein responded to the rTM treatment within a few days. The HGF level and PT recovered to the normal range. The levels of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) were suppressed by the administration of rTM. The patient's hepatic function (e.g., PT and albumin) completely recovered without plasma exchange. rTM may modulate the over-response of SIRS with the improvement of proinflammatory cytokines. The underlying mechanism is thought to be the inhibitory effect of rTM on high-mobility group box 1 (HMBG1). The pathogenesis of HMBG1 protein in fulminant hepatic failure has been already known. A novel favorable effect of rTM for SIRS would be promising for FHF, and the wide application of rTM for SIRS should be considered.

  20. Effect of protamine on lipoprotein lipase and hepatic lipase in rats.

    PubMed Central

    Hultin, M; Olivecrona, G; Olivecrona, T

    1994-01-01

    The polycation protamine impedes the catabolism of triglyceride-rich lipoproteins and this has been suggested to be due to intravascular inactivation of lipoprotein lipase. We have made intravenous injections of protamine to rats and found that both lipoprotein lipase and hepatic lipase activities were released to plasma. The effect of protamine was more short-lived than that obtained by injection of heparin. The release of hepatic lipase by protamine was as effective as the release by heparin, while the amount of lipoprotein lipase released by protamine was only about one-tenth of that released by heparin. This was not due to inactivation of lipoprotein lipase, since injection of an excess of heparin 10 min after injection of protamine released as much lipoprotein lipase activity to plasma as in controls. The results in vivo differed from those obtained in model experiments in vitro. Protamine was able to almost quantitatively release both lipoprotein lipase and hepatic lipase from columns of heparin-agarose. The displacement was dependent on the total amount of protamine that had passed over the column, indicating that it was due to occupation by protamine of all available binding sites. Our results in vivo showed that the binding sites for lipoprotein lipase were not blocked as efficiently as those for hepatic lipase, indicating that the binding structures were not identical. It was concluded that the impaired turnover of lipoproteins by protamine probably was due to prevention of binding of the lipoproteins to endothelial cell surfaces rather than to impaired lipase function. PMID:7818503

  1. Effects of extracellular matrixes and growth factors on the hepatic differentiation of human embryonic stem cells.

    PubMed

    Ishii, Takamichi; Fukumitsu, Ken; Yasuchika, Kentaro; Adachi, Keiko; Kawase, Eihachiro; Suemori, Hirofumi; Nakatsuji, Norio; Ikai, Iwao; Uemoto, Shinji

    2008-08-01

    Hepatocytes derived from human embryonic stem cells (hESCs) are a potential cell source for regenerative medicine. However, the definitive factors that are responsible for hepatic differentiation of hESCs remain unclear. We aimed to evaluate the effects of various extracellular matrixes and growth factors on endodermal differentiation and to optimize the culture conditions to induce hepatic differentiation of hESCs. The transgene vector that contained enhanced green fluorescent protein (EGFP) under the control of human alpha-fetoprotein (AFP) enhancer/promoter was transfected into hESC lines. The transgenic hESCs were cultured on extracellular matrixes (collagen type I, laminin, and Matrigel) in the presence or absence of growth factors including hepatocyte growth factor (HGF), bone morphogenetic protein 4, fibroblast growth factor 4, all-trans-retinoic acid, and activin A. The expression of AFP-EGFP was measured by flow cytometry. The culture on Matrigel-coated dishes with 100 ng/ml activin A showed 19.5% of EGFP-positive proportions. Moreover, the sequential addition of 100 ng/ml activin A and 20 ng/ml HGF resulted in 21.7% and produced a higher yield of EGFP-positive cells than the group stimulated by activin A alone. RT-PCR and immunocytochemical staining revealed these EGFP-positive cells to differentiate into mesendoderm-like cells by use of activin A and then into hepatic endoderm cells by use of HGF. Two other hESC lines also differentiated into endoderm on the hepatic lineage by our method. In conclusion, we therefore found this protocol to effectively differentiate multiple hESC lines to early hepatocytes using activin A and HGF on Matrigel.

  2. Parallel evolution of tumour subclones mimics diversity between tumours.

    PubMed

    Martinez, Pierre; Birkbak, Nicolai Juul; Gerlinger, Marco; McGranahan, Nicholas; Burrell, Rebecca A; Rowan, Andrew J; Joshi, Tejal; Fisher, Rosalie; Larkin, James; Szallasi, Zoltan; Swanton, Charles

    2013-08-01

    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome.

  3. Parallel evolution of tumour subclones mimics diversity between tumours.

    PubMed

    Martinez, Pierre; Birkbak, Nicolai Juul; Gerlinger, Marco; McGranahan, Nicholas; Burrell, Rebecca A; Rowan, Andrew J; Joshi, Tejal; Fisher, Rosalie; Larkin, James; Szallasi, Zoltan; Swanton, Charles

    2013-08-01

    Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome. PMID:23716380

  4. Carryover effects of dichloroacetic acid on hepatic tumorigenesis in mice.

    EPA Science Inventory

    Introduction: Dichloroacetic acid (DCA) is a major by-product of drinking water chlorination. Chronic DCA exposure has been shown to increase liver tumors in mice, although carryover effects and interactions with other promotional agents are not known. Here we evaluated effects...

  5. Selective in vitro replication of herpes simplex virus type 1 (HSV-1) ICP34.5 null mutants in primary human CNS tumours--evaluation of a potentially effective clinical therapy.

    PubMed Central

    McKie, E. A.; MacLean, A. R.; Lewis, A. D.; Cruickshank, G.; Rampling, R.; Barnett, S. C.; Kennedy, P. G.; Brown, S. M.

    1996-01-01

    Primary tumours of the central nervous system (CNS) are an important cause of cancer-related deaths in adults and children. CNS tumours are mostly glial cell in origin and are predominantly astrocytomas. Conventional therapy of high-grade gliomas includes maximal resection followed by radiation treatment. The addition of adjuvant chemotherapy provides little improvement in survival time and hence assessment of novel therapies is imperative. We have evaluated the potential therapeutic use of the herpes simplex virus (HSV) mutant 1716 in the treatment of primary brain tumours. The mutant is deleted in the RL1 gene and fails to produce the virulence factor ICP34.5. 1716 replication was analysed in both established human glioma cell lines and in primary cell cultures derived from human tumour biopsy material. In the majority of cultures, virus replication occurred and consequential cell death resulted. In the minority of tumour cell lines which are non-permissive for mutant replication, premature shut-off of host cell protein synthesis was induced in response to lack of expression of ICP34.5. Hence RL1-negative mutants have the distinct advantage of providing a double hit phenomenon whereby cell death could occur by either pathway. Moreover, 1716, by virtue of its ability to replicate selectively within a tumour cell, has the potential to deliver a 'suicide' gene product to the required site immediately. It is our opinion that HSV which fails to express ICP34.5 could provide an effective tumour therapy. Images Figure 4 Figure 5 PMID:8795577

  6. Primary retroperitoneal tumours and cysts.

    PubMed

    Bors, G; Polyák, L; Frang, D

    1986-01-01

    The authors give a summarizing report on retroperitoneal tumours and cysts. They review the origin and classification of tumours and cysts, their diagnostic and differential diagnostic possibilities as well as the therapeutic measures. Finally, their own 3 cases are reported.

  7. Management of hepatic epithelioid haemangio-endothelioma in children: what option?

    PubMed

    Sharif, K; English, M; Ramani, P; Alberti, D; Otte, J-B; McKiernan, P; Gosseye, S; Jenney, M; de Ville de Goyet, J

    2004-04-19

    Hepatic epithelioid haemangio-endothelioma (HEHE) is an endothelium-derived tumour of low-to-medium grade malignancy. It is predominantly seen in adults and is unresponsive to chemotherapy. Liver transplantation is an accepted indication when the tumour is unresectable. Hepatic epithelioid haemangio-endothelioma is very rare in children and results after transplantation are not reported. The aim of this study is to review the experience of three European centres in the management of HEHE in children. A retrospective review of all paediatric patients with HEHE managed in three European centres is presented. Five children were identified. Four had unresectable tumours. The first had successful resection followed by chemotherapy and is alive, without disease 3 years after diagnosis. One child died of sepsis and one of tumour recurrence in the graft and lungs 2 and 5 months, respectively, after transplant. Two children who had progressive disease with ifosfamide-based chemotherapy have had a reduction in clinical symptoms and stabilisation of disease up to 18 and 24 months after the use of platinum-based chemotherapy. HEHE seems more aggressive in children than reported in adults and the curative role of transplantation must be questioned. Ifosfamide-based chemotherapy was not effective. Further studies are necessary to confirm if HEHE progression in children may be influenced by platinum-based chemotherapy. PMID:15083175

  8. Cohort effects in dynamic models and their impact on vaccination programmes: an example from Hepatitis A

    PubMed Central

    Srinivasa Rao, Arni SR; Chen, Maggie H; Pham, Ba' Z; Tricco, Andrea C; Gilca, Vladimir; Duval, Bernard; Krahn, Murray D; Bauch, Chris T

    2006-01-01

    Background Infection rates for many infectious diseases have declined over the past century. This has created a cohort effect, whereby older individuals experienced a higher infection rate in their past than younger individuals do now. As a result, age-stratified seroprevalence profiles often differ from what would be expected from constant infection rates. Methods Here, we account for the cohort effect by fitting an age-structured compartmental model with declining transmission rates to Hepatitis A seroprevalence data for Canadian-born individuals. We compare the predicted impact of universal vaccination with and without including the cohort effect in the dynamic model. Results We find that Hepatitis A transmissibility has declined by a factor of 2.8 since the early twentieth century. When the cohort effect is not included in the model, incidence and mortality both with and without vaccination are significantly over-predicted. Incidence (respectively mortality) over a 20 year period of universal vaccination is 34% (respectively 90%) higher than if the cohort effect is included. The percentage reduction in incidence and mortality due to vaccination are also over-predicted when the cohort effect is not included. Similar effects are likely for many other infectious diseases where infection rates have declined significantly over past decades and where immunity is lifelong. Conclusion Failure to account for cohort effects has implications for interpreting seroprevalence data and predicting the impact of vaccination programmes with dynamic models. Cohort effects should be included in dynamic modelling studies whenever applicable. PMID:17147828

  9. The effects of booster vaccination on combined hepatitis A and hepatitis B vaccine in both anti-HBs and anti-HAV negative children 5-15 years after hepatitis B vaccine primary immunization.

    PubMed

    Chen, Yongdi; Gu, Hua; Cheng, Suyun; Shen, Lingzhi; Cui, Fujiang; Wang, Fuzhen; Yao, Jun; Xia, Shichang; Lv, Huakun; Liang, Xiaofeng

    2013-04-01

    In the present study, we investigated the changes in both anti-HAV lgG and anti-HBs lgG levels and compared the antibody seroconversion rates of different doses of combined hepatitis A and hepatitis B vaccine in children. Children who were vaccinated as infants with Hepatitis B vaccine were revaccinated at 5-15 y of age, then the antibody titers were monitored. Among 283 children, this study found that the anti-HAV seroconversion rates (defined as anti-HAV ≥ 1 mIU/ml) after the first and the third dose were 79.9% and 100% respectively; these observed differences were statistically significant (P<0.05); the corresponding geometric mean titers (GMTs) were 4.72 ± 2.63 mIU/ml and 13.46 ± 1.16 mIU/ml respectively. The anti-HBs seroconversion rates (defined as an anti-HBs ≥ 10 mIU/ml) were 82.3% and 99.0% respectively; these observed differences were statistically significant (P<0.05); and the corresponding titers were 319.95 ± 5.16 mIU/ml and 418.59 ± 3.89 mIU/ml respectively. After the first booster dose, the difference in anti-HAV seroconversion rate was statistically significant in children aged 5-9 y and 10-15 y (P<0.05), as was the difference of anti-HBs seroconversion, whereas after the third dose the difference was not statistically significant (P>0.05). This study demonstrated that the immunization effects of booster vaccination with combined hepatitis A and hepatitis B vaccine is successful for children. A single booster dose is adequate for younger children, while three doses are needed for older children.

  10. Effect of Green Tea Extract Encapsulated Into Chitosan Nanoparticles on Hepatic Fibrosis Collagen Fibers Assessed by Atomic Force Microscopy in Rat Hepatic Fibrosis Model.

    PubMed

    Safer, Abdel-Majeed A; Hanafy, Nomany A; Bharali, Dhruba J; Cui, Huadong; Mousa, Shaker A

    2015-09-01

    The present study examined the effect of Green Tea Extract (GTE) encapsulated into Chitosan Nanoparticles (CS-NPs) on hepatic fibrosis in rat model as determined by atomic force microscopy (AFM). The bioactive compounds in GTE encapsulated into CS-NPs were determined using LC-MS/MS method. Additionally, the uptake of GTE-CS NPs in HepG2 cells showed enhanced uptake. In experimental fibrosis model, AFM was used as a high resolution microscopic tool to investigate collagen fibers as an indicator of hepatic fibrosis induced by treatment with CCl4. Paraffin sections of fibrotic liver tissues caused by CC4 treatment of rats and the effect of GTE-CS NPs treatment with or without CCl4 on hepatic fibrosis were examined. Liver tissues from the different groups of animals were de-waxed and processed as for normal H/E staining and Masson's trichrome staining to locate the proper area of ECM collagen in the CCl4 group versus collagen in liver tissues treated with the GTE-CS NPs with or without CCl4. Selected areas of paraffin sections were trimmed off and fixed flat on top of mica and inserted in the AFM stage. H/E staining, Masson's trichrome stained slides, and AFM images revealed that collagen fibers of 250 to 300 nm widths were abundant in the fibrotic liver samples while those of GTE-CS NPs were clear as in the control group. Data confirmed the hypothesis that GTE-CS NPs are effective in removing all the extracellular collagen caused by CCl4 in the hepatic fibrosis rat liver.

  11. The effect of cold on serum thyroid hormones and hepatic 5 prime mono-deiodinase activity

    SciTech Connect

    Hesslink, R.L. Jr.; Quesada, M.; D'Alesandro, M.; Homer, L.D.; Reed, J.L.; Christopherson, R.; Young, B.A. Univ. of Alberta, Edmonton )

    1991-03-11

    Cold exposed swine have an increases serum concentration of triiodothyronine (T{sub 3}) and increased T{sub 3} production rate. It is thought that hepatic thyroxine (T{sub 4}) deiodination (5DI) contributes to circulating T{sub 3} concentrations. The authors investigated the effects of cold exposure (14 days) on energy intake, serum free T{sub 3} (FT{sub 3}) and free T{sub 4} (FT{sub 4}) levels; and 5DI in 5-month boars. Hepatic 5DI activity was determined by measuring the {sup 125}I generated from trace amounts of {sup 125}I T{sub 4}. FT{sub 3} and FT{sub 4} were assayed by RIA. Swine were housed in either 20C (control; n = 5) or 4C (cold; n = 7) chambers and given food ad libitum. Cold exposure increased energy intake by 42%. The increase (93%) in hepatic 5DI V{sub max} after cold exposure parallels the increase in whole animal T{sub 3} production and may account for FT{sub 3} values found after cold exposure.

  12. Effects of beta-naphthoflavone on hepatic biotransformation and glutathione biosynthesis in largemouth bass (Micropterus salmoides).

    PubMed

    Hughes, Erin M; Gallagher, Evan P

    2004-01-01

    We are investigating the effects of in vivo exposure of prototypical enzyme inducing agents on hepatic biotransformation enzyme expression in largemouth bass (Micropterus salmoides), a predatory game fish found throughout the United States and Canada. The current study targeted those genes involved in biotransformation and oxidative stress that may be regulated by Ah-receptor-dependent pathways. Exposure of bass to beta-naphthoflavone (beta-NF, 66 mg/kg, i.p.) elicited a 7-9-fold increase in hepatic microsomal cytochrome P4501A-dependent ethoxyresorufin O-deethylase (EROD) activities, but did not affect cytosolic GST catalytic activities toward 1-chloro-2,4-dinitrobenzene (CDNB) or 5-androstene-3,17-dione (ADI). Glutathione S-transferase A (GST-A) mRNA expression exhibited a transient, but non-significant increase following exposure to beta-NF, and generally tracked the minimal changes observed in GST-CDNB activities. Expression of the mRNA encoding glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in glutathione (GSH) biosynthesis, was increased 1.7-fold by beta-NF. Changes in GCLC mRNA expression were paralleled by increases in intracellular GSH. In summary, largemouth bass hepatic CYP1A-dependent and GSH biosynthetic pathways, and to a lesser extent GST, are responsive to exposure to beta-NF.

  13. Estrogens regulate the hepatic effects of growth hormone, a hormonal interplay with multiple fates.

    PubMed

    Fernández-Pérez, Leandro; Guerra, Borja; Díaz-Chico, Juan C; Flores-Morales, A

    2013-01-01

    The liver responds to estrogens and growth hormone (GH) which are critical regulators of body growth, gender-related hepatic functions, and intermediate metabolism. The effects of estrogens on liver can be direct, through the direct actions of hepatic ER, or indirect, which include the crosstalk with endocrine, metabolic, and sex-differentiated functions of GH. Most previous studies have been focused on the influence of estrogens on pituitary GH secretion, which has a great impact on hepatic transcriptional regulation. However, there is strong evidence that estrogens can influence the GH-regulated endocrine and metabolic functions in the human liver by acting at the level of GHR-STAT5 signaling pathway. This crosstalk is relevant because the widespread exposition of estrogen or estrogen-related compounds in human. Therefore, GH or estrogen signaling deficiency as well as the influence of estrogens on GH biology can cause a dramatic impact in liver physiology during mammalian development and in adulthood. In this review, we will summarize the current status of the influence of estrogen on GH actions in liver. A better understanding of estrogen-GH interplay in liver will lead to improved therapy of children with growth disorders and of adults with GH deficiency.

  14. Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology.

    PubMed

    Graichen, M E; Neptun, D A; Dent, J G; Popp, J A; Leonard, T B

    1985-02-01

    Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens. PMID:2859228

  15. Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-alpha-dependent hepatic apoptosis in mice.

    PubMed

    Hase, K; Xiong, Q; Basnet, P; Namba, T; Kadota, S

    1999-06-15

    We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective agent from Swertia japonica, on tumor necrosis factor-alpha (TNF-alpha)-dependent hepatic apoptosis induced by D-galactosamine (D-GalN) (700 mg/kg, i.p.) and lipopolysaccharide (LPS) (10 microg/kg, i.p.) in mice. Apoptotic symptoms were observed at the initial stage of liver damage. By 5 hr after intoxication, hepatic DNA fragmentation had risen to 2123%, with the value in untreated mice set at 100%, without a significant elevation of serum alanine transaminase (ALT) activity. There was a parallel increase in hepatocytes undergoing chromatin condensation and apoptotic body formation. By 8 hr after intoxication, serum ALT activity had risen to 3707 U/L. Pretreatment with THS (50 mg/kg, p.o.) at 18 and 2 hr before intoxication significantly reduced DNA fragmentation to 821% of that in untreated mice and prevented the emergence of chromatin condensation and apoptotic body formation. A significant and dose-dependent reduction in serum ALT activity at 8 hr also was observed with THS pretreatment. These effects of THS were different from those observed from pretreatment with glycyrrhizin (GCR), which is a clinically used hepatoprotective agent with membrane-stabilizing activity. GCR pretreatment (100 mg/kg, p.o.) did not inhibit hepatic DNA fragmentation (1588% of untreated mice), although this compound significantly protected against serum ALT elevation (1463 U/L). These data suggest that an inhibitory effect on the progression of hepatic apoptosis prior to liver injury may be involved in the hepatoprotective mechanisms of THS, whereas it appears that GCR affects the processes after apoptosis. In a separate experiment, we found that the concentration of serum TNF-alpha rose to 2016 pg/mL at 1 hr after intoxication of mice with D-GalN and LPS, but this increase was suppressed by THS pretreatment (10, 50, or 200 mg/kg, p.o.) to 716, 454, or 406 pg/mL, respectively. Further study with a reverse

  16. Effect of chronic renal insufficiency on hepatic and renal udp-glucuronyltransferases in rats.

    PubMed

    Yu, Chuanhui; Ritter, Joseph K; Krieg, Richard J; Rege, Bhaskar; Karnes, Thomas H; Sarkar, Mohamadi A

    2006-04-01

    Significant evidence exists regarding altered CYP450 enzymes in chronic renal insufficiency (CRI), although none exists for the phase II enzymes. The objective of this study was to investigate the effect of CRI on hepatic and renal UDP-glucuronyltransferase (UGT) enzymes. Three groups of rats were included: CRI induced by the 5/6th nephrectomy model, control, and control pair-fed (CPF) rats. UGT activities were determined in liver and kidney microsomes by the 3- and 17-glucuronidation of beta-estradiol (E2-3G and E2-17G), glucuronidation of 4-methylumbelliferone (4-MUG), and 3-glucuronidation of morphine (M3G). UGT isoforms responsible for these catalytic activities were screened using recombinant rat UGT1A1, UGT1A2, UGT1A3, UGT1A7, UGT2B2, UGT2B3, and UGT2B8. UGT protein levels were examined by Western blot analysis using polyclonal antibodies. There was no significant difference between CRI and CPF rats in hepatic and/or renal E2-3G (UGT1A1), E2-17G (UGT2B3), 4-MUG (UGT1A6), and M3G (UGT2B1) formation. Formation of E2-17G and 4-MUG in the liver and E2-3G and 4-MUG in the kidney was significantly reduced (p < 0.05) in CPF and CRI rats compared with control rats. The down-regulated glucuronidation activities were accompanied by corresponding reductions in protein content of specific UGT isoforms. These results suggest that CRI does not seem to influence the protein levels or catalytic activity of most of the major hepatic or renal UGT enzymes. The observed down-regulation of hepatic and renal UGTs in CRI and CPF rats could be caused by restricted food intake in these groups of rats.

  17. Protective effect of naringenin on hepatic and renal dysfunction and oxidative stress in arsenic intoxicated rats.

    PubMed

    Mershiba, Sam Daniel; Dassprakash, M Velayutham; Saraswathy, Sundara Dhakshinamurthy

    2013-05-01

    Arsenic has a long history as a potent human poison, chronic exposure over a period of time may result in the manifestation of toxicity in practically all systems of the body. In the present investigation the efficacy of naringenin (NRG), a naturally occurring citrus flavanone against arsenic-induced hepatotoxic and nephrotoxic manifestations have been studied in rats. Arsenic trioxide was administered orally at the dose of 2 mg/kg/day with or without combination of NRG (20 or 50 mg/kg/day) for 28 days. At the end of the experimental period the hepatic and renal dysfunction was evaluated by histological examination, serum biomarkers and markers of oxidative stress; lipid peroxidation (LPO), reduced glutathione (GSH) and antioxidant enzymes. Arsenic intoxication increased serum bilirubin, urea, uric acid and creatinine levels, additionally enhanced the activities of hepatic marker enzymes aspartate transaminase, alanine transaminase and alkaline phosphatase. Also, the hepatic and renal tissues showed a marked elevation in LPO levels with a decrease in GSH content and the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase on arsenic treatment. Simultaneous treatment with NRG restored the activities of serum biomarkers and antioxidant enzymes in the tissues in a dose-dependent manner. Furthermore, the histopathological studies confirmed the protective effect of NRG co-treatment by reducing the pathological changes due to arsenic intoxication in both liver and kidney. Thus, our present study demonstrates that NRG has a potential to protect arsenic-induced oxidative hepatic and renal dysfunction. PMID:23283742

  18. Tumour Cell Heterogeneity

    PubMed Central

    Gay, Laura; Baker, Ann-Marie; Graham, Trevor A.

    2016-01-01

    The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID:26973786

  19. Elastosis in malignant tumours.

    PubMed

    Isaacson, C; Greeff, H; Murray, J F; Posen, J; Schmaman, A

    1985-07-01

    Elastosis is common in infiltrating ductal and lobular carcinomas of the breast, occurring in approximately 90% of cases. It is also well described in some benign lesions of the breast and tumours of the salivary gland. Reports of venous elastosis in association with large-bowel carcinomas are rare. We describe elastosis in single cases of prostatic, gastric, bronchiolar-alveolar and cervical carcinoma.

  20. Effects of resveratrol and other polyphenols in hepatic steatosis

    PubMed Central

    Aguirre, Leixuri; Portillo, Maria Puy; Hijona, Elizabeth; Bujanda, Luis

    2014-01-01

    Non-alcoholic fatty liver disease covers a wide spectrum of liver pathologies which range from simple steatosis to non-alcoholic steatohepatitis. Polyphenols are members of a very large family of plant-derived compounds that can have beneficial effects on human health, and thus their study has become an increasingly important area of human nutrition research. The aim of the present review is to compile published data concerning the effects of both isolated polyphenols as well as polyphenol extracts, on hepatocyte and liver fat accumulation under different steatosis-inducing conditions. The results reported clearly show that this group of biomolecules is able to reduce fat accumulation, but further studies are needed to establish the optimal dose and treatment period length. With regard to the potential mechanisms of action, there is a good consensus. The anti-lipidogenic effect of polyphenols is mainly due to reduced fatty acid and triacylglycerol synthesis, increased in fatty acid oxidation, and reduced of oxidative stress and inflammation. As a general conclusion, it can be stated that polyphenols are biomolecules which produce hepatoprotective effects. To date, these beneficial effects have been demonstrated in cultured cells and animal models. Thus, studies performed in humans are needed before these molecules can be considered as truly useful tools in the prevention of liver steatosis. PMID:24966607

  1. Combined liver transplantation plus imatinib for unresectable metastases of gastrointestinal stromal tumours.

    PubMed

    Serralta, Alfonso S; Sanjuan, Fernando R; Moya, Angel H; Orbis, Francisco C; López-Andújar, Rafael; Pareja, Eugenia I; Vila, Juan C; Rayón, Miguel; Juan, Manuel B; Mir, José P

    2004-11-01

    Therapeutic options for treating unresectable hepatic metastases of leiomyosarcomas were scarce until a few years ago. Recent advances in the study of the biology of intestinal tumours have radically changed our knowledge of their pathogenesis. Many of the tumours previously considered as leiomyosarcomas are now identified as gastrointestinal stromal tumours (GISTs). The introduction of imatinib (an antineoplasic drug that specifically acts on the pathogenesis of these tumours) has shown promising results in patients with advanced GISTs. We present three patients with the initial diagnosis of unresectable hepatic metastases of leiomyosarcomas. They received liver transplants. All three had tumour recurrences after transplantation. Histological re-evaluation identified a stromal origin of the tumours, and the patients were treated with imatinib therapy (400 mg/day). Recurrence occurred in all patients after a mean of 38.3 months, but imatinib treatment achieved control of the tumours. The current survival times with the combination of transplantation and imatinib are 92, 48 and 46 months for the three patients. This series is small and inconclusive, but imatinib treatment showed promising results. The treatment options for patients with unresectable metastases of GISTs must be defined, as in these three patients liver transplantation achieved a disease-free status but all had tumour recurrences before starting the imatinib treatment.

  2. Effects of glucagon and vasopressin on hepatic Ca2+ release.

    PubMed Central

    Kraus-Friedmann, N

    1986-01-01

    The effects of physiological levels of glucagon on Ca2+ efflux were examined in the perfused rat liver. Two methods were used to estimate Ca2+ efflux: prior labeling of the calcium pools with 45Ca2+ and measurement of perfusate Ca2+ with atomic absorption. According to both methods, glucagon administration at the physiological level evoked Ca2+ release. The released Ca2+ originated mostly from a carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-depletable pool and also from an FCCP-insensitive pool from which Ca2+ could be released with A23187. Maximally effective doses of glucagon and vasopressin had no additive effect on Ca2+ release. Prior administration of vasopressin resulted in markedly reduced Ca2+ release by glucagon. These results indicate that glucagon releases Ca2+ from the same pool that vasopressin does. PMID:3466169

  3. 1H MRS markers of tumour growth in intrasplenic tumours and liver metastasis induced by injection of HT-29 cells in nude mice spleen.

    PubMed

    Moreno, A; López, L A; Fabra, A; Arús, C

    1998-05-01

    We have characterized, by in vitro magnetic resonance spectroscopy (MRS), the metabolite pattern of perchloric acid (PCA) extracts of intrasplenic tumours and hepatic metastasis, produced by intra-spleen injection of the human colorectal carcinoma cell line HT-29 and its metastatic variant HT-29 MMM into nude mice. Our aim was to gain further understanding of colorectal tumour metabolism as a basis for future in vivo studies of human colon cancer by 1H MRS. Metabolite PCA extract analysis showed a good reproduction of the spectral pattern observed in human primary colon tumours, while they were very different from the spectral pattern of the host tissues (spleen and liver). The main differences between host and tumour tissues involved taurine, phosphocholine (PC), phosphoethanolamine (PE), creatine, glycogen and glucose. Creatine is the most promising marker to follow tumour growth because of its practical absence in the nude mice host tissues. Detection of variable levels of this compound and of taurine in hepatic foci in man, are suggested as possible diagnostic markers. No correlation could be found between spectral pattern differences and the different ability to metastasize of the two HT-29 cell lines used. Furthermore, indirect evidence for a functional link between taurine and myo-inositol in colon tumour cells is presented. In summary, our data suggest that the nude mice model may be a suitable system for the MRS study of the changes taking place in host tissues upon tumour progression.

  4. Cardiovascular and Hepatic Toxicity of Cocaine: Potential Beneficial Effects of Modulators of Oxidative Stress

    PubMed Central

    Graziani, Manuela; Antonilli, Letizia; Togna, Anna Rita; Grassi, Maria Caterina; Badiani, Aldo; Saso, Luciano

    2016-01-01

    Oxidative stress (OS) is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators (such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants) for the treatment of cocaine toxicity. We conclude that available OS modulators do not appear to have clinical efficacy. PMID:26823954

  5. Effects of Dietary Exposure to Sulfamethazine on the Hematological Parameters and Hepatic Oxidative Stress Biomarkers in Nile Tilapia (Oreochromis niloticus).

    PubMed

    Sampaio, Fernanda Garcia; Carra, Maria Lídia; Jonsson, Claudio Martin; Gonçalves, Vitoria Teodoro; Dal'Bo, Genoefa; Nunes, Kátia Santos Damacena; Valim, José Henrique; Dallago, Bruno Stéfano Lima; do Nascimento de Queiroz, Sonia Claudia; Reyes, Felix Guillermo Reyes

    2016-10-01

    Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia.

  6. Effects of Dietary Exposure to Sulfamethazine on the Hematological Parameters and Hepatic Oxidative Stress Biomarkers in Nile Tilapia (Oreochromis niloticus).

    PubMed

    Sampaio, Fernanda Garcia; Carra, Maria Lídia; Jonsson, Claudio Martin; Gonçalves, Vitoria Teodoro; Dal'Bo, Genoefa; Nunes, Kátia Santos Damacena; Valim, José Henrique; Dallago, Bruno Stéfano Lima; do Nascimento de Queiroz, Sonia Claudia; Reyes, Felix Guillermo Reyes

    2016-10-01

    Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia. PMID:27225508

  7. Effect of co-administration of Angelicae gigantis radix and Lithospermi radix on rat hepatic injury induced by carbon tetrachloride

    PubMed Central

    Lim, Chi-Yeon; Kim, Bu-Yeo; Lim, Se-Hyun; Cho, Su-In

    2015-01-01

    Background: Co-administration of Angelicae gigantis radix (AGR) and Lithospermi radix (LR) has been commonly applied to patients to treat cardiac and hepatic disorders. Individual bioactivities of these herbal medicines have been widely investigated, but the hepatoprotective effects of co-treatment of AGR and LR have yet to be clarified. Objective: The present study investigated the protective effects of extracts of AGR and LR on carbon tetrachloride (CCl4) induced hepatic injury. Materials and Methods: In this study, we measured the hepatoprotective activity of individual and co-treatment of the two herbal medicines on hepatic injury induced by CCl4 by measuring different biochemical parameters such as serum aspartate aminotransaminase (AST) and serum alanine aminotransaminase (ALT). Microarray technology also used to compare ontological difference with individual and co-treatment of these two. Results: Combined treatment with AGR and LR (AGR + LR) decreased AST and ALT level in serum which demonstrate hepatoprotective effect of the therapy. When the effect of AGR and LR according to treatment conditions was measured, co-treatment showed the most prominent effect on hepatic injury by CCl4 rather than individual treatment condition. We further defined gene set that could be the molecular target of herbal effect on hepatic injury by CCl4 using bioinformatical analysis of interaction network. Highly recovered genes by treating AGR + LR play significant roles in response to hepatic injury induced by CCl4. Conclusion: Combined treatment with AGR and LR showed synergistic protective effects on the CCl4-induced rat hepatic tissue injury. PMID:25829781

  8. Cancerogenic effect of different fragments of the hepatitis C virus core protein.

    PubMed

    Feng, Xiaoyan; Zhang, Heqiu; Liu, Hezhong; Song, Xiaoguo; Wang, Guohua; Chen, Kun; Ling, Shigan

    2007-08-01

    The hepatitis C virus core protein plays an extremely important role in the hepatocarcinogenesis of hepatitis C virus. Little, however, is known about the oncogenic potency of fragments. Thus, the purpose of the present study is to investigate the cancerogenic effects of the different core protein fragments. Two series of recombinant plasmids containing hepatitis C virus core gene fragments encoding the different-length core protein were constructed using plasmid enhanced green fluorescent protein (pEGFP)-C1 and pcDNA3.1(+), respectively. Human hepatocyte L02 cells transiently transfected with pEGFP-C1-based plasmids were subjected to confocal laser scanning microscopy analysis to determine the localization of the different core protein fragments. The stably transfected L02 cells with the pcDNA3.1(+)-based core protein plasmids were used to investigate the ultrastructural effects of the core protein and the tumorigenicity of L02 cells expressing core protein fragments in athymic nude mice. The full-length core protein and Core130-191 were completely localized in the cytoplasm, while Core1-59 existed exclusively in the nucleus. On the other hand, Core50-140 and Core1-140 were observed in both the nucleus and the cytoplasm. Ultrastructural changes of L02 cells expressing the full-length core protein were comprehensive and included, for example, irregular nuclear, increased nuclear/cytoplasmic ratio and mitochondria swelling. The slight changes were observed in the cells expressing Core50-140 and Core130-191, whereas the ultrastructure of the cells expressing Core1-59 remained normal. All the L02 cells stably expressing different fragments of the core protein, with the exception of the C-terminal truncated fragment Core1-59, could induce the occurrence of tumor in the nude mice. The N-terminal fragment of the core protein, Core1-59, was not oncogenic, while the intermediate and posterior segments of the hepatitis C virus core protein had the cancerogenic potency. In

  9. The effects of acute ethanol exposure on inhibitors of hepatic regenerative activity in the rat.

    PubMed

    Zhang, M N; Gong, Y; Minuk, G Y

    2000-04-01

    The purpose of this study was to identify the mechanism(s) whereby acute ethanol exposure inhibits hepatic regenerative activity in the rat. Adult, male, Sprague-Dawley rats (200-250 g) were randomized to receive either ethanol (1 g/kg i.p. q 4 h) or an equal volume of saline (controls) for 24 h beginning 1 h prior to a 70% partial hepatectomy (PHx). At 0, 3, 6, 12 and 24 h post-PHx, rats were sacrificed (N = 4-6/group), and the expression of the following genes associated with inhibition of hepatocyte proliferation were documented; p53, p21, transforming growth factor-beta1 (TGF-beta1) and gamma aminobutyric acid transport protein (GABA-TP). Inhibition of hepatic regenerative activity was confirmed by 3H-thymidine incorporation into hepatic DNA at 24 h post-PHx. The results of the study revealed that in ethanol-treated rats, DNA synthesis was inhibited by 37% when compared to saline-treated controls (p < 0.01). Regarding suppressor gene expression, both p21 and TGF-beta1 mRNA expression in ethanol-treated rats were similar to those obtained in saline-treated controls. Although p53 mRNA expression differed in the two groups, in the ethanol-treated group, p53 mRNA expression was decreased rather than increased (relative to controls) at 24 h post-PHx, a finding not in keeping with inhibition of DNA synthesis. GABA-TP mRNA was strongly expressed prior to PHx in both ethanol- and saline-treated rats. Following PHx, GABA-TP mRNA expression decreased in both groups but remained low in the saline-treated group while returning to pre-PHx values in ethanol-treated rats. In summary, the results of this study indicate that the inhibitory effects of ethanol on hepatic regeneration are not associated with significant or the appropriate changes in mRNA expression of the p53, p21 or TGF-beta1 suppressor genes. On the other hand, transcriptional changes in GABA-TP gene expression post-PHx are in keeping with an inhibitory effect of GABA on hepatic regeneration.

  10. Effect of lipid on proliferation and activation of rat hepatic stellate cells (I)

    PubMed Central

    Lu, Lun-Gen; Zeng, Min-De; Li, Ji-Qiang; Hua, Jing; Fan, Jian-Gao; Fan, Zhu-Ping; Qiu, De-Kai

    1998-01-01

    AIM: To study the effect of lipid (triglyceride and very low-density lipoprotein, VLDL) on proliferation and activation of rat hepatic stellate cells (HSC). METHODS: HSC were isolated and cultured from liver of Wistar rats by in situperfusion with pronase and collagenase and density gradient centrifugation with Nycodenz. HSC proliferation was examined with MTT colorimetric assay. RESULT: Triglyceride of 12.5 mg/L had a promoting effect on proliferation of HSC (P < 0.05), 25, 50, 100 and 200 mg/L had no effects (P > 0.05), but 400 mg/L had an inhibiting effect (P < 0.01). VLDL of 6.25 and 12.5 mg/L had no effect on proliferation of HSC (P > 0.05), but increased concentration of VLDL could promote the HSC proliferation (P < 0.05). CONCLUSION: Lipid had an effect on proliferation of HSC. Triglyceride and VLDL may promote HSC proliferation and may be associated with fatty liver and hepatic fibrogenesis. PMID:11819353

  11. Recombinant human alpha fetoprotein synergistically potentiates the anti-cancer effects of 1′-S-1′-acetoxychavicol acetate when used as a complex against human tumours harbouring AFP-receptors

    PubMed Central

    Arshad, Norhafiza M.; In, Lionel L.A.; Soh, Tchen Lin; Azmi, Mohamad Nurul; Ibrahim, Halijah; Awang, Khalijah; Dudich, Elena; Tatulov, Eduard; Nagoor, Noor Hasima

    2015-01-01

    Purpose Previous in vitro and in vivo studies have reported that 1′-S-1′-acetoxychavicol acetate (ACA) isolated from rhizomes of the Malaysian ethno-medicinal plant Alpinia conchigera Griff (Zingiberaceae) induces apoptosis-mediated cell death in tumour cells via dysregulation of the NF-κB pathway. However there were some clinical development drawbacks such as poor in vivo solubility, depreciation of biological activity upon exposure to an aqueous environment and non-specific targeting of tumour cells. In the present study, all the problems above were addressed using the novel drug complex formulation involving recombinant human alpha fetoprotein (rhAFP) and ACA. Experimental Design To study the synergistic effect of both agents on human cancer xenografts, athymic nude (Nu/Nu) mice were used and treated with various combination regimes intraperitoneally. Serum levels of tumour markers for carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) were assessed using sandwich ELISA. IHC and Western blotting were also conducted on in vivo tumour biopsies to investigate the involvement of NF-κB regulated genes and inflammatory biomarkers. Quantification and correlation between drug efficacies and AFP-receptors were done using IF-IC and Pearson's correlation analysis. Results Mice exposed to combined treatments displayed higher reductions in tumour volume compared to stand alone agents, consistent with in vitro cytotoxicity assays. Milder signs of systemic toxicity, such as loss in body weight and inflammation of vital organs were also demonstrated compared to stand alone treatments. Tumour marker levels were consistent within all rhAFP/ACA treatment groups where levels of CEA and PSA were initially elevated upon commencement of treatment, and consecutively reduced corresponding to a decrease in tumour bulk volume. Both IHC and Western blotting results indicated that the combined action of rhAFP/ACA was not only able to down-regulate NF-κB activation

  12. Modelling hepatitis C therapy—predicting effects of treatment

    DOE PAGESBeta

    Perelson, Alan S.; Guedj, Jeremie

    2015-06-30

    Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of themore » initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In addition, there also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.« less

  13. Modelling hepatitis C therapy—predicting effects of treatment

    SciTech Connect

    Perelson, Alan S.; Guedj, Jeremie

    2015-06-30

    Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In addition, there also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.

  14. Modelling hepatitis C therapy—predicting effects of treatment

    PubMed Central

    Perelson, Alan S.; Guedj, Jeremie

    2015-01-01

    Mathematically modelling HCV RNA changes measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of antiviral agent effectiveness at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV infected cell from the slope of the subsequent viral decline and, determine the duration of therapy needed to cure infection. Our understanding of HCV RNA decline under IFN-based therapies needs to be revised in order to understand the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). In this Review, we also discuss the unresolved issues involving understanding therapies with combinations of DAAs, such as whether a sustained virological response necessarily involves elimination of all infected cells PMID:26122475

  15. Multiple Effects of Silymarin on the Hepatitis C Virus Lifecycle

    PubMed Central

    Wagoner, Jessica; Negash, Amina; Kane, Olivia J.; Martinez, Laura E.; Nahmias, Yaakov; Bourne, Nigel; Owen, David M.; Grove, Joe; Brimacombe, Claire; McKeating, Jane A.; Pécheur, Eve-Isabelle; Graf, Tyler N.; Oberlies, Nicholas H.; Lohmann, Volker; Cao, Feng; Tavis, John E.; Polyak, Stephen J.

    2010-01-01

    Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit HCV infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against HCVcc infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells, but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited JFH-1 genotype 2a NS5B-dependent RNA polymerase activity at concentrations 5–10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in 5 independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus. While inhibition of in-vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell. PMID:20512985

  16. Effects of intravenous immunoglobulins on T-cell mediated, concanavalin A-induced hepatitis in mice.

    PubMed

    Shirin, H; Bruck, R; Aeed, H; Hershkoviz, R; Lider, O; Kenet, G; Avni, Y; Halpern, Z

    1997-12-01

    Concanavalin A (ConA) activates T lymphocytes and causes T-cell mediated hepatic injury in mice. The intravenous administration of human immunoglobulins has beneficial effects in T-cell mediated diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis. In the present study, we examined the effects of intravenous immunoglobulins in a mouse model of T-cell mediated, acute liver injury induced by concanavalin A. Balb/c mice were inoculated with 12 mg/kg concanavalin A with or without intravenous immunoglobulins at doses of 0.4, 0.6, 0.8 g/kg body wt. The serum levels of liver enzymes, tumor necrosis factor-alpha, interferon-gamma and interleukin-6 were assayed 2, 6 and 24 h after concanavalin A administration. Intravenous immunoglobulins did not prevent concanavalin A-induced hepatitis, as manifested by elevation of serum aminotransferases and histopathological evaluation. The serum levels of tumor necrosis factor-alpha in mice pretreated with immunoglobulins, measured 2 h after ConA treatment were reduced, while interferon-gamma levels measured 6 h after ConA inoculation were 5-fold higher than control levels. There was no effect of intravenous immunoglobulins on the release of interleukin 6. In conclusion, these results indicate that intravenous immunoglobulin is not effective in preventing T-cell mediated concanavalin A-induced hepatitis. The increased secretion of interferon-gamma and the incomplete suppression of tumor necrosis factor-alpha release may explain the lack of efficacy of intravenous immunoglobulin in this experimental model. PMID:9455732

  17. Anticytoproliferative effect of Vitamin C on rat hepatic stellate cell

    PubMed Central

    Su, Min; Chao, Guo; Liang, Minqing; Song, Jianhua; Wu, Ka

    2016-01-01

    This study was conducted to investigate the potential therapeutical benefit of Vitamin (VC), a potent antioxidant, on suppressing proliferation of immortalized rat liver stellate cell line (HSC-T6) in vitro, and to discuss the underlying mechanism. HSC-T6 was co-treated with different concentrations of VC (50, 100, 200 μmol/L) on designed time points. Then, cell viability was assessed by using MTT analysis, and the changes of cytomorphology was observed with apoptosis-specific TUNEL and immunohistochemical stains, as well as the intracellular target genes was determined by using RT-PCR, respectively. As the outcomes, VC-treated HSC-T6 showed significantly inhibited cell growth in a dose-dependent manner when compared to the vehicle control. Cytologically, VC increased TUNEL-labeled positive cells in cultured HSC-T6, which the cell count was greater than vehicle control. Meanwhile, VC-treated HSC-T6 showed elevated immunoreactive for TGF-β1-labeled cells. Moreover, VC contributed to down-regulated expressions of intracellular c-myc, cyclin D1, mTOR mRNAs in HSC-T6. Collectively, these preliminary findings have demonstrated that VC-mediated anti-proliferative effect on HSCs is involved in molecular mechanisms of promoting apoptosis and blocking endogenous collagenation. PMID:27398165

  18. Experimental studies on the inhibition effects of 1000 Chinese medicinal herbs on the surface antigen of hepatitis B virus.

    PubMed

    Zheng, M; Zheng, Y

    1992-09-01

    The reverse passive hemagglutination inhibition test was used in the screening of 1000 Chinese materia medica for inhibitors of hepatitis B virus surface antigen. The herbal drugs were commercially available and the surface antigen was from sera of hepatitis B patients. 127 effective drugs were obtained from the survey of which 28 were highly inhibitory (8:1), 35 were moderately effective (4:1), and 64 mildly effective (2:1). Further experiments with varying dosages of the drug, dosages of HBsAg and duration of contact showed 10 drugs to be of optimal effect. PMID:1453758

  19. Effects of restricted feeding on daily fluctuations of hepatic functions including p450 monooxygenase activities in rats.

    PubMed

    Hirao, Jun; Arakawa, Shingo; Watanabe, Kyoko; Ito, Kazumi; Furukawa, Tadashi

    2006-02-10

    Hepatic P450 monooxygenase activities, assessed by measurement of 7-alkoxycoumarin O-dealkylase (ACD) activities, show obvious daily fluctuations in male rats with high values during the dark period and low values during the light period. We have already confirmed that the ACD activities are controlled by the suprachiasmatic nucleus (SCN), which is well known as the oscillator of circadian rhythm. Recently, it is reported that circadian oscillators exist not only in the SCN but also in peripheral organs. To date, it is unclear which circadian oscillators predominantly drive the daily fluctuations of hepatic ACD activities. To address this question, we examined the effects of restricted feeding, which uncouples the circadian oscillators in the liver from the central pacemaker in the SCN, on the daily fluctuations in hepatic ACD activities in male rats. Here we show that restricted feeding inverts the oscillation phase of the daily fluctuations in hepatic ACD activities. Regarding the hepatic P450 content, there were no fluctuations between the light and dark periods under ad libitum and restricted feeding conditions. Therefore, it is considered that the daily fluctuations in hepatic ACD activities are predominantly driven by the circadian factors in peripheral organs rather than by the oscillator in the SCN directly.

  20. Hepatic and hematological adverse effects of long-term low-dose methotrexate therapy in rheumatoid arthritis: An observational study

    PubMed Central

    Dubey, Lily; Chatterjee, Suparna; Ghosh, Alakendu

    2016-01-01

    Objectives: Methotrexate (MTX) is the most commonly used cost-effective disease-modifying antirheumatoid drug (DMARD). Its main dose-limiting adverse effects are hepatic and hematopoietic. This cross-sectional, observational study evaluated the prevalence of hepatic and hematological adverse effects with long-term low-dose MTX therapy. Materials and Methods: Rheumatoid arthritis (RA) patients taking ≤15 mg/week MTX for at least 2 years were enrolled from the rheumatology outpatient department. Demographic, disease, drug treatment profiles, and hematological and hepatic enzyme levels were noted. Results: Of the 204 patients enrolled, the frequency of raised alanine transaminase level (≥3-fold rise above the upper limit of normal) was 6.37% (95% confidence interval of 3.76–10.59) including two biopsy-proven hepatic fibrosis cases. About 5.4% had severe anemia (<8 g/dl) and 4.4% had leukopenia. Conclusion: Long-term low-dose MTX is safe in RA patients in the Indian population. The patterns of adverse effects were similar to those documented in earlier studies. However, our study results suggest that disease duration, cumulative MTX dose, concomitant DMARD intake are not risk factors associated with hepatic or hematological adverse effects.

  1. Effects of humic acid-metal complexes on hepatic carnitine palmitoyltransferase, carnitine acetyltransferase and catalase activities

    SciTech Connect

    Fungjou Lu; Youngshin Chen . Dept. of Biochemistry); Tienshang Huang . Dept. of Medicine)

    1994-03-01

    A significant increase in activities of hepatic carnitine palmitoyltransferase and carnitine acetyltransferase was observed in male Balb/c mice intraperitoneally injected for 40 d with 0.125 mg/0.1 ml/d humic acid-metal complexes. Among these complexes, the humic acid-As complex was relatively effective, whereas humic acid-25 metal complex was more effective, and humic acid-26 metal complex was most effective. However, humic acid or metal mixtures, or metal such as As alone, was not effective. Humic acid-metal complexes also significantly decreased hepatic catalase activity. A marked decrease of 60-kDa polypeptide in liver cytoplasm was also observed on SDS-polyacrylamide gel electrophoresis after the mice had been injected with the complexes. Morphological analysis of a histopathological biopsy of such treated mice revealed several changes in hepatocytes, including focal necrosis and cell infiltration, mild fatty changes, reactive nuclei, and hypertrophy. Humic acid-metal complexes affect activities of metabolic enzymes of fatty acids, and this results in accumulation of hydrogen peroxide and increase of the lipid peroxidation. The products of lipid peroxidation may be responsible for liver damage and possible carcinogenesis. Previous studies in this laboratory had shown that humic acid-metal complex altered the coagulation system and that humic acid, per se, caused vasculopathy. Therefore, humic acid-metal complexes may be main causal factors of not only so-called blackfoot disease, but also the liver cancer prevailing on the southwestern coast of Taiwan.

  2. In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

    PubMed Central

    Veen, A H van der; Seynhaeve, A L B; Breurs, J; Nooijen, P T G A; Marquet, R L; Eggermont, A M M

    1999-01-01

    Isolated perfusion of the extremities with high-dose tumour necrosis factor α (TNF-α) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-α and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 μg TNF-α. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-α and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-α alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-α, the minimal threshold concentration of TNF-α to exert its anti-tumour effects was not reached. The applicability of TNF-α in isolated kidney perfusion for human tumours seems, therefore, questionable. © 1999 Cancer Research Campaign PMID:10027309

  3. Laryngeal solitary fibrous tumour.

    PubMed

    Stomeo, Francesco; Padovani, Davide; Bozzo, Corrado; Pastore, Antonio

    2007-09-01

    Solitary fibrous tumours (SFT) are rare neoplasms, with an uncommon laryngeal involvement. Only five cases of laryngeal localization have been described in literature. The following is a case of a 75-year-old man with a supraglottic neoplasm of the larynx; after the biopsy immunohistochemical study demonstrated a strong positivity for vimentin, CD34 and Bcl-2. The neoplasm was consequently classified as a SFT. CO(2) laser surgery of the supraglottic larynx, with a wide excision of the neoplasm, was performed. Twenty-four months on, the patient is alive, well and free of disease. Surgical resection is the treatment of choice for laryngeal SFT, but tumour-free resection margins must be achieved to prevent the possibility of local recurrence. Endoscopic resection by means of the CO(2) laser must be accurately planned with MRI or CT imaging to confirm of this kind of surgery.

  4. Effects of nanogold on the alleviation of carbon tetrachloride-induced hepatic injury in rats.

    PubMed

    Chen, Yi-Peng; Dai, Zong-Her; Liu, Pan-Chen; Chuu, Jiunn-Jye; Lee, Kuo-Yang; Lee, Shun-Lai; Chen, Yun-Ju

    2012-10-31

    Gold particles have been used in complementary medicine for decades, and many beneficial effects have been reported. Our present study sought to evaluate the therapeutic effects of nanogold in carbon tetrachloride (CCl₄)-injured liver of rats. Male SD rats were subjected to liver injury induction by CCl₄, then the rats were fed with zero to high dose (0, 1, 5 or 10 ppm) of nanogold water every day for 4 weeks. Biochemical analyses on liver functions were then performed to evaluate the therapeutic effects of nanogold. Our results revealed that gold nanoparticles lowered serum aspartate aminotransaminase (AST) and alanine aminotransferase and exerted serum total protein-recovering effects, which might be partially associated with the elevation of anti-inflammatory cytokine IL-10 level. In addition, serum triglyceride level fell after continuous ingestion of nanogold. Finally, the experimental animals recovered body weight after 4 weeks of nanogold ingestion. This is the first report indicating inflammation alleviating effects of nanogold on hepatic injury.

  5. Effect of Experimentally Induced Hepatic and Renal Failure on the Pharmacokinetics of Topiramate in Rats

    PubMed Central

    Matar, Kamal M.; Tayem, Yasin I.

    2014-01-01

    We aimed to investigate the effect of induced hepatic and renal failure on the pharmacokinetics of topiramate (TPM) in rats. Twenty-four Sprague-Dawley rats were used in this study. Renal or hepatic failure was induced by a single i.p. dose of 7.5 mg/kg cisplatin (n = 8) or 0.5 mL/kg carbon tetrachloride (CCl4) (n = 8), respectively. Three days after cisplatin dose or 24 h after CCl4 dose, the rats were administered a single oral dose of 20 mg/kg TPM. The plasma samples were quantified by LC-MS/MS method. Compared to control, plasma concentration-time profile in CCl4-treated and, to a lesser extent, in cisplatin-treated rats decreased more slowly particularly in the elimination phase. TPM oral clearance (CL/F) in CCl4-treated group was significantly lower than that in control (P < 0.001), whereas AUC0−∞, T1/2, and Vd/F were significantly higher in CCl4-treated rats compared to the control (P < 0.01). The CL/F was not significantly different between cisplatin-treated rats and control (P > 0.05). However, in cisplatin-treated rats, the T1/2 and Vd/F were significantly higher than that in the control group (P < 0.01). Both conditions failed to cause a significant effect on Cmax or Tmax. The present findings suggest that induced hepatic or renal failure could modify the pharmacokinetic profile of TPM in the rat. PMID:25009818

  6. Tumour Angiogenesis and Angiogenic Inhibitors: A Review

    PubMed Central

    Yadav, Lalita; Puri, Naveen; Satpute, Pranali; Sharma, Vandana

    2015-01-01

    Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of angiogenic mechanism have lead to the development of several anti-angiogenic and anti-metastatic agents that use the strategy of regulation of angiogenic switch. Antiangiogenic therapy is a form of treatment not cure for cancer and represents a highly effective strategy for destroying tumour because vascular supply is the fundamental requirement for growth of tumour. Because of the quiescent nature of normal adult vasculature, angiogenic inhibitors are expected to confer a degree of specificity when compared to nonspecific modalities of chemo and radiotherapy, so it has the advantage of less toxicities, does not induce drug resistance and deliver a relatively non toxic, long term treatment of tumour. PMID:26266204

  7. Postprandial thermic effect of chicken involves thyroid hormones and hepatic energy metabolism in rats.

    PubMed

    Wakamatsu, Jun-ichi; Takabayashi, Naomasa; Ezoe, Misako; Hasegawa, Takanori; Fujimura, Tatsuya; Takahata, Yoshihisa; Morimatsu, Fumiki; Nishimura, Takanori

    2013-01-01

    We investigated the postprandial thermic effect of chicken and its mechanisms in rats. A chicken diet showed a strong thermic effect after consumption, and the removal of fat induced more rapid and stronger thermogenesis. Although thermogenesis induced by a purified chicken protein diet was also strong, the thermic reaction was not so rapid and a remarkable rise of peripheral temperatures was not observed. Defatted chicken and purified chicken protein activated the thyroid hormone system and up-regulated rate-limiting enzyme genes of glucose metabolism and the tricarboxylic acid (TCA) cycle in the liver. Moreover, chicken protein up-regulated the mRNA expression of a rate-limiting enzyme of hepatic lipid metabolism. It is possible that the mechanisms by which body temperature is raised are different between chicken protein and defatted chicken. On the other hand, it is possible that chicken fat suppressed the expression of energy metabolism-related genes that was induced by the consumption of lean chicken. As a result, a rise of postprandial body temperature might not have been induced after consumption of chicken fat. These results suggest that the consumption of lean chicken activates the thyroid hormone system and hepatic energy metabolism and consequently induces the postprandial thermic effect of chicken.

  8. MRI of paediatric liver tumours: How we review and report.

    PubMed

    Shelmerdine, Susan C; Roebuck, Derek J; Towbin, Alexander J; McHugh, Kieran

    2016-01-01

    Liver tumours are fortunately rare in children. Benign tumours such as haemangiomas and cystic mesenchymal hamartomas are typically seen in infancy, often before 6 months of age. After that age, malignant hepatic tumours increase in frequency. The differentiation of a malignant from benign lesion on imaging can often negate the need for biopsy. Ultrasound is currently the main screening tool for suspected liver pathology, and is ideally suited for evaluation of hepatic lesions in children due to their generally small size. With increasing research, public awareness and parental anxiety regarding radiation dosage from CT imaging, MRI is now unquestionably the modality of choice for further characterisation of hepatic mass lesions.Nevertheless the cost, length of imaging time and perceived complexity of a paediatric liver MR study can be intimidating to the general radiologist and referring clinician. This article outlines standard MR sequences utilised, reasons for their utilisation, types of mixed hepatocyte specific/extracellular contrast agents employed and imaging features that aid the interpretation of paediatric liver lesions. The two commonest paediatric liver malignancies, namely hepatoblastoma and hepatocellular carcinoma are described. Differentiation of primary hepatic malignancies with metastatic disease and mimickers of malignancy such as focal nodular hyperplasia (FNH) and hepatic adenomas are also featured in this review..Imaging should aim to clarify the presence of a lesion, the likelihood of malignancy and potential for complete surgical resection. Reviewing and reporting the studies should address these issues in a systematic fashion whilst also commenting upon background liver parenchymal appearances. Clinical information and adequate patient preparation prior to MR imaging studies help enhance the diagnostic yield. PMID:27526937

  9. Treatment of primary brain tumours in adults.

    PubMed

    McNamara, Shanne

    This article considers the complexities of caring for patients with primary brain tumours. The incidence, classification and clinical signs and symptoms are outlined. Adult patients experience disabling effects as a result of a brain tumour, which is often accompanied by high morbidity and mortality rates. The various treatment options available are summarised. However, for many patients, there are limited curative treatment options and the main focus is palliative care. The nurse's contribution to care and support of these patients and their families is discussed, with the aim of improving their quality of life.

  10. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats

    PubMed Central

    Milton Prabu, S.; Muthumani, M.; Shagirtha, K.

    2012-01-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats. PMID:23961183

  11. Effects of salvianolic acids on oxidative stress and hepatic fibrosis in rats

    SciTech Connect

    Tsai, M.-K.; Lin, Y.-L.; Huang, Y.-T.

    2010-01-15

    Enhanced oxidative stress is associated with hepatic fibrosis. Salvianolic acids A (Sal A) and B (Sal B) have been reported to be strong polyphenolic antioxidants and free radical scavengers. The present study is to investigate if Sal A and B could attenuate oxidative stress and liver fibrosis in rats. A cell line of rat hepatic stellate cells (HSCs) was stimulated with platelet-derived growth factor (PDGF, 10 ng/ml). The inhibitory effects of Sal A and B on intracellular hydrogen peroxide levels were measured with dichlorofluorescein diacetate (DCF-DA) dye assay. alpha-Smooth muscle actin (alpha-SMA), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits were measured by Western blotting. Liver fibrosis was induced by intraperitoneal injections of thioacetamide (TAA, 200 mg/kg) twice per week for 6 weeks. Sal A (10 mg/kg), Sal B (50 mg/kg) or S-adenosylmethionine (SAMe, 10 mg/kg), was given by gavage twice per day consecutively for 4 weeks starting 2 weeks after TAA injection. In vitro, PDGF increased the accumulation of hydrogen peroxide in HSCs, which was attenuated by Sal A (10 muM) and Sal B (200 muM). Sal A and B attenuated the PDGF-stimulated expressions of alpha-SMA and NADPH oxidase subunits gp91{sup phox} and p47{sup phox} in membrane fractions. In vivo studies showed that the hepatic levels of collagen, malondialdehyde, TNF-alpha, IL-6, and IL-1beta, fibrosis scores and protein expressions of alpha-SMA, heme-oxygenase-1, iNOS, and gp91{sup phox}, and serum levels of ALT, AST, IL-6, and IL-1beta were increased in TAA-intoxicated rats, all of which were attenuated by 4-week treatment of Sal A or Sal B. Our results showed that Sal A and B attenuated PDGF-induced ROS formation in HSCs, possibly through inhibition of NADPH oxidase. Sal A and B treatments were also effective against hepatic fibrosis in TAA-intoxicated rats.

  12. Hepatic Epithelioid Hemangioendothelioma in an Eight Year old - A Case Report

    PubMed Central

    Nayal, Bhavna; Nagel, Bhawna; Rao, Lakshmi

    2014-01-01

    Hepatic epithelioid haemangio-endothelioma (HEHE) is a rare vascular tumour of endothelial origin. The etiology of this tumour is unknown and has a variable clinical outcome. It usually affects adults and is extremely rare in children. Histologically, HEHE is characterized by epithelioid to dendritic tumour cells with intracytoplasmic lumina containing RBCs and a myxoid to sclerotic stroma. Being a rare entity, awareness and a high degree of suspicion is required to correctly identify this tumour. We report a case of hepatic hemangioendothelioma in an 8-year-old child. PMID:25653958

  13. Hepatic Epithelioid Hemangioendothelioma in an Eight Year old - A Case Report.

    PubMed

    Vasudevan, Geetha; Nayal, Bhavna; Nagel, Bhawna; Rao, Lakshmi

    2014-12-01

    Hepatic epithelioid haemangio-endothelioma (HEHE) is a rare vascular tumour of endothelial origin. The etiology of this tumour is unknown and has a variable clinical outcome. It usually affects adults and is extremely rare in children. Histologically, HEHE is characterized by epithelioid to dendritic tumour cells with intracytoplasmic lumina containing RBCs and a myxoid to sclerotic stroma. Being a rare entity, awareness and a high degree of suspicion is required to correctly identify this tumour. We report a case of hepatic hemangioendothelioma in an 8-year-old child. PMID:25653958

  14. Anti-tumour activity of Ruta graveolens extract.

    PubMed

    Preethi, K C; Kuttan, Girija; Kuttan, Ramadasan

    2006-01-01

    An extract of Ruta graveolens was found to be cytotoxic to Dalton's lymphoma ascites (DLA), Ehrlich ascites carcinoma (EAC) and L929 cells in culture (IC100=16 mg/ml) and also to increase the lifespan of tumour bearing animals. The extract further decreased solid tumours developing from DLA and EAC cells when given simultaneously with elongation of the lifespan of tumour-bearing animals. A homeopathic preparation of Ruta graveolens (200 c) was equally effective. Neither was effective for reducing already developed tumours. The Ruta graveolens extract was found to scavenge hydroxyl radicals and inhibit lipid peroxidation at low concentrations. However, at higher concentrations the extract acted as a prooxidant as inhibition of lipid peroxidation and scavenging of hydroxyl radical was minimal. These data indicates that the prooxidant activity of Ruta graveolens may be responsible for the cytocidal action of the extract and its ability to produce tumour reduction.

  15. Anti-tumour activity of Ruta graveolens extract.

    PubMed

    Preethi, K C; Kuttan, Girija; Kuttan, Ramadasan

    2006-01-01

    An extract of Ruta graveolens was found to be cytotoxic to Dalton's lymphoma ascites (DLA), Ehrlich ascites carcinoma (EAC) and L929 cells in culture (IC100=16 mg/ml) and also to increase the lifespan of tumour bearing animals. The extract further decreased solid tumours developing from DLA and EAC cells when given simultaneously with elongation of the lifespan of tumour-bearing animals. A homeopathic preparation of Ruta graveolens (200 c) was equally effective. Neither was effective for reducing already developed tumours. The Ruta graveolens extract was found to scavenge hydroxyl radicals and inhibit lipid peroxidation at low concentrations. However, at higher concentrations the extract acted as a prooxidant as inhibition of lipid peroxidation and scavenging of hydroxyl radical was minimal. These data indicates that the prooxidant activity of Ruta graveolens may be responsible for the cytocidal action of the extract and its ability to produce tumour reduction. PMID:17059340

  16. Hepatitis virus panel

    MedlinePlus

    Hepatitis A antibody test; Hepatitis B antibody test; Hepatitis C antibody test; Hepatitis D antibody test ... or past infection, or immunity to hepatitis A Hepatitis B tests: Hepatitis B surface antigen (HBsAg), you have ...

  17. Hepatitis C and HIV

    MedlinePlus

    ... Problems : Hepatitis C Subscribe Translate Text Size Print Hepatitis C What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis B . Hepatitis C and HIV About 25% of people living ...

  18. Hepatitis B and HIV

    MedlinePlus

    ... Problems : Hepatitis B Subscribe Translate Text Size Print Hepatitis B What is Hepatitis? Hepatitis means inflammation of the liver. This condition ... our related pages, Hepatitis A and Hepatitis C . Hepatitis B and HIV About 10% of people living ...

  19. Protective effects of Parinari curatellifolia flavonoids against acetaminophen-induced hepatic necrosis in rats

    PubMed Central

    Olaleye, Mary Tolulope; Amobonye, Ayodeji Emmannuel; Komolafe, Kayode; Akinmoladun, Afolabi Clement

    2014-01-01

    In the present study, we investigated the hepatoprotective potential of Parinari curatellifolia Planch (Chrysobalanaceae) in experimental rats in order to ascertain the validity of folkloric claims of its effectiveness in the treatment of hepatic-related disorders. Flavonoid extract of P. curatellifolia seed, PCF (10-, 20- or 30 mg/kg body weight) or silymarin (25 mg/kg), dissolved in corn oil, was administered by gavage to experimental animals once daily for 14 consecutive days before liver damage was chemically induced through the administration of acetaminophen (2 g/kg p.o.) on the 14th day. Hepatoprotection was assessed by analyzing liver homogenate and serum for markers of hepatotoxicity – alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT) and lactate dehydrogenase (LDH) activities as well as prothrombin time (PT). Evaluation of biochemical indices of oxidative stress – level of lipid peroxides (LPO), activities of superoxide dismutase (SOD) and catalase, along with histological assessment of hepatic tissue sections were also carried out. Results revealed that all doses of PCF significantly (P < 0.001) and dose dependently prevented acetaminophen-induced increase in serum activities of hepatic enzymes (ALT, AST, GGT, LDH) and PT. Furthermore, PCF (10- and 20 mg/kg) significantly (P < 0.001) reduced lipid peroxidation in liver tissue and restored the activities of the antioxidant enzymes SOD and catalase toward normal levels. Histopathology of the liver tissue showed that PCF mitigated the toxicant-induced hepatocellular necrosis, reduced inflammatory cell infiltration and enhanced hepatocyte regeneration. The results indicated that P. curatellifolia flavonoids demonstrated remarkable hepatoprotective activity in acute liver injury caused by acetaminophen. PMID:25313285

  20. Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure.

    PubMed

    Kim, Seok-Joo; Cho, Hong-Ik; Kim, So-Jin; Park, Jin-Hyun; Kim, Joon-Sung; Kim, Young Ho; Lee, Sang Kook; Kwak, Jong-Hwan; Lee, Sun-Mee

    2014-09-01

    Linarin was isolated from Chrysanthemum indicum L. Fulminant hepatic failure is a serious clinical syndrome that results in massive inflammation and hepatocyte death. Apoptosis is an important cellular pathological process in d-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, and regulation of liver apoptosis might be an effective therapeutic method for fulminant hepatic failure. This study examined the cytoprotective mechanisms of linarin against GalN/LPS-induced hepatic failure. Mice were given an oral administration of linarin (12.5, 25 and 50mg/kg) 1h before receiving GalN (800 mg/kg)/LPS (40 μg/kg). Linarin treatment reversed the lethality induced by GalN/LPS. After 6h of GalN/LPS injection, the serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-α, interleukin-6 and interferon-γ were significantly elevated. GalN/LPS increased toll-like receptor 4 and interleukin-1 receptor-associated kinase protein expression. These increases were attenuated by linarin. Linarin attenuated the increased expression of Fas-associated death domain and caspase-8 induced by GalN/LPS, reduced the cytosolic release of cytochrome c and caspase-3 cleavage induced by GalN/LPS, and reduced the pro-apoptotic Bim phosphorylation induced by GalN/LPS. However, linarin increased the level of anti-apoptotic Bcl-xL and phosphorylation of STAT3. Our results suggest that linarin alleviates GalN/LPS-induced liver injury by suppressing TNF-α-mediated apoptotic pathways.

  1. Paraumbilical vein patency in cirrhosis: effects on hepatic hemodynamics evaluated by Doppler sonography.

    PubMed

    Sacerdoti, D; Bolognesi, M; Bombonato, G; Gatta, A

    1995-12-01

    Doppler sonographic portal vein parameters are used for the noninvasive evaluation of portal hypertension in cirrhosis. The patency of a paraumbilical vein is a rather frequent finding in cirrhosis, which may affect hepatic hemodynamics and function. We evaluated portal and hepatic arterial parameters in 184 cirrhotic patients with and without a patent paraumbilical vein and the relationships with paraumbilical blood flow. A patent paraumbilical vein was found in 33.7% of patients. The prevalence was higher (56.8%) in Child C patients. Portal blood flow velocity (PBV) (10.8 +/- 2.2 vs. 9.8 +/- 2.4 cm/sec; P < .01) and volume (PBF) (995.0 +/- 383.8 vs. 811.6 +/- 318.7 mL/min; P < .001) was significantly higher, and effective portal liver perfusion (PLP) (portal blood flow--paraumbilical blood flow) (621.3 +/- 420.8 vs. 811.6 +/- 318.7 mL/min; P < .001) was significantly lower in patients with a patent paraumbilical vein than in those without. These differences were more evident in Child C patients (10.7 +/- 2.0 vs. 8.3 +/- 2.3 cm/sec; 935.7 +/- 378.3 vs. 680.6 +/- 239.4 mL/min; 369.0 +/- 282.0 vs. 680.6 +/- 239.4 mL/min). Portal vein diameter, the congestion index (CI) of the portal vein, hepatic arterial resistance indexes, and the severity of esophageal varices did not differ between the two groups. In patients with a patent paraumbilical vein, the Child-Pugh score and the prevalence of ascites were significantly higher than in those without. In conclusion, the evaluation of PBV and PBF in cirrhotic patients can provide misleading results if a paraumbilical vein is patent, underestimating the degree of portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Maspin as a Tumour Suppressor in Salivary Gland Tumour

    PubMed Central

    Ashok, Nipun; Sheirawan, Mohammad Kinan; Altamimi, Mohammed Alsakran; Alenzi, Faris; Azzeghaiby, Saleh Nasser; Baroudi, Kusai; Nassani, Mohammad Zakaria

    2014-01-01

    Maspin is a protein that belongs to serin protease inhibitor (serpin) superfamily. The purpose of this study was to review the literature concerning the expression of maspin in salivary gland tumours. A literature search was done using MEDLINE, accessed via the National Library of Medicine PubMed interface. Statistical analysis was not done because only seven studies were available in literature, the collected data were different and the results could not be compared. Expression of maspin was down regulated in more aggressive salivary gland tumours. Maspin may function as a tumour suppressor in salivary gland tumours. PMID:25654053

  3. Transillumination imaging of intraocular tumours.

    PubMed

    Kjersem, Bård; Krohn, Jørgen

    2013-06-01

    The purpose of this paper is to discuss a recently described modification of a standard photo slit lamp system for ocular transillumination, with special emphasis on the light transmission through the eye wall and the photographic technique. Transillumination photography was carried out with the Haag-Streit Photo-Slit Lamp BX 900 (Haag-Streit AG, Koeniz, Switzerland). After having released the background lighting optic fibre cable from its holder, the patient was positioned at the slit lamp, and the fibre tip was gently pressed against the sclera or the cornea of the patient's eye. During about 1/1000 of a second, the eye was illuminated by the flash and the scleral shadow of the tumour was exposed to the camera sensor. The images were of good diagnostic quality, making it easy to outline the tumours and to evaluate the involvement of intraocular structures. None of the examined patients experienced discomfort or negative side effects. The method is recommended in cases where photographic transillumination documentation of intraocular pathologies is considered important. PMID:23641762

  4. Cholestatic hepatitis as a possible new side-effect of oxycodone: a case report

    PubMed Central

    Ho, Vincent; Stewart, Maxwell; Boyd, Peter

    2008-01-01

    Introduction Oxycodone is a widely-used semisynthetic opioid analgesic that has been used for over eighty years. Oxycodone is known to cause side effects such as nausea, pruritus, dizziness, constipation and somnolence. As far as we are aware cholestatic hepatitis as a result of oxycodone use has not been reported so far in the world literature. Case presentation A 34-year-old male presented with cholestatic jaundice and severe pruritus after receiving oxycodone for analgesia post-T11 vertebrectomy. Extensive laboratory investigations and imaging studies did not reveal any other obvious cause for his jaundice and a liver biopsy confirmed canalicular cholestatis suggestive of drug-induced hepatotoxicity. The patient's symptoms and transaminases normalised on withdrawal of oxycodone confirming that oxycodone was the probable cause of the patient's hepatotoxicity. Conclusion We conclude that cholestatic hepatitis is possibly a rare side effect of oxycodone use. Physicians should be aware of the possibility of this potentially serious picture of drug-induced hepatotoxicity. PMID:18452597

  5. Effect of polybrominated biphenyls on hepatic excretory function in rats and mice.

    PubMed

    Cagen, S Z; Gibson, J E

    1978-04-01

    The purpose of this investigation was to determine the influence of polybrominated biphenyls (PBBs) on hepatic excretory function in developing and adult rats and mice. Prenatal or postnatal dietary exposure to PBBs (50 ppm in diet of pregnant or lactating mother or in diet of rat weanlings) resulted in elevated liver weight in developing rats. In 15-day-old rats that had been treated with PBBs increased liver weight correlated to enhanced ouabain transport from plasma into bile. Liver weight was also elevated in 21, 35, and 49-day-old rats exposed to PBBs, but this effect was not associated with stimulation of ouabain transport in these animals. However, adult rats fed 100 ppm PBBs for two weeks had significantly lower plasma concentrations of sulfobromophthalein (BSP) and increased biliary excretion of BSP, when compared to controls. PBBs-fed adult rats also excreted a greater percentage conjugated BSP (BSP-GSH) into bile. Two week dietary treatment of 100, 150, and 200 ppm PBBs resulted in enhanced initial disappearance of indocyanine green (ICG) from plasma of adult mice. However, dietary doses of 100 and 200 ppm PBBs to adult mice was not associated with enhanced capacity for ouabain excretion. In contrast, treatment with PBBs through the mother's diet (50 ppm) resulted in an almost twofold increase in cumulative ouabain excretion in 15-day-old mice. The results suggest that PBBs stimulate hepatic drug elimination in rats and mice, but the magnitude of the effect is dependent on age and transported compound.

  6. Decellularized liver scaffolds effectively support the proliferation and differentiation of mouse fetal hepatic progenitors

    PubMed Central

    Wang, Xiaojun; Cui, Jing; Zhang, Bing-Qiang; Zhang, Hongyu; Bi, Yang; Kang, Quan; Wang, Ning; Bie, Ping; Yang, Zhanyu; Wang, Huaizhi; Liu, Xiangde; Haydon, Rex C; Luu, Hue H; Tang, Ni; Dong, Jiahong; He, Tong-Chuan

    2014-01-01

    Decellularized whole organs represent ideal scaffolds for engineering new organs and/or cell transplantation. Here, we investigate whether decellularized liver scaffolds provide cell-friendly biocompatible three-dimensional environment to support the proliferation and differentiation of hepatic progenitor cells. Mouse liver tissues are efficiently decellularized through portal vein perfusion. Using the reversibly immortalized mouse fetal hepatic progenitor cells (iHPCs), we are able to effectively recellularize the decellularized liver scaffolds. The perfused iHPCs survive and proliferate in the three-dimensional scaffolds in vitro for 2 weeks. When the recellularized scaffolds are implanted into the kidney capsule of athymic nude mice, cell survival and proliferation of the implanted scaffolds are readily detected by whole body imaging for 10 days. Furthermore, EGF is shown to significantly promote the proliferation and differentiation of the implanted iHPCs. Histologic and immunochemical analyses indicate that iHPCs are able to proliferate and differentiate to mature hepatocytes upon EGF stimulation in the scaffolds. The recellularization of the biomaterial scaffolds is accompanied with vascularization. Taken together, these results indicate that decullarized liver scaffolds effectively support the proliferation and differentiation of iHPCs, suggesting that decellularized liver matrix may be used as ideal biocompatible scaffolds for hepatocyte transplantation. PMID:23625886

  7. Inhibition of intracellular hepatitis C virus replication by nelfinavir and synergistic effect with interferon-alpha.

    PubMed

    Toma, S; Yamashiro, T; Arakaki, S; Shiroma, J; Maeshiro, T; Hibiya, K; Sakamoto, N; Kinjo, F; Tateyama, M; Fujita, J

    2009-07-01

    Liver diseases associated with hepatitis C virus (HCV) infection have become the major cause of mortality in patients with human immunodeficiency virus (HIV) infection since the introduction of highly active anti-retroviral therapy. HCV-related liver disease is more severe in HIV-infected patients than in non-HIV-infected patients, but the standard therapies used to treat chronic hepatitis C in HCV/HIV coinfected patients are the same as those for patients infected with HCV alone. HIV protease inhibitors might have potential to down-regulate HCV load of HCV/HIV coinfected patients. In this study, we evaluated the effects of nelfinavir on intracellular HCV replication using the HCV replicon system. We constructed an HCV replicon expressing a neomycin-selectable chimeric firefly luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir were assessed and synergism between nelfinavir and interferon (IFN) was calculated using CalcuSyn analysis. Nelfinavir dose-dependently repressed HCV replication at low concentrations (IC(50), 9.88 micromol/L). Nelfinavir failed to induce cytotoxicity or apoptosis at concentrations that inhibited HCV replication. Clinical concentrations of nelfinavir (5 micromol/L) combined with IFN showed synergistic inhibition of HCV replication in our replicon model. Our results suggest that the direct effects of nelfinavir on the HCV subgenome and its synergism with IFN could improve clinical responses to IFN therapy in HCV/HIV coinfected patients.

  8. Anthropogenic selection enhances cancer evolution in Tasmanian devil tumours

    PubMed Central

    Ujvari, Beata; Pearse, Anne-Maree; Swift, Kate; Hodson, Pamela; Hua, Bobby; Pyecroft, Stephen; Taylor, Robyn; Hamede, Rodrigo; Jones, Menna; Belov, Katherine; Madsen, Thomas

    2014-01-01

    The Tasmanian Devil Facial Tumour Disease (DFTD) provides a unique opportunity to elucidate the long-term effects of natural and anthropogenic selection on cancer evolution. Since first observed in 1996, this transmissible cancer has caused local population declines by >90%. So far, four chromosomal DFTD variants (strains) have been described and karyotypic analyses of 253 tumours showed higher levels of tetraploidy in the oldest strain. We propose that increased ploidy in the oldest strain may have evolved in response to effects of genomic decay observed in asexually reproducing organisms. In this study, we focus on the evolutionary response of DFTD to a disease suppression trial. Tumours collected from devils subjected to the removal programme showed accelerated temporal evolution of tetraploidy compared with tumours from other populations where no increase in tetraploid tumours were observed. As ploidy significantly reduces tumour growth rate, we suggest that the disease suppression trial resulted in selection favouring slower growing tumours mediated by an increased level of tetraploidy. Our study reveals that DFTD has the capacity to rapidly respond to novel selective regimes and that disease eradication may result in novel tumour adaptations, which may further imperil the long-term survival of the world's largest carnivorous marsupial. PMID:24567746

  9. Hepatic PEComa: a potential pitfall in the evaluation of hepatic neoplasms

    PubMed Central

    Khan, Hadi Mohammad; Katz, Steven C; Libbey, N Peter; Somasundar, Ponnandai S

    2014-01-01

    Perivascular epithelioid cell tumour (PEComa) of the liver is very uncommon and may be overlooked in the clinical and histological differential diagnosis of a liver tumour. We report the case of an incidentally discovered liver mass suspicious for hepatocellular carcinoma, which on biopsy was suggestive of a pseudocyst but after resection was found to be hepatic PEComa with some of the usual characteristics of this neoplasm as well as several less familiar features. We have also reviewed cases of hepatic PEComa from the literature in order to provide insight into recognising possible PEComa preoperatively and assessing its risk of malignancy after diagnosis. PMID:24907216

  10. Application of Bayesian Approach to Cost-Effectiveness Analysis of Antiviral Treatments in Chronic Hepatitis B

    PubMed Central

    Zhang, Hua; Huo, Mingdong; Chao, Jianqian; Liu, Pei

    2016-01-01

    Background Hepatitis B virus (HBV) infection is a major problem for public health; timely antiviral treatment can significantly prevent the progression of liver damage from HBV by slowing down or stopping the virus from reproducing. In the study we applied Bayesian approach to cost-effectiveness analysis, using Markov Chain Monte Carlo (MCMC) simulation methods for the relevant evidence input into the model to evaluate cost-effectiveness of entecavir (ETV) and lamivudine (LVD) therapy for chronic hepatitis B (CHB) in Jiangsu, China, thus providing information to the public health system in the CHB therapy. Methods Eight-stage Markov model was developed, a hypothetical cohort of 35-year-old HBeAg-positive patients with CHB was entered into the model. Treatment regimens were LVD100mg daily and ETV 0.5 mg daily. The transition parameters were derived either from systematic reviews of the literature or from previous economic studies. The outcome measures were life-years, quality-adjusted lifeyears (QALYs), and expected costs associated with the treatments and disease progression. For the Bayesian models all the analysis was implemented by using WinBUGS version 1.4. Results Expected cost, life expectancy, QALYs decreased with age. Cost-effectiveness increased with age. Expected cost of ETV was less than LVD, while life expectancy and QALYs were higher than that of LVD, ETV strategy was more cost-effective. Costs and benefits of the Monte Carlo simulation were very close to the results of exact form among the group, but standard deviation of each group indicated there was a big difference between individual patients. Conclusions Compared with lamivudine, entecavir is the more cost-effective option. CHB patients should accept antiviral treatment as soon as possible as the lower age the more cost-effective. Monte Carlo simulation obtained costs and effectiveness distribution, indicate our Markov model is of good robustness. PMID:27574976

  11. Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice

    PubMed Central

    Di Scala, Marianna; Otano, Itziar; Gil-Fariña, Irene; Vanrell, Lucia; Hommel, Mirja; Olagüe, Cristina; Vales, Africa; Galarraga, Miguel; Guembe, Laura; Ortiz de Solorzano, Carlos; Ghosh, Indrajit; Maini, Mala K.; Prieto, Jesús

    2016-01-01

    ABSTRACT In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8+ T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-α) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8+ immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-α, which, given together, constitute a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions. IMPORTANCE With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not

  12. Effect of Octreotide on Hepatic Steatosis in Diet-Induced Obesity in Rats

    PubMed Central

    Li, Mao; Ye, Ting; Wang, Xiao-Xia; Li, Xian; Qiang, Ou; Yu, Tao; Tang, Cheng-Wei; Liu, Rui

    2016-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) caused by liver lipid dysregulation is linked to obesity. Somatostatin (SST) and its analogs have been used to treat pediatric hypothalamic obesity. However, the application of such drugs for the treatment of NAFLD has not been evaluated. Objective This study aimed to investigate the expression levels of important regulators of hepatic lipid metabolism and the possible effect of the SST analog octreotide on these regulators. Methods SD rats were assigned to a control group and a high-fat diet group. Obese rats from the high-fat diet group were further divided into the obese and octreotide-treated groups. The body weight, plasma SST, fasting plasma glucose (FPG), insulin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels were measured. Hepatic steatosis was evaluated based on the liver TG content, HE staining and oil red O staining. The SREBP-1c, ACC1, FAS, MTP, apoB and ADRP expression levels in the liver were also determined by RT-PCR, qRT-PCR, western blot or ELISA. Results The obese rats induced by high-fat diet expressed more SREBP-1c, FAS and ADRP but less MTP protein in the liver than those of control rats, whereas octreotide intervention reversed these changes and increased the level of apoB protein. Compared to the control group, obese rats showed increased liver ACC1, SREBP-1c and apoB mRNA levels, whereas octreotide-treated rats showed decreased mRNA levels of apoB and SREBP-1c. This was accompanied by increased body weight, liver TG contents, FPG, TG, TC, LDL-C, FFA, insulin and derived homeostatic model assessment (HOMA) values. Octreotide intervention significantly decreased these parameters. Compared to the control group, the obese group showed a decreasing trend on plasma SST levels, which were significantly increased by the octreotide intervention. Conclusion Octreotide can

  13. Effect of curcumin on hepatic heme oxygenase 1 expression in high fat diet fed rats: is there a triangular relationship?

    PubMed

    Öner-İyidoğan, Yildiz; Tanrıkulu-Küçük, Sevda; Seyithanoğlu, Muhammed; Koçak, Hikmet; Doğru-Abbasoğlu, Semra; Aydin, A Fatih; Beyhan-Özdaş, Şule; Yapişlar, Hande; Koçak-Toker, Necla

    2014-10-01

    High fat diet (HFD) is associated with oxidative stress induced fatty liver. Curcumin, an extract of Curcuma longa, has been shown to possess potent antioxidant and hypolipidemic properties. In this study, we investigated the effect of curcumin treatment on hepatic heme oxygenase-1 (HO-1) expression along with pro-oxidant-antioxidant status and lipid accumulation in rats fed an HFD. Male Sprague-Dawley rats were distributed among 4 groups: Group 1, which was fed the control diet (10% of total calories from fat); Group 2, which was fed the HFD (60% of total calories from fat); and groups 3 and 4, which received the HFD supplemented with curcumin and the control diet supplemented with curcumin (1 g/kg diet; w/w), respectively, for 16 weeks. HFD caused increases in hepatic lipid levels, production of reactive oxygen species, and lipid peroxidation. Further, HO-1 expression was significantly decreased. Histopathological examination showed hepatic fat accumulation and slight fibrotic changes. Curcumin treatment reduced hepatic lipids and oxidative stress parameters, and HO-1 expression was significantly increased. These findings suggest that increased HO-1 expression, along with suppressed oxidative stress as well as reduced hepatic fat accumulation and fibrotic changes, contribute to the beneficial effects of curcumin in attenuating the pathogenesis of fatty liver induced metabolic diseases.

  14. 3,5,3'-Triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) synthesis in rats hosting the R3230AC mammary tumour.

    PubMed

    Ong, M L; Kellen, J A; Malkin, D G; Malkin, A

    1986-01-01

    Generation of T3 and rT3 from T4 was studied in R3230AC mammary tumours grown in Fischer 344 rats as well as in the liver and kidney of these tumour-bearing hosts. The primary objective of this study was to determine if reversion of T3 to rT3 synthesis occurs in this experimental tumour model and in organs remote from the tumour site. Tumours, hepatic and renal homogenates were analyzed 14-16 days following tumour implantation for 5- and 5'-iodothyronine deiodinase activity using thyroxine as substrate. It was observed that similar to the liver and kidney, the mammary tumour was capable of generating both T3 and rT3 from T4; renal synthesis of T3 was significantly greater than that of rT3 in tumour hosts and controls. In contrast, there was no significant difference between T3 and rT3 synthesis in the tumour itself and the livers of normal and tumour-bearing animals. Hepatic and renal T3 synthesis were greater in the tumour-bearing than in the normal rats; no difference in the hepatic and renal rT3 synthesis was observed between the tumour-bearing and the normal animals. Despite the fact that serum T3 was significantly lower in the tumour-bearing than in the normal rats, no difference in the serum rT3 level was observed between the two groups of animals. Our data demonstrate that in this particular animal model there is no evidence of dedifferentiation of iodothyronine deiodinase activity either within the tumour or in remote tissues.

  15. Differential effects on portal and effective hepatic blood flow. A comparison between transjugular intrahepatic portasystemic shunt and small-diameter H-graft portacaval shunt.

    PubMed Central

    Rosemurgy, A S; Zervos, E E; Goode, S E; Black, T J; Zwiebel, B R

    1997-01-01

    OBJECTIVE: This study was undertaken to determine the effects of transjugular intrahepatic portasystemic shunt (TIPS) and small-diameter prosthetic H-graft portacaval shunt (HGPCS) on portal and effective hepatic blood flow. SUMMARY BACKGROUND DATA: Mortality after TIPS is higher than after HGPCS for bleeding varices. This higher mortality is because of hepatic failure, possibly a result of excessive diminution of hepatic blood flow. METHODS: Forty patients randomized prospectively to undergo TIPS or HGPCS had effective hepatic blood flow determined 1 day preshunt and 5 days postshunt using low-dose galactose clearance. Portal blood flow was determined using color-flow Doppler ultrasound. RESULTS: Treatment groups were similar in age, gender, and Child's class. Each procedure significantly reduced portal pressures and portasystemic pressure gradients. Portal flow after TIPS increased (21 mL/second +/- 11.9 to 31 mL/second +/- 16.9, p < 0.05), whereas it remained unchanged after HGPCS (26 mL/second +/- 27.7 to 14 mL/second +/- 41.1, p = n.s.). Effective hepatic blood flow was diminished significantly after TIPS (1684 mL/minute +/- 2161 to 676 mL/minute +/- 451, p < 0.05) and was unaffected by HGPCS (1901 mL/ minute +/- 1818 to 1662 mL/minute +/- 1035, p = n.s.). CONCLUSIONS: Both TIPS and HGPCS achieved significant reductions in portal vein pressure gradients. Portal flow increased after TIPS, although most portal flow was diverted through the shunt. Effective hepatic flow is reduced significantly after TIPS but well preserved after HGPCS. Hepatic decompensation and mortality after TIPS may be because, at least in part, of reductions in nutrient hepatic flow. PMID:9193187

  16. The effects of dexamethasone and chlorpromazine on tumour necrosis factor-alpha, interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-10 in human volunteers.

    PubMed Central

    Bleeker, M W; Netea, M G; Kullberg, B J; Van der Ven-Jongekrijg, J; Van der Meer, J W

    1997-01-01

    Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production. PMID:9378493

  17. An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

    NASA Astrophysics Data System (ADS)

    Adhikarla, Vikram; Jeraj, Robert

    2016-05-01

    Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (t peak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t peak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30–40%). Interestingly, both pO2peak and t peak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [64Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for

  18. An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

    NASA Astrophysics Data System (ADS)

    Adhikarla, Vikram; Jeraj, Robert

    2016-05-01

    Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (t peak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t peak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30-40%). Interestingly, both pO2peak and t peak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [64Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for analysing

  19. Cost-effectiveness of sofosbuvir for the treatment of chronic hepatitis C-infected patients.

    PubMed

    Cure, S; Guerra, I; Dusheiko, G

    2015-11-01

    The efficacy of treatment for hepatitis C genotype 1 infection has significantly improved with the introduction of first-generation protease inhibitors. However, there remains a need for effective treatments for patients infected with other genotypes, for nonresponders and patients unsuitable for interferon. Sofosbuvir is the first nucleotide polymerase inhibitor with pan-genotypic activity. Sofosbuvir-based regimens have resulted in >90% sustained virological response across treatment-naïve genotype 1-6 patients in five phase III clinical trials of sofosbuvir administered with ribavirin or pegylated interferon and ribavirin. This analysis evaluates the cost-effectiveness of sofosbuvir within the current licensed indication, for genotype 1-6 in the UK. A Markov model followed a cohort of 10 000 patients over lifetime, with approximately 20% initiating treatment for compensated cirrhosis. Sofosbuvir-regimens were compared to telaprevir, boceprevir, pegylated interferon and ribavirin, or no treatment. Costs and outcomes were discounted at 3.5%. The cost perspective utilized costs applicable to the National Health Service in the UK. Sofosbuvir proved to be cost-effective in most patient populations with incremental cost-effectiveness ratios (ICERs) at £11 836/QALY and £7292/QALY against telaprevir and boceprevir, respectively. In genotype 3, sofosbuvir had a weighted ICER of £18 761/QALY. Sofosbuvir-based regimens are a cost-effective option for the majority of hepatitis C-infected patients in the United Kingdom although the incremental cost-effectiveness varies by genotype and regimen. Sofosbuvir and ribavirin is an alternative regimen for patients unsuitable for interferon.

  20. Brain Tumours Simulating Psychiatric Disease

    PubMed Central

    Hobbs, G. E.

    1963-01-01

    Brain tumours may present with symptoms indistinguishable from psychiatric disease. The impression of most psychiatrists is that individuals suffering from brain tumour rarely appear among their patients. A priori reasoning based on evidence from neurological, neurosurgical and pathological sources suggests the contrary. The present study is a frequency analysis of cases of previously undiagnosed brain tumours admitted to either an open psychoneurotic ward or a mental hospital over a period of 15 years. The results support the impression held by psychiatrists that brain tumours are uncommon among psychiatric patients. PMID:13954870

  1. Effect of chemotherapy on autoimmune hepatitis in thymoma: a case report and literature review

    PubMed Central

    Mejri, Nesrine; Chabchoub, Imen; Gargouri, Ines; Belaid, Imtinen; Ezairi, Faten; Hmissa, Sihem; Ben Ahmed, Slim

    2013-01-01

    Autoimmune hepatitis (AIH) has rarely been described as an autoimmune paraneoplastic syndrome of thymoma. This case is the seventh case of AIH revealed by cholestasis few years after the diagnosis of thymoma and the first case treated with chemotherapy alone. We report in this paper a new approach to this rare severe condition. A 29 year-old man presented with chest pain and dyspnea with a history of thymoma surgically removed 4 years ago. CT scan showed the recurrence of an anterior mediastinal mass. Biology showed elevated liver enzymes and profound cholestasis. No sign of viral or toxic hepatitis or bile duct abnormalities were observed. Autoimmune antibodies, except for the anti-nuclear antibody, were negative. Liver biopsy showed active chronic AIH. The patient was diagnosed with recurrent thymoma with AIH and underwent 6 cycles of chemotherapy. A complete response on thymoma and cholestasis was obtained after 10 months of follow-up. Steroids and immunosuppressors are the standard treatment for AIH. The effect of chemotherapy as a specific treatment of this paraneoplastic syndrome needs to be considered. PMID:24379993

  2. Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon tetrachloride-induced hepatic damage in rats.

    PubMed

    Achliya, Girish S; Wadodkar, Sudhir G; Dorle, Avinash K

    2004-02-01

    Amalkadi Ghrita (AG), a polyherbal formulation, was evaluated for its hepatoprotective activity against carbon tetrachloride (CCl4)-induced hepatic damage in rats. The hepatoprotective activity of AG was evaluated by measuring levels of serum marker enzymes like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and acid phosphatase (ACP). The serum levels of total proteins and bilirubin were also estimated. The histological studies were also carried out to support the above parameters. Silymarin was used as standard drug. Administration of AG (100 and 300 mg/kg, p.o.) markedly prevented CCl4-induced elevation of levels of serum GPT, GOT, ACP, ALP, and bilirubin. The decreased level of total proteins due to hepatic damage induced by CCl4 was found to be increased in AG-treated group. The results are comparable to that of silymarin. A comparative histopathological study of liver exhibited almost normal architecture, as compared to CCl4-treated group. Hepatoprotective effect of AG is probably due to combined action of all ingredients. PMID:15013185

  3. Hepatoprotective effect of biherbal ethanolic extract against paracetamol-induced hepatic damage in albino rats

    PubMed Central

    Anantha, Krishna Chaitanya D.; Siva, Reddy Challa; Manohar, Reddy A.

    2012-01-01

    Aim: The combined hepatoprotective effect of Bi-herbal ethanolic extract (BHEE) was evaluated against paracetamol induced hepatic damage in albino rats. Materials and Methods: Liver function tests and biochemical parameters were estimated using standard kits. Livers were quickly removed and fixed in 10% formalin and subjected to histopathological studies. Results: Ethanolic extract from the leaves of Aerva lanata and leaves of Achyranthes aspera at a dose level of 200 mg/kg, 400mg/kg body weight was administered orally once for 3 days. Substantially elevated serum marker enzymes such as SGOT, SGPT, ALP, due to paracetamol treatment were restored towards normal. Biochemical parameters like total protein, total bilirubin, total cholesterol, triglycerides, and urea were also restored towards normal levels. In addition, BHEE significantly decreased the liver weight of paracetamol intoxicated rats. Silymarin at a dose level of 25 mg/kg used as a standard reference also exhibited significant hepatoprotective activity against paracetamol induced hepatotoxicity. Conclusion: The results of this study strongly indicate that BHEE has got a potent hepatoprotective action against paracetamol induced hepatic damage in rats. PMID:23326091

  4. Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog

    PubMed Central

    Liu, Ying; Hu, Xiaoqing; Takeda, Shunichi; Qing, Yong

    2016-01-01

    Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1-/- mutant cells defective in single-strand break (SSB) repair were the most sensitive to entecavir. Brca1-/-, Ubc13-/- and translesion-DNA-synthesis deficient cells including Rad18-/- and Rev3-/- were hypersensitive to entecavir. XPA-/- mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. γ-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1-/-, Rad18-/- and Brca1-/- mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1-/-, Brca1-/-, Rad18-/- and Rev3-/- cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity. PMID:26800464

  5. Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog.

    PubMed

    Jiang, Lei; Wu, Xiaohua; He, Fang; Liu, Ying; Hu, Xiaoqing; Takeda, Shunichi; Qing, Yong

    2016-01-01

    Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1-/- mutant cells defective in single-strand break (SSB) repair were the most sensitive to entecavir. Brca1-/-, Ubc13-/- and translesion-DNA-synthesis deficient cells including Rad18-/- and Rev3-/- were hypersensitive to entecavir. XPA-/- mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. γ-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1-/-, Rad18-/- and Brca1-/- mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1-/-, Brca1-/-, Rad18-/- and Rev3-/- cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity. PMID:26800464

  6. Malignant testicular tumours

    PubMed Central

    Vecchio, Pierre Del; Tawil, Elie; Béland, Gilles

    1974-01-01

    A series of 71 patients with malignant testicular tumours treated primarily by orchiectomy and irradiation is reviewed with respect to pathological and clinical features and modes of treatment. The three-year crude survival rate in 36 patients with seminoma was 86% and in 24 patients with carcinoma it was 41.7%. There were no survivors among patients with choriocarcinoma. Our results are comparable with those of other series. A prospective study is proposed of the value of irradiation and subsequent limited lymph node dissection following orchiectomy in cases of carcinoma of the testis. PMID:4855670

  7. The antifibrotic effects of TGF-{beta}1 siRNA on hepatic fibrosis in rats

    SciTech Connect

    Lang, Qing; Liu, Qi; Xu, Ning; Qian, Ke-Li; Qi, Jing-Hu; Sun, Yin-Chun; Xiao, Lang; Shi, Xiao-Feng

    2011-06-10

    Highlights: {yields} We constructed CCL4 induced liver fibrosis model successfully. {yields} We proofed that the TGF-{beta}1 siRNA had a definite therapy effect to CCL4 induced liver fibrosis. {yields} The therapy effect of TGF-{beta}1 siRNA had dose-dependent. -- Abstract: Background/aims: Hepatic fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs), which proliferate during fibrotic liver injury. Transforming growth factor (TGF)-{beta}1 is the dominant stimulus for extracellular matrix (ECM) production by stellate cells. Our study was designed to investigate the antifibrotic effects of using short interference RNA (siRNA) to target TGF-{beta}1 in hepatic fibrosis and its mechanism in rats exposed to a high-fat diet and carbon tetrachloride (CCL4). Methods: A total of 40 healthy, male SD (Sprague-Dawley) rats were randomly divided into five even groups containing of eight rats each: normal group, model group, TGF-{beta}1 siRNA 0.125 mg/kg treatment group, TGF-{beta}1 siRNA 0.25 mg/kg treatment group and TGF-{beta}1 siRNA negative control group (0.25 mg/kg). CCL4 and a high-fat diet were used for 8 weeks to induce hepatic fibrosis. All the rats were then sacrificed to collect liver tissue samples. A portion of the liver samples were soaked in formalin for Hematoxylin-Eosin staining, classifying the degree of liver fibrosis, and detecting the expression of type I and III collagen and TGF-{beta}1; the remaining liver samples were stored in liquid nitrogen to be used for detecting TGF-{beta}1 by Western blotting and for measuring the mRNA expression of type I and III collagen and TGF-{beta}1 by quantitative real-time polymerase chain reaction. Results: Comparing the TGF-{beta}1 siRNA 0.25 mg/kg treatment group to the model group, the TGF-{beta}1 siRNA negative control group and the TGF-{beta}1 siRNA 0.125 mg/kg treatment group showed significantly reduced levels of pathological changes, protein expression and the m

  8. The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression

    PubMed Central

    Houthuijzen, J M; Daenen, L G M; Roodhart, J M L; Voest, E E

    2012-01-01

    It is becoming increasingly clear that the tumour microenvironment has a very important role in tumour progression and drug resistance. Many different cell types within the tumour stroma have an effect on tumour progression either in a positive or in a negative way. Mesenchymal stem cells (MSCs) are a distinct population of cells that have been linked with tumour growth. Mesenchymal stem cells can home to tumours where they modulate the immune system and facilitate tumour growth, angiogenesis and metastasis. Recent studies have shown that MSCs also have an important role in the resistance to various anti-cancer drugs. This mini-review provides an overview of the functional properties of MSCs in tumour progression and drug resistance. PMID:22596239

  9. Defining the clonal dynamics leading to mouse skin tumour initiation.

    PubMed

    Sánchez-Danés, Adriana; Hannezo, Edouard; Larsimont, Jean-Christophe; Liagre, Mélanie; Youssef, Khalil Kass; Simons, Benjamin D; Blanpain, Cédric

    2016-08-18

    The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin. PMID:27459053

  10. Evaluation of the effectiveness of treatment with prednisone and azathioprine of autoimmune hepatitis in children

    PubMed Central

    Sobolewska-Pilarczyk, Małgorzata; Pawłowska, Małgorzata

    2015-01-01

    Introduction Autoimmune hepatitis is rarely diagnosed in children, but the course of the disease is often aggresive. Combination therapy with prednisone and azathioprine improves the prognosis of patients. Aim To evaluate the effectiveness of combination therapy with prednisone and azathioprine of autoimmune hepatitis (AIH) in children. Material and methods There was a retrospective analysis of the medical records of 15 patients with AIH, diagnosed before18 years of age, treated in the Provincial Infectious Diseases Hospital in Bydgoszcz in the years 2002 to 2013. We analysed the results of laboratory tests, ultrasound examination, endoscopy, and morphological liver pictures, as well as periods of exacerbation of inflammation and side effects of therapy. Results Biochemical remission of the disease was achieved on average after 36 days of treatment. Histopathological regression in the control liver biopsy was found in 7/15 patients and progression in 2/15 patients. In the study group 10/15 patients experienced exacerbation of the disease from 1 to 3 times during observation, with an increase of ALT activity to greater than 3 norm, and the remaining 5/15 patients had no increase of ALT activity. In total, 10 patients in the study group experienced 17 exacerbations. In 13/17 cases of exacerbations they were associated with a reduction in the dose of immunosuppressive drugs. There was no correlation between the biochemical exacerbation and changes in the histopathological image. Steroidside effects occurred in 14/15 patients. Conclusions The treatment allows for biochemical remission of the disease and significantly improves the prognosis of most patients. However, significant side effects of treatment indicate the need for further exploration of effective and safe therapy, especially in the paediatric population. PMID:27110306

  11. Assessing Hepatitis C Burden and Treatment Effectiveness through the British Columbia Hepatitis Testers Cohort (BC-HTC): Design and Characteristics of Linked and Unlinked Participants

    PubMed Central

    Janjua, Naveed Zafar; Kuo, Margot; Chong, Mei; Yu, Amanda; Alvarez, Maria; Cook, Darrel; Armour, Rosemary; Aiken, Ciaran; Li, Karen; Mussavi Rizi, Seyed Ali; Woods, Ryan; Godfrey, David; Wong, Jason; Gilbert, Mark; Tyndall, Mark W.; Krajden, Mel

    2016-01-01

    Background The British Columbia (BC) Hepatitis Testers Cohort (BC-HTC) was established to assess and monitor hepatitis C (HCV) epidemiology, cost of illness and treatment effectiveness in BC, Canada. In this paper, we describe the cohort construction, data linkage process, linkage yields, and comparison of the characteristics of linked and unlinked individuals. Methods The BC-HTC includes all individuals tested for HCV and/or HIV or reported as a case of HCV, hepatitis B (HBV), HIV or active tuberculosis (TB) in BC linked with the provincial health insurance client roster, medical visits, hospitalizations, drug prescriptions, the cancer registry and mortality data using unique personal health numbers. The cohort includes data since inception (1990/1992) of each database until 2012/2013 with plans for annual updates. We computed linkage rates by year and compared the characteristics of linked and unlinked individuals. Results Of 2,656,323 unique individuals available in the laboratory and surveillance data, 1,427,917(54%) were included in the final linked cohort, including about 1.15 million tested for HCV and about 1.02 million tested for HIV. The linkage rate was 86% for HCV tests, 89% for HCV cases, 95% for active TB cases, 48% for HIV tests and 36% for HIV cases. Linkage rates increased from 40% for HCV negatives and 70% for HCV positives in 1992 to ~90% after 2005. Linkage rates were lower for males, younger age at testing, and those with unknown residence location. Linkage rates for HCV testers co-infected with HIV, HBV or TB were very high (90–100%). Conclusion Linkage rates increased over time related to improvements in completeness of identifiers in laboratory, surveillance, and registry databases. Linkage rates were higher for HCV than HIV testers, those testing positive, older individuals, and females. Data from the cohort provide essential information to support the development of prevention, care and treatment initiatives for those infected with HCV

  12. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice.

    PubMed

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-03-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  13. Effects of sodium butyrate on the differentiation of pancreatic and hepatic progenitor cells from mouse embryonic stem cells.

    PubMed

    Ren, Meng; Yan, Li; Shang, Chang-Zhen; Cao, Jun; Lu, Li-Hong; Min, Jun; Cheng, Hua

    2010-01-01

    Recently significant progress has been made in differentiating embryonic stem (ES) cells toward pancreatic cells. However, little is known about the generation and identification of pancreatic progenitor cells from ES cells. Here we explored the influence of sodium butyrate on pancreatic progenitor differentiation, and investigated the different effects of sodium butyrate on pancreatic and hepatic progenitor formation. Our results indicated that different concentration and exposure time of sodium butyrate led to different differentiating trends of ES cells. A relatively lower concentration of sodium butyrate with shorter exposure time induced more pancreatic progenitor cell formation. When stimulated by a higher concentration and longer exposure time of sodium butyrate, ES cells differentiated toward hepatic progenitor cells rather than pancreatic progenitor cells. These progenitor cells could further mature into pancreatic and hepatic cells with the supplement of exogenous inducing factors. The resulting pancreatic cells expressed specific markers such as insulin and C-peptide, and were capable of insulin secretion in response to glucose stimulation. The differentiated hepatocytes were characterized by the expression of a number of liver-associated genes and proteins, and had the capability of glycogen storage. Thus, the current study demonstrated that sodium butyrate played different roles in inducing ES cells toward pancreatic or hepatic progenitor cells. These progenitor cells could be further induced into mature pancreatic cells and hepatocytes. This finding may facilitate the understanding of pancreatic and hepatic cell differentiation from ES cells, and provide a potential source of transplantable cells for cell-replacement therapies.

  14. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice

    PubMed Central

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-01-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  15. The effect of combined exposures to ethanol and xylene on rat hepatic microsomal monooxygenase activities.

    PubMed

    Wiśniewska-Knypl, J M; Wrońska-Nofer, T; Jajte, J; Jedlińska, U

    1989-01-01

    Studies on rats treated for 8 months with ethanol (10% solution in drinking water) and simultaneously exposed to xylene vapour (12,000 mg/m3, 5 hr daily) for the last 9 days revealed that the chemicals exert additive stimulatory effect on hepatic microsomal monooxygenase: the activity of aniline p-hydroxylase increased by 380%, microsomal ethanol oxidizing system by 92%, NADPH-cyt. c reductase by 30% and the level of cytochrome P-450 by 70%. The changes were accompanied by a marked proliferation of smooth endoplasmic reticulum (a subcellular site of cytochrome P-450 monooxygenases in the hepatocytes) and an increased NADPH-Fe2+- and ascorbate-Fe2+-driven lipid peroxidation in microsomal membranes--a potential toxic mechanism. Interaction of ethanol and xylene with cytochrome P-450 monooxygenases may enhance metabolic capacity of the liver and in consequence modify biological/toxic effects of occupational exposure to solvents in the case of alcohol abuse.

  16. Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

    PubMed Central

    El-Abhar, Hanan S.; Schaalan, Mona F.

    2012-01-01

    Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis. PMID:22649556

  17. The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model.

    PubMed

    Möser, Christine V; Meissner, Markus; Laarmann, Kathrin; Olbrich, Katrin; King-Himmelreich, Tanya S; Wolters, Miriam C; Geisslinger, Gerd; Niederberger, Ellen

    2016-03-01

    Inhibitor-kappaB kinase epsilon (IKKε) constitutes a non-canonical I-κB kinase, which amongst others modulates NF-κB activity. IKKε and NF-κB have both been described for their role in cell proliferation and their dysregulation has been associated with tumourigenesis and metastasis in multiple cancer types. Accordingly, overexpression and constitutive activation of NF-κB have also been shown in melanoma, however, the role of IKKε in this cancer type has not been investigated so far. Thus, we determined IKKε expression in malignant melanoma cells and we were able to show a significant overexpression of IKKε in tumour cells in comparison to melanocytes. Inhibition of IKKε either by shRNA or the pharmacological inhibitor amlexanox resulted in reduced cell proliferation associated with a cell cycle block in the G1-phase. Functional analysis indicated that NF-κB, Akt1 and MAPK pathways might be involved in the IKKε-mediated effects. In vivo, we applied a mouse melanoma skin cancer model to assess tumour growth and melanoma-associated pain in IKKε knockout mice as well as C57BL/6 mice after inoculation with IKKε-negative cells. In IKKε knockout mice, tumour growth was not altered as compared to IKKε wild type mice. However, melanoma associated pain was strongly suppressed accompanied by a reduced mRNA expression of a number of pain-relevant genes. In contrast, after inoculation of IKKε-depleted tumour cells, the development of melanoma was almost completely prevented. In conclusion, our data suggest that IKKε in the tumour plays an essential role in tumour initiation and progression while IKKε expression in tumour surrounding tissues contributes to melanoma-associated pain.

  18. Induction of IL-25 secretion from tumour-associated fibroblasts suppresses mammary tumour metastasis

    PubMed Central

    Yin, Shu-Yi; Jian, Feng-Yin; Chen, Yung-Hsiang; Chien, Shih-Chang; Hsieh, Mao-Chih; Hsiao, Pei-Wen; Lee, Wen-Hwa; Yang, Ning-Sun

    2016-01-01

    Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities. PMID:27089063

  19. Effects of acute ethanol exposure on hepatic metallothionein, zinc and glutathione in male and female rats

    SciTech Connect

    Harris, J.; Harrell, B. )

    1991-03-15

    The purpose of this study was to determine the simultaneous responses of hepatic metallothionein (MT), zinc (Zn) and glutathione (GSH) in male and female rats to an acute ethanol dose. In male rats, hepatic MT has been shown to be induced by an acute ethanol dose. The Sprague-Dawley rats were fed the Lieber-DeCarli control diet for a five day period and then divided into 6 groups: baseline females and males, ethanol-treated females and males, pair-fed females and males. At t=0, baseline rats were killed, ethanol-treated rats were given ethanol by intragastric tube, and pair-fed rats were given ethanol by intragastric tube, and pair-fed rats were given an isocaloric sucrose solution by intragastric tube. At t=24 h, the ethanol-treated and pair-fed rats were killed. Livers were assayed for MT. Zn and GSH. Concentrations of blood ethanol (BEC) were significantly greater for male than female rats. A two way ANOVA with the independent variables being time and sex was performed to analyze differences for hepatic MT, Zn and GSH. For rats dosed with ethanol and killed 24 h later compared with rats at baseline, hepatic MT was significantly greater and hepatic Zn and GSH were not significantly different. Hepatic MT, Zn and GSH were not significantly different by sex. A significant correlation existed between hepatic Zn/g and MT/g. In conclusion, 24 h after an acute dose of ethanol, female as well as male rats responded with the induction of hepatic MT; and enough cysteine was available for the induction of hepatic MT and the maintenance of hepatic GSH levels. The measurement of Zn bound to hepatic MT rather than total hepatic Zn would be desirable to discern if changes in Zn distribution occur.

  20. Study on the Antifibrotic Effects of Recombinant Shark Hepatical Stimulator Analogue (r-sHSA) in Vitro and in Vivo.

    PubMed

    Wang, Ying; Zhang, Xiaoyuan; Yang, Yang; Yang, Xiaohong; Ye, Boping

    2015-08-18

    Hepatic fibrosis is an effusive wound healing process, characterized by an excessive deposition of extracellular matrix (ECM), as the consequence of chronic liver injury of any etiology. Current therapeutic repertoire for hepatic fibrosis is limited to withdrawal of the noxious agent, which is not always feasible. Hence, in this article, the antifibrotic effects and possible mechanisms of r-sHSA, a recombinant protein with hepatoprotection potential, were investigated. Using NIH/3T3 (mouse embro-fibroblast cell line), skin fibroblasts (human skin fibroblasts, SFBs) and HSC-T6 (rat hepatic stellate cell line), the in vitro effect of r-sHSA was evaluated by measuring the expression levels of alpha-1 Type I collagen (Col1A1) and α-smooth muscle actin (α-SMA). It turned out those fibrosis indicators were typically inhibited by r-sHSA, suggesting its capacity in HSCs inactivation. The antifibrotic activity of r-sHSA was further investigated in vivo on CCl4-induced hepatic fibrosis, in view of significant improvement of the biochemical and histological indicators. More specifically, CCl4-intoxication induced a significant increase in serological biomarkers, e.g., transaminase (AST, ALT), and alkaline phosphatase (ALP), as well as disturbed hepatic antioxidative status; most of the parameters were spontaneously ameliorated to a large extent by withdrawal of CCl4, although the fibrotic lesion was observed histologically. In contrast, r-sHSA treatment markedly eliminated fibrous deposits and restored architecture of the liver in a dose dependent manner, concomitantly with the phenomena of inflammation relief and HSCs deactivation. To sum up, these findings suggest a therapeutic potential for r-sHSA in hepatic fibrosis, though further studies are required.

  1. Neuroendocrine tumours - Medical therapy: Biological.

    PubMed

    Rinke, Anja; Krug, Sebastian

    2016-01-01

    Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, long-acting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon-α (IFNα) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNα. PMID:26971845

  2. Potent hepatoprotective effect in CCl4-induced hepatic injury in mice of phloroacetophenone from Myrcia multiflora

    PubMed Central

    Ferreira, Eduardo Antonio; Gris, Eliana Fortes; Felipe, Karina Bettega; Correia, João Francisco Gomes; Cargnin-Ferreira, Eduardo; Wilhelm Filho, Danilo; Pedrosa, Rozangela Curi

    2010-01-01

    Background This study investigated the hepatoprotective effect and antioxidant properties of phloroacetophenone (2′,4′,6′-trihydroxyacetophenone – THA), an acetophenone derived from the plant Myrcia multiflora. Material & Method The free radical scavenging activity in vitro and induction of oxidative hepatic damage by carbon tetrachloride (CCl4) (0.5 ml/kg, i.p.) were tested in male Swiss mice (25±5 g). Results This compound exhibited in vitro antioxidant effects on FeCl2–ascorbate-induced lipid peroxidation (LPO) in mouse liver homogenate, scavenging hydroxyl and superoxide radicals, and 2,2-diphenyl-1-picrylhydrazyl. The in vivo assays showed that THA significantly (p<0.01) prevented the increases of hepatic LPO as measured by the levels of thiobarbituric acid-reactive substances, mitochondrial swelling. It also protected hepatocytes against protein carbonylation and oxidative DNA damage. Consistent with these observations, THA pre-treatment normalized the activities of antioxidant enzymes, such as catalase, glutathione peroxidase, and superoxide dismutase, and increased the levels of reduced glutathione (GSH) in CCl4-treated mice. In addition, THA treatment significantly prevented the elevation of serum enzymatic activities of alanine amino transferase, aspartate amino transferase, and lactate dehydrogenase, as well as histological alterations induced by CCl4. Silymarin (SIL) (24 mg/kg), a known hepatoprotective drug used for comparison, led to a significant decrease (p<0.01) in activities of theses enzymes in way very similar to that observed in pre-treatment with THA. Conclusion These results suggest that the protective effects are due to reduction of oxidative damage induced by CCl4 resulting from the antioxidant properties of THA. PMID:21483585

  3. The effects of low-frequency vibrations on hepatic profile of blood

    NASA Astrophysics Data System (ADS)

    Damijan, Z.

    2008-02-01

    Body vibrations training has become popular in sports training, fitness activity, it is still a rare form of physical rehabilitation.. Vibrations are transmitted onto the whole body or some body parts of an exercising person via a vibration platform subjected to mechanical vertical vibrations. During the training session a participant has to maintain his body position or do exercises that engage specific muscles whilst vibrations of the platform are transmitted onto the person's body. This paper is the continuation of the earlier study covering the effects of low-frequency vibrations on selected physiological parameters of the human body. The experiments were conducted to find the answer to the question if vibration exposure (total duration of training sessions 6 hours 20 min) should produce any changes in hepatic profile of blood. Therefore a research program was undertaken at the University of Science and Technology AGH UST to investigate the effects of low-frequency vibration on selected parameters of hepatic profile of human blood. Cyclic fluctuations of bone loading were induced by the applied harmonic vibration 3.5 Hz and amplitude 0.004 m. The experiments utilizing two vibrating platforms were performed in the Laboratory of Structural Acoustics and Biomedical Engineering AGH-UST. The applied vibrations were harmless and not annoying, in accordance with the standard PN-EN ISO 130901-1, 1998. 23 women volunteers had 19 sessions on subsequent working days, at the same time of day. during the tests the participants remained in the standing position, passive. The main hypothesis has it that short-term low-frequency vibration exposure might bring about the changes of the hepatic profile of blood, including: bilirubin (BILIRUBIN), alkaline phosphatase (Alp), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (ALBUMIN) levels. Research data indicate the low-frequency vibrations exposure produces statistically significant decrease of

  4. Transsphenoidal surgery for pituitary tumours

    PubMed Central

    Massoud, A; Powell, M; Williams, R; Hindmarsh, P; Brook, C

    1997-01-01

    Accepted 29 January 1997
 OBJECTIVES—Transsphenoidal surgery (TSS) is the preferred method for the excision of pituitary microadenomas in adults. This study was carried out to establish the long term efficacy and safety of TSS in children.
STUDY DESIGN—A 14 year retrospective analysis was carried out on 23 children (16 boys and seven girls), all less than 18 years of age, who had undergone TSS at our centre.
RESULTS—Twenty nine transsphenoidal surgical procedures were carried out. The most common diagnosis was an adrenocorticotrophic hormone (ACTH) secreting adenoma (14 (61%) patients). The median length of follow up was 8.0 years (range 0.3-14.0 years). Eighteen (78%) patients were cured after the first procedure. No death was related to the operation. The most common postoperative complication was diabetes insipidus, which was transient in most patients. Other complications were headaches in two patients and cerebrospinal fluid leaks in two patients. De novo endocrine deficiencies after TSS in children were as follows: three (14%) patients developed panhypopituitarism, eight (73%) developed growth hormone insufficiency, three (14%) developed secondary hypothyroidism, and four (21%) developed gonadotrophin deficiency. Permanent ACTH deficiency occurred in five (24%) patients, though all patients received postoperative glucocorticoid treatment until dynamic pituitary tests were performed three months after TSS.
CONCLUSIONS—TSS in children is a safe and effective treatment for pituitary tumours, provided it is performed by surgeons with considerable experience and expertise. Surgical complications are minimal. Postoperative endocrine deficit is considerable, but is only permanent in a small proportion of patients.

 • Transsphenoidal surgery is a safe and effective treatment for pituitary tumours in children • Transsphenoidal surgery should be performed by surgeons with considerable experience and expertise • Surgical complications of

  5. Evaluation of tumour promoting potency of fish borne toxaphene residues, as compared to technical toxaphene and UV-irradiated toxaphene.

    PubMed

    Besselink, H; Nixon, E; McHugh, B; Rimkus, G; Klungsøyr, J; Leonards, P; De Boer, J; Brouwer, A

    2008-08-01

    In this study the potential impact of food chain-based biotransformation and physico-chemical weathering of toxaphene on its tumour promoting potential was investigated in vitro and in vivo. Human exposure to toxaphene is mainly through consumption of contaminated fish, therefore fish-borne residues of toxaphene (cod liver extract, CLE) were prepared by exposing cod to technical toxaphene (TT) for 63 days. UV-irradiated toxaphene (uvT) was included to represent a physico-chemical weathered toxaphene mixture. In vitro, TT, uvT and CLE all showed a dose- and time-dependent inhibition of gap junctional intercellular communication (GJIC) with a relative potency of CLE>TT=uvT. Tumour promoting potency was further studied in vivo in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats, using an increase in altered hepatic foci positive for glutathione-S-transferase-P (AHF-GST-P) as read out. No increase in AHF-GST-P occurred following exposure to either TT, uvT, or CLE, except for the positive control group (2,3,7,8-TCDD). Based on this study the no observed adverse effect level (NOAEL) for tumour promoting potency is at least 12.5mg/kg/week, or higher for CLE. Considering current human exposure levels in Europe it is doubtful that consumption of fish at current levels of toxaphene contamination give rise to human health risk. PMID:18558458

  6. Adapting radiotherapy to hypoxic tumours

    NASA Astrophysics Data System (ADS)

    Malinen, Eirik; Søvik, Åste; Hristov, Dimitre; Bruland, Øyvind S.; Rune Olsen, Dag

    2006-10-01

    In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO2-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO2-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO2 Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO2 values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields

  7. Dural invasion by pituitary tumours.

    PubMed

    Shaffi, O M; Wrightson, P

    1975-04-23

    In 12 cases of pituitary tumour the dura mater of the sella turcica or diaphragma sellae in contact with the tumour was examined histologically. In nine cases tumour cells were found lying deep in the substance of the dura. Dura from the sella of seven subjects without pituitary disease, obtianed at autopsy, showed no inclusions of pituitary tissue. Four of the cases studied were known before death to suffer from an invasive pituitary adenoma. Of eight surviving cases operated upon in the last two years, five showed dural invasion by tumour. The present report suggests that the condition may be more frequent than expected and that with more study it may provide an index of prognosis. It also defines a requirement for the surgeon aiming to prevent recurrence of tumour after operation or to achieve a complete endocrine ablation.

  8. Hepatitis A/B vaccination of adults over 40 years old: comparison of three vaccine regimens and effect of influencing factors.

    PubMed

    Van der Wielen, Marie; Van Damme, Pierre; Chlibek, Roman; Smetana, Jan; von Sonnenburg, Frank

    2006-06-29

    Challenged by contrasting data on low immune responses in the elderly with a combined hepatitis A/B vaccine, a randomised, controlled study was conducted to assess the immunogenicity of three hepatitis A and B vaccination regimens (group 1: combined hepatitis A/B vaccine Twinrix [GSK]; group 2: co-administered hepatitis A vaccine, Havrix [GSK]+hepatitis B vaccine Engerix -B [GSK], group 3: co-administered hepatitis A vaccine, Vaqta [Sanofi-Pasteur MSD]+hepatitis B vaccine HB VAX PRO [Sanofi-Pasteur MSD]) and the effect of influencing factors in subjects >40 years. On completion of the full vaccination course, anti-HBs seroprotection (SP) rates were 92, 80 and 71% in groups 1, 2 and 3, respectively; anti-HAV seropositivity (S+) rates were 97, 99 and 99%, respectively. In group 1, anti-HBs SP rate was non-inferior as well as superior and anti-HAV S+ rate was non-inferior to that in groups 2 and 3. Anti-HBs response was most significantly influenced by the vaccine regimen, followed by age, gender and BMI (stepwise multiple regression analysis). BMI had the most significant influence on HAV response followed by age, gender and vaccine regimen. In conclusion, Twinrix induced superior hepatitis B SP rates and similar hepatitis A S+ rates compared to concomitant administration of monovalent vaccines in subjects aged >40 years.

  9. Analysis of nanoparticle delivery to tumours

    NASA Astrophysics Data System (ADS)

    Wilhelm, Stefan; Tavares, Anthony J.; Dai, Qin; Ohta, Seiichi; Audet, Julie; Dvorak, Harold F.; Chan, Warren C. W.

    2016-05-01

    Targeting nanoparticles to malignant tissues for improved diagnosis and therapy is a popular concept. However, after surveying the literature from the past 10 years, only 0.7% (median) of the administered nanoparticle dose is found to be delivered to a solid tumour. This has negative consequences on the translation of nanotechnology for human use with respect to manufacturing, cost, toxicity, and imaging and therapeutic efficacy. In this article, we conduct a multivariate analysis on the compiled data to reveal the contributions of nanoparticle physicochemical parameters, tumour models and cancer types on the low delivery efficiency. We explore the potential causes of the poor delivery efficiency from the perspectives of tumour biology (intercellular versus transcellular transport, enhanced permeability and retention effect, and physicochemical-dependent nanoparticle transport through the tumour stroma) as well as competing organs (mononuclear phagocytic and renal systems) and present a 30-year research strategy to overcome this fundamental limitation. Solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.

  10. [Hepatic lesions after effective external cardiac massage--an iatrogenic complication not to be overlooked].

    PubMed

    Froment, P; Savioz, D; Robertson, M; Morel, P

    1998-01-01

    After external cardiac massage, 3-8% of patients present potentially dangerous liver lacerations. Here we discuss the case of a patient who presented a major haemodynamic instability following external cardiac massage and thrombolytic therapy. Falsely attributed to a cardiac complication, this was actually consecutive to a hepatic haemorrhage originating from liver lacerations caused by the cardiac massage. Haemodynamic stability was obtained by reestablishing blood volume and coagulation factors. Following this the patient evolved favorably. We discuss the importance of evoking the possible existence of abdominal lacerations after external cardiac massage and the therapeutic attitude which must be adopted towards these, particularly in the light of thrombolytic therapy used in interventional cardiology and its effect on these complications. PMID:9816931

  11. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle.

    PubMed

    Khachatoorian, Ronik; Arumugaswami, Vaithilingaraja; Raychaudhuri, Santanu; Yeh, George K; Maloney, Eden M; Wang, Julie; Dasgupta, Asim; French, Samuel W

    2012-11-25

    We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.

  12. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle

    SciTech Connect

    Khachatoorian, Ronik; Arumugaswami, Vaithilingaraja; Raychaudhuri, Santanu; Yeh, George K.; Maloney, Eden M.; Wang, Julie; and others

    2012-11-25

    We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.

  13. Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle

    PubMed Central

    Khachatoorian, Ronik; Arumugaswami, Vaithilingaraja; Raychaudhuri, Santanu; Yeh, George K.; Maloney, Eden M.; Wang, Julie; Dasgupta, Asim; French, Samuel W.

    2012-01-01

    We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV. PMID:22975673

  14. Effect of discounting on estimation of benefits determined by hepatitis C treatment

    PubMed Central

    Messori, Andrea; Fadda, Valeria; Maratea, Dario; Trippoli, Sabrina

    2012-01-01

    The combination of either boceprevir or telaprevir with ribavirin and interferon (triple therapy) has been shown to be more effective than ribavirin+interferon (dual therapy) for the treatment of genotype 1 hepatitis C. Since the benefit of these treatments takes place after years, simulation models are needed to predict long-term outcomes. In simulation models, the choice of different values of yearly discount rates (e.g., 6%, 3.5%, 2%, 1.5% or 0%) influences the results, but no studies have specifically addressed this issue. We examined this point by determining the long-term benefits under different conditions on the basis of standard modelling and using quality-adjusted life years (QALYs) to quantify the benefits. In our base case scenario, we compared the long-term benefit between patients given a treatment with a 40% sustained virologic response (SVR) (dual therapy) and patients given a treatment with a 70% SVR (triple therapy), and we then examined how these specific yearly discount rates influenced the incremental benefit. The gain between a 70% SVR and a 40% SVR decreased from 0.45 QALYs with a 0% discount rate to 0.22 QALYs with a 6% discount rate (ratio between the two values = 2.04). Testing the other discounting assumptions confirmed that the discount rate has a marked impact on the magnitude of the model-estimated incremental benefit. In conclusion, the results of our analysis can be helpful to better interpret cost-effectiveness studies evaluating new treatment for hepatitis C. PMID:22736930

  15. Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

    PubMed Central

    Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

    2015-01-01

    The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

  16. Effects of chronic ethanol administration on hepatic glycoprotein secretion in the rat

    SciTech Connect

    Sorrell, M.F.; Nauss, J.M.; Donohue, T.M. Jr.; Tuma, D.J.

    1983-03-01

    The effects of chronic ethanol feeding on protein and glycoprotein synthesis and secretion were studied in rat liver slices. Liver slices from rats fed ethanol for 4-5 wk showed a decreased ability to incorporate (/sup 14/C)glucosamine into medium trichloracetic acid-precipitable proteins when compared to the pair-fed controls; however, the labeling of hepatocellular glycoproteins was unaffected by chronic ethanol treatment. Immunoprecipitation of radiolabeled secretory (serum) glycoproteins with antiserum against rat serum proteins showed a similar marked inhibition in the appearance of glucosamine-labeled proteins in the medium of slices from ethanol-fed rats. Minimal effects, however, were noted in the labeling of intracellular secretory glycoproteins. Protein synthesis, as determined by measuring (/sup 14/C)leucine incorporation into medium and liver proteins, was decreased in liver slices from ethanol-fed rats as compared to the pair-fed controls. This was the case for both total proteins as well as immunoprecipitable secretory proteins, although the labeling of secretory proteins retained in the liver slices was reduced to a lesser extent than total radiolabeled hepatic proteins. When the terminal sugar, (/sup 14/C)fucose, was employed as a precursor in order to more closely focus on the final steps of hepatic glycoprotein secretion, liver slices obtained from chronic ethanol-fed rats exhibited impaired secretion of fucose-labeled proteins into the medium. When ethanol (5 or 10 mM) was added to the incubation medium containing liver slices from the ethanol-fed rats, the alterations in protein and glycoprotein synthesis and secretion caused by the chronic ethanol treatment were further potentiated. The results of this study indicate that liver slices prepared from chronic ethanol-fed rats exhibit both impaired synthesis and secretion of proteins and glycoproteins, and these defects are further potentiated by acute ethanol administration.

  17. The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function

    PubMed Central

    van der Aa, Evelyn; Buschow, Sonja I.; Biesta, Paula J.; Janssen, Harry L. A.; Woltman, Andrea M.

    2016-01-01

    Chronic hepatitis B virus (HBV) infection results from inadequate HBV-specific immunity. BDCA3+ dendritic cells (DCs) are professional antigen presenting cells considered to be important for antiviral responses because of specific characteristics, including high interferon-λ production. BDCA3+ DCs may thus also have a role in the immune response against HBV, and immunotherapeutic strategies aiming to activate DCs, including BDCA3+ DCs, in patient livers may represent an interesting treatment option for chronic HBV. However, neither the effect of chronic hepatitis B (CHB) infection on the frequency and function of BDCA3+ DCs in liver and blood, nor the effect of the viral surface protein (HBsAg) that is abundantly present in blood of infected individuals are known. Here, we provide an overview of BDCA3+ DC frequency and functional capacity in CHB patients. We find that intrahepatic BDCA3+ DC numbers are increased in CHB patients. BDCA3+ DCs from patient blood are not more mature at steady state, but display an impaired capacity to mature and to produce interferon-λ upon polyI:C stimulation. Furthermore, in vitro experiments exposing blood and intrahepatic BDCA3+ DCs to the viral envelope protein HBsAg demonstrate that HBsAg does not directly induce phenotypical maturation of BDCA3+ DCs, but may reduce IFN-λ production via an indirect unknown mechanism. These results suggest that BDCA3+ DCs are available in the blood and on site in HBV infected livers, but measures may need to be taken to revive their function for DC-targeted therapy. PMID:27529176

  18. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

    PubMed Central

    Howell, A.; DeFriend, D. J.; Robertson, J. F.; Blamey, R. W.; Anderson, L.; Anderson, E.; Sutcliffe, F. A.; Walton, P.

    1996-01-01

    We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer. PMID:8688341

  19. Anti-invasive effects of Celastrus Orbiculatus extract on interleukin-1 beta and tumour necrosis factor-alpha combination-stimulated fibroblast-like synoviocytes

    PubMed Central

    2014-01-01

    Background Invasion of fibroblast-like synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of nuclear factor-kappa B (NF-κB) pathway play a critical role in RA-FLS invasion induced by interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α). The present study aimed to explore the anti-invasive activity and mechanism of Celastrus orbiculatus extract (COE) on IL-1β and TNF-α combination-stimulated human RA-FLSs. Methods We investigated the effect of COE on IL-1β and TNF-α combination-induced FLS invasion as well as MMP expression and explored upstream signal transduction. Results COE suppressed IL-1β and TNF-α combination-stimulated FLSs invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that COE inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of NF-κB in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB. Conclusions COE inhibits IL-1β and TNF-α combination-induced FLSs invasion by suppressing NF-κB-mediated MMP-9 expression. PMID:24552146

  20. The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis.

    PubMed

    Inanir, A; Ozoran, K; Tutkak, H; Mermerci, B

    2004-01-01

    Seventy post-menopausal women with osteoporosis were randomized into two groups: 40 patients received calcitriol (0.5 microg/day) and calcium (1000 mg/day); and 30 control patients received calcium (1000 mg/day) alone. Thirty healthy women formed the healthy control group. Bone mineral density (BMD) and serum interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha) concentrations were measured at baseline and after 6 months of treatment. Calcitriol treatment for 6 months significantly increased BMD and reduced serum IL-1 and TNF-alpha concentrations compared with no significant changes in patients treated with calcium alone. Both treatments increased serum calcium and decreased parathyroid hormone concentrations. The healthy control group had a significantly lower IL-6 concentration than the post-menopausal women with osteoporosis. We have shown that calcitriol was an effective treatment for osteoporosis. Significant reductions in serum IL-1 and TNF-alpha concentrations suggest that, in addition to increasing the absorption of calcium, calcitriol may directly affect bone metabolism via cytokines.

  1. The effect of ketanserin upon postoperative blood pressure, cerebral blood flow and oxygen metabolism in patients subjected to craniotomy for cerebral tumours.

    PubMed

    Felding, M; Cold, G E; Jacobsen, C J; Stjernholm, P; Voss, K

    1995-07-01

    Hypertension and cerebral hyperperfusion are often seen in the immediate postoperative period after craniotomy for supratentorial tumours. This study was performed to evaluate the effect of ketanserin, given at the end of the peroperative period, upon cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) before extubation. Mean arterial blood pressure (MABP), cerebral arterio-venous oxygen content difference (AVDO2), PaO2, and PaCO2 were repeatedly measured during the operation, and 180 minutes after extubation. Ten patients were included in this study. The results were compared to those from a recent study in which ten patients served as control. All patients were anaesthetized with thiopentone, fentanyl, nitrous oxide 67%, halothane 0.5% anesthesia. Ten patients were given ketanserin 10-20 mg (mean 18.5 mg) before extubation. There was no significant difference in CBF- and CMRO2 values between the two groups. During the period between closure of the dura and 5 minutes after extubation, an increase in MABP was observed in the control group (P < 0.05) but not in the ketanserin group. During the same period, a decrease in AVDO2 was observed in both groups (P < 0.05) and during the next 10 minutes an increase was observed. However, no difference in AVDO2 values between the two groups was found. These findings suggest that peroperative treatment with ketanserin reduces postoperative hypertension without influencing the cerebral blood flow or metabolism. PMID:7572004

  2. Effectiveness of hepatitis B virus vaccination program in Egypt: Multicenter national project

    PubMed Central

    Salama, Iman I; Sami, Samia M; Said, Zeinab Nabil Ahmed; El-Sayed, Manal H; El Etreby, Lobna A; Rabah, Thanaa M; Elmosalami, Dalia M; Abdel Hamid, Amany T; Salama, Somaia I; Abdel Mohsen, Aida M; Emam, Hanaa M; Elserougy, Safaa M; Hassanain, Amal I; Abd Alhalim, Naglaa F; Shaaban, Fatma A; Hemeda, Samia A; Ibrahim, Nihad A; Metwally, Ammal M

    2015-01-01

    AIM: To assess the effectiveness of hepatitis B virus (HBV) vaccination program among fully vaccinated children. METHODS: A national community based cross-sectional study was carried out in 6 governorates representing Egypt. A total of 3600 children aged from 9 mo to 16 years who were fully vaccinated with HBV vaccine during infancy were recruited. Face to face interviews were carried out and sera were evaluated for hepatitis B surface antigen (HBsAg), anti-HBV core antibodies (total) and quantitative detection of hepatitis B surface antibody using enzyme linked immunoassays techniques. Samples positive to HBsAg/anti-HBV core antibodies were subjected to quantitative HBV-DNA detection by real time polymerase chain reaction with 3.8 IU/L detection limit. RESULTS: Sero-protection was detected among 2059 children (57.2%) with geometric mean titers 75.4 ± 3.6 IU/L compared to 3.1 ± 2.1 IU/L among non-seroprotected children. Multivariate logistic analysis revealed that older age and female gender were the significant predicting variables for having non sero-protective level, with adjusted odds ratio 3.3, 9.1 and 14.2 among children aged 5 to < 10, 10 to < 15 and ≥ 15 years respectively compared to those < 5 years and 1.1 among girls compared to boys with P < 0.01. HBsAg was positive in 0.11% and breakthrough infection was 0.36% and 0.39% depending on positivity of anti-HBc and DNA detection respectively. The prevalence of HBV infection was significantly higher among children aged ≥ 7 years (0.59%) compared to 0.07% among younger children with odds ratio equal to 8.4 (95%CI: 1.1-64.2) and P < 0.01.The prevalence was higher among girls (0.48%) than boys (0.29%) with P > 0.05. CONCLUSION: The Egyptian compulsory HBV vaccination program provides adequate protection. Occult HBV infection exists among apparently healthy vaccinated children. Adherence to infection control measures is mandatory. PMID:26464758

  3. Hepatitis C: Treatment

    MedlinePlus

    ... Public Home » Hepatitis C » Hepatitis C Treatment Viral Hepatitis Menu Menu Viral Hepatitis Viral Hepatitis Home For ... Enter ZIP code here Enter ZIP code here Hepatitis C Treatment for Veterans and the Public Treatment ...

  4. Hepatitis C and Incarceration

    MedlinePlus

    HEPATITIS C & INCARCERATION What is hepatitis? “Hepatitis” means inflammation or swelling of the liver. The liver is an important ... viral hepatitis: Hepatitis A, Hepatitis B, and Hepatitis C. They are all different from each other and ...

  5. Hepatitis A

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis A, is caused by the hepatitis A virus (HAV). The disease spreads through contact with ... washed in untreated water Putting into your mouth a finger or object that came into contact with ...

  6. Autoimmune hepatitis

    MedlinePlus

    Lupoid hepatitis; Chronic acute liver disease ... This form of hepatitis is an autoimmune disease . The body's immune system cannot tell the difference between healthy body tissue and harmful, outside ...

  7. Hepatitis D

    MedlinePlus

    ... if the hepatitis B virus is also present. Transmission Hepatitis D can be found in the blood, ... other body fluids of people who are infected. Transmission happens when infected body fluid enters another person’s ...

  8. Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

    PubMed Central

    2015-01-01

    Objective Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS. Methods We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model. Results A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi. Conclusion There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy. PMID:26110878

  9. Radionuclide therapy in neuroendocrine tumours: a systematic review.

    PubMed

    Gulenchyn, K Y; Yao, X; Asa, S L; Singh, S; Law, C

    2012-05-01

    The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be

  10. Tumour cells engineered to secrete interleukin-15 augment anti-tumour immune responses in vivo

    PubMed Central

    Hazama, S; Noma, T; Wang, F; Iizuka, N; Ogura, Y; Yoshimura, K; Inoguchi, E; Hakozaki, M; Hirose, K; Suzuki, T; Oka, M

    1999-01-01

    We examined the effect of interleukin-15 (IL-15) gene transfer into tumour cells on the host's anti-tumour response. In BALB/c mice IL-15 producing Meth-A cells (Meth-A/IL-15) underwent complete rejection, in a response characterized by massive infiltration of CD4+ T-cells and neutrophils. In contrast, Meth-A cells transfected with vector alone (Meth-A/Neo) grew rapidly. Moreover, rechallenged parental cells also were rejected in association with CD8+ T-cell infiltration. However, in nude mice there was no drastic difference between Meth-A/IL-15 and Meth-A/Neo cells. These results demonstrate that IL-15-secreting tumour cells can stimulate local and systemic T-cell-dependent immunity and therefore may have a potential role in cancer therapy. © 1999 Cancer Research Campaign PMID:10424745

  11. Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling.

    PubMed

    Zuckermann, Marc; Hovestadt, Volker; Knobbe-Thomsen, Christiane B; Zapatka, Marc; Northcott, Paul A; Schramm, Kathrin; Belic, Jelena; Jones, David T W; Tschida, Barbara; Moriarity, Branden; Largaespada, David; Roussel, Martine F; Korshunov, Andrey; Reifenberger, Guido; Pfister, Stefan M; Lichter, Peter; Kawauchi, Daisuke; Gronych, Jan

    2015-06-11

    In vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited to validate their role in tumorigenesis. For tumour suppressor genes this has proven more challenging due to technical aspects. To provide a flexible and effective method for investigating somatic loss-of-function alterations and their influence on tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo targeting of TSGs. Here we demonstrate the utility of this approach by deleting single (Ptch1) or multiple genes (Trp53, Pten, Nf1) in the mouse brain, resulting in the development of medulloblastoma and glioblastoma, respectively. Using whole-genome sequencing (WGS) we characterized the medulloblastoma-driving Ptch1 deletions in detail and show that no off-targets were detected in these tumours. This method provides a fast and convenient system for validating the emerging wealth of novel candidate tumour suppressor genes and the generation of faithful animal models of human cancer.

  12. Suppressive effect of accumulated aluminum trichloride on the hepatic microsomal cytochrome P450 enzyme system in rats.

    PubMed

    Zhu, Yanzhu; Han, Yanfei; Zhao, Hansong; Li, Jing; Hu, Chongwei; Li, Yanfei; Zhang, Zhigang

    2013-01-01

    Aluminum (Al) is a low toxicological metal and can accumulate in the liver. The hepatic microsomal cytochrome P450 enzyme system (CYPS) plays important role in the transformation of the toxic materials. It is not clear if the CYPS is affected by Al exposure. Thus, the aim of this study is to investigate the effects of aluminum trichloride (AlCl(3)) on CYPS in rats. Forty male Wistar rats (5weeks old) weighing 110-120g were randomly allocated and orally exposed to 0, 64.18, 128.36 and 256.72mg/kg body weight (BW) AlCl(3) in drinking water for 120days. The body weight (BW) of rats, hepatosomatic index (HSI), hepatic Al content, the concentrations of cytochrome P450 (CYP450), cytochrome B5 (B5), microsomal protein and the activities of NADPH-cytochrome c reductase (CR), aminopyrin N-demethylase (AND), erythromycin N-demethylase (ERND) and aniline-4-hydeoxylase (AH) were assessed at the end of the experiment. The results showed that the increase in Al concentration decreased BW, HIS, concentrations of CYP450, B5, microsomal protein and the activity of CR, AND, ERND and AH in hepatic microsomes. The results revealed that exposure to AlCl(3) inhibited the microsomal CYP450 dependent enzyme system of liver. Our findings suggest that long term daily exposure of AlCl(3) exerts the suppressive effects and thus may cause dysfunction of hepatic CYP450 dependent enzyme system of rat.

  13. Comparison of the effects of enteral feeding with continuous and intermittent parenteral nutrition on hepatic triglyceride secretion in human beings

    SciTech Connect

    Isabel-Martinez, L.; Skinner, C.; Parkin, A.; Hall, R.I.

    1989-03-01

    Plasma triglyceride turnover was measured during steady-state conditions in 22 postoperative patients. Nine had received nutritional support with an enteral regimen, seven had received an equivalent regimen as continuous parenteral nutrition, and six received the same parenteral regimen as a cyclical infusion. After 5 days of nutritional support, each patient received an intravenous bolus of tritiated glycerol. Plasma radiolabeled triglyceride content was measured during the subsequent 24 hours. The data were analyzed by means of a simple deterministic model of plasma triglyceride kinetics and compared with the results obtained by stochastic analysis. The rates of hepatic triglyceride secretion obtained by deterministic analysis were higher than those obtained by the stochastic approach. However, the mode of delivery of the nutritional regimen did not affect the rate of hepatic triglyceride secretion regardless of the method of analysis. The results suggest that neither complete nutritional bypass of the gastrointestinal tract nor interruption of parenteral nutrition in an attempt to mimic normal eating has any effect on hepatic triglyceride secretion. Any beneficial effect that enteral feeding or cyclical parenteral nutrition may have on liver dysfunction associated with standard parenteral nutrition appears to be unrelated to changes in hepatic triglyceride secretion.

  14. The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

    PubMed

    Aboelwafa, Hanaa R; Yousef, Hany N

    2015-08-01

    The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues. PMID:25821896

  15. Hepatitis A

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Español Hepatitis A Page Content On this page: What is ... Nutrition Points to Remember Clinical Trials What is hepatitis A? Hepatitis * A is a virus , or infection, ...

  16. Autoimmune Hepatitis

    MedlinePlus

    ... Organizations ​​ (PDF, 341 KB)​​​​​ Alternate Language URL Autoimmune Hepatitis Page Content On this page: What is autoimmune ... Points to Remember Clinical Trials What is autoimmune hepatitis? Autoimmune hepatitis is a chronic—or long lasting— ...

  17. Hepatitis C

    MedlinePlus

    ... an inflammation of the liver. One type, hepatitis C, is caused by the hepatitis C virus (HCV). It usually spreads through contact with ... childbirth. Most people who are infected with hepatitis C don't have any symptoms for years. If ...

  18. Subacute effects of hexabromocyclododecane (HBCD) on hepatic gene expression profiles in rats

    SciTech Connect

    Canton, Rocio F. Peijnenburg, Ad A.C.M.; Hoogenboom, Ron L.A.P.; Piersma, Aldert H.; Ven, Leo T.M. van der; Berg, Martin van den; Heneweer, Marjoke

    2008-09-01

    Hexabromoyclododecane (HBCD), used as flame retardant (FR) mainly in textile industry and in polystyrene foam manufacture, has been identified as a contaminant at levels comparable to other brominated FRs (BFRs). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. The toxicological database of HBCD is too limited to perform at present a solid risk assessment, combining data from exposure and effect studies. In order to fill in some gaps, a 28-day HBCD repeated dose study (OECD407) was done in Wistar rats. In the present work liver tissues from these animals were used for gene expression profile analysis. Results show clear gender specificity with females having a higher number of regulated genes and therefore being more sensitive to HBCD than males. Several specific pathways were found to be affected by HBCD exposure, like PPAR-mediated regulation of lipid metabolism, triacylglycerol metabolism, cholesterol biosynthesis, and phase I and II pathways. These results were corroborated with quantitative RT-PCR analysis. Cholesterol biosynthesis and lipid metabolism were especially down-regulated in females. Genes involved in phase I and II metabolism were up-regulated predominantly in males, which could explain the observed lower HBCD hepatic disposition in male rats in this 28-day study. These sex-specific differences in gene expression profiles could also underlie sex-specific differences in toxicity (e.g. decreased thyroid hormone or increased serum cholesterol levels). To our knowledge, this is the fist study that describes the changes in rat hepatic gene profiles caused by this commonly used flame retardant.

  19. Toxicogenomic analysis of the hepatic effects of perfluorooctanoic acid on rare minnows (Gobiocypris rarus)

    SciTech Connect

    Wei Yanhong; Liu Yang; Wang Jianshe; Tao Yi; Dai Jiayin

    2008-02-01

    Perfluorooctanoic acid (PFOA) is a ubiquitous environmental contaminant that has been detected in a variety of terrestrial and aquatic organisms. To assess the effects of PFOA in fish and predict its potential mode of action, a toxicogenomic approach was applied to hepatic gene expression profile analysis in male and female rare minnows (Gobiocypris rarus) using a custom cDNA microarray containing 1773 unique genes. Rare minnows were treated with continuous flow-through exposure to PFOA at concentrations of 3, 10, and 30 mg/L for 28 days. Based on the observed histopathological changes, the livers from fish exposed to 10 mg/L PFOA were selected for further hepatic gene expression analysis. While 124 and 171 genes were significantly altered by PFOA in males and females, respectively, of which 43 genes were commonly regulated in both sexes. The affected genes are involved in multiple biological processes, including lipid metabolism and transport, hormone action, immune responses, and mitochondrial functions. PFOA exposure significantly suppressed genes involved in fatty acid biosynthesis and transport but induced genes associated with intracellular trafficking of cholesterol. Alterations in expression of genes associated with mitochondrial fatty acid {beta}-oxidation were only observed in female rare minnows. In addition, PFOA inhibited genes responsible for thyroid hormone biosynthesis and significantly induced estrogen-responsive genes. These findings implicate PFOA in endocrine disruption. This work contributes not only to the elucidation of the potential mode of toxicity of PFOA to aquatic organisms but also to the use of toxicogenomic approaches to address issues in environmental toxicology.

  20. Pioglitazone, quercetin and hydroxy citric acid effect on hepatic biomarkers in Non Alcoholic Steatohepatitis

    PubMed Central

    Surapaneni, Krishna Mohan; Jainu, Mallika

    2014-01-01

    Background: Non alcoholic steatohepatitis (NASH), severe form of diseases belonging to the spectrum of the Non alcoholic fatty liver disease (NAFLD). It is an asymptomatic disease which leads to fibrosis and finally to cirrhosis, an end stage liver disease. Objective: To study the effect of pioglitazone, quercetin and hydroxy citric acid on hepatic biomarkers and various biochemical parameters in experimentally induced non alcoholic steatohepatitis (NASH). Materials and Methods: Male Wister rats were divided into 8 groups. The activities of alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and γ-Glutamyl Transferase (GGT) were assayed in serum. The levels of various other biochemical parameters such as serum albumin, total bilirubin, creatinine, urea, uric acid and glucose were also estimated in experimental NASH. Results: The NASH group produced severe liver injury by significantly increasing the serum levels of ALT, AST, GGT and LDH compared with that of the control. However, the experimental NASH rats treated with pioglitazone, with quercetin and with hydroxy citric acid showed an obvious decrease in ALT, AST, GGT and LDH levels when compared with that of NASH induced group. A significant increase in the levels of albumin, creatinine, urea, uric acid, glucose and total bilirubin was noticed in experimentally induced NASH group (group 2) when compared to rats in control group (group 1). Conclusion: It could be inferred from this study that, pioglitazone, quercetin and hydroxy citric acid may afford protection to the liver against NASH, as evidenced by the results of this study on the levels of various biochemical parameters such as glucose, urea, uric acid, creatinine and bilirubin. Whereas from the results of hepatic marker enzymes, it is evident that optimal protection was observed after quercetin treatment against experimental NASH whereas pioglitazone and hydroxy citric acid also confers

  1. Can antiviral treatment for hepatitis C be safely and effectively delivered in primary care?

    PubMed Central

    Brew, Iain F; Butt, Christine; Wright, Nat

    2013-01-01

    Background The burden of hepatitis C (HCV) treatment is growing, as is the political resolve to tackle the epidemic. Primary care will need to work more closely with secondary care to succeed in reducing the prevalence of chronic HCV. Aim To identify research relating to the provision of antiviral treatment for HCV in primary care. Design and setting A narrative systematic review of six databases. Method Medline, Embase, Cinahl, PsycINFO, Web of Science, and Cochrane were searched. Relevant journals were searched by hand for articles to be included in the review. Reference lists of relevant papers were reviewed and full-text papers were retrieved for those deemed to potentially fulfil the inclusion criteria of the review. Results A total of 683 abstracts led to 77 full-text articles being retrieved, of which 16 were finally included in the review. An evidence base emerged, highlighting that community-based antiviral treatment provision is feasible and can result in clinical outcomes comparable to those achieved in hospital outpatient settings. Such provision can be in mainstream general practice, at community addiction centres, or in prisons. GPs must be trained before offering such a service and there is also a need for ongoing specialist supervision of primary care practice. Such training and supervision can be delivered by teleconference, although, even with such ready availability of training and supervision, only a minority of GPs are likely to want to provide antiviral treatment. Conclusion There is emerging evidence supporting the effectiveness of antiviral treatment provision for patients with chronic hepatitis C in a wide variety of primary care and wider community settings. Training and ongoing supervision of primary care practitioners by specialists is a prerequisite. There is an opportunity through future research activity to evaluate typologies of patients who would be best served by primary care-based treatment and those for whom hospital

  2. Anti-tumour activity of bisphosphonates in preclinical models of breast cancer.

    PubMed

    Holen, Ingunn; Coleman, Robert E

    2010-01-01

    There is increasing evidence of anti-tumour effects of bisphosphonates from pre-clinical studies, supporting a role for these drugs beyond their traditional use in treatment of cancer-induced bone disease. A range of model systems have been used to investigate the effects of different bisphosphonates on tumour growth, both in bone and at peripheral sites. Most of these studies conclude that bisphosphonates cause a reduction in tumour burden, but that early intervention and the use of high and/or repeated dosing is required. Successful eradication of cancer may only be achievable by targeting the tumour cells directly whilst also modifying the tumour microenvironment. In line with this, bisphosphonates are demonstrated to be particularly effective at reducing breast tumour growth when used in combination with agents that directly target cancer cells. Recent studies have shown that the effects of bisphosphonates on breast tumours are not limited to bone, and that prolonged anti-tumour effects may be achieved following their inclusion in combination therapy. This has opened the field to a new strand of bisphosphonate research, focussed on elucidating their effects on cells and components of the local, regional and distal tumour microenvironment. This review highlights the recent developments in relation to proposed anti-tumour effects of bisphosphonates reported from in vitro and in vivo models, and summarises the data from key breast cancer studies. Evidence for effects on different processes and cell types involved in cancer development and progression is discussed, and the main outstanding issues identified.

  3. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

    PubMed Central

    Le, Caroline P.; Nowell, Cameron J.; Kim-Fuchs, Corina; Botteri, Edoardo; Hiller, Jonathan G.; Ismail, Hilmy; Pimentel, Matthew A.; Chai, Ming G.; Karnezis, Tara; Rotmensz, Nicole; Renne, Giuseppe; Gandini, Sara; Pouton, Colin W.; Ferrari, Davide; Möller, Andreas; Stacker, Steven A.; Sloan, Erica K.

    2016-01-01

    Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. PMID:26925549

  4. Sympathetic nervous system regulation of the tumour microenvironment

    PubMed Central

    Cole, Steven W.; Nagaraja, Archana S.; Lutgendorf, Susan K.; Green, Paige A.; Sood, Anil K.

    2016-01-01

    The peripheral autonomic nervous system (ANS) is known to regulate gene expression in primary tumours and their surrounding microenvironment. Activation of the sympathetic division of the ANS in particular modulates gene expression programs that promote metastasis of solid tumours by stimulating macrophage infiltration, inflammation, angiogenesis, epithelial-mesenchymal transition, and tumour invasion, and by inhibiting cellular immune responses and programmed cell death. Haematological cancers are modulated by sympathetic nervous system (SNS) regulation of stem cell biology and hematopoietic differentiation programs. In addition to identifying a molecular basis for physiologic stress effects on cancer, these findings have also identified new pharmacologic strategies to inhibit cancer progression in vivo. PMID:26299593

  5. The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence

    PubMed Central

    Barker, Holly E.; Paget, James T. E.; Khan, Aadil A.; Harrington, Kevin J.

    2016-01-01

    Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focussed on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes induced in the tumour microenvironment by irradiation and discuss how they may promote radioresistance and tumour recurrence. Subsequently, we highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy. PMID:26105538

  6. Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

    PubMed

    Varma, Manthena V; El-Kattan, Ayman F

    2016-07-01

    A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay.

  7. Transporter-Enzyme Interplay: Deconvoluting Effects of Hepatic Transporters and Enzymes on Drug Disposition Using Static and Dynamic Mechanistic Models.

    PubMed

    Varma, Manthena V; El-Kattan, Ayman F

    2016-07-01

    A large body of evidence suggests hepatic uptake transporters, organic anion-transporting polypeptides (OATPs), are of high clinical relevance in determining the pharmacokinetics of substrate drugs, based on which recent regulatory guidances to industry recommend appropriate assessment of investigational drugs for the potential drug interactions. We recently proposed an extended clearance classification system (ECCS) framework in which the systemic clearance of class 1B and 3B drugs is likely determined by hepatic uptake. The ECCS framework therefore predicts the possibility of drug-drug interactions (DDIs) involving OATPs and the effects of genetic variants of SLCO1B1 early in the discovery and facilitates decision making in the candidate selection and progression. Although OATP-mediated uptake is often the rate-determining process in the hepatic clearance of substrate drugs, metabolic and/or biliary components also contribute to the overall hepatic disposition and, more importantly, to liver exposure. Clinical evidence suggests that alteration in biliary efflux transport or metabolic enzymes associated with genetic polymorphism leads to change in the pharmacodynamic response of statins, for which the pharmacological target resides in the liver. Perpetrator drugs may show inhibitory and/or induction effects on transporters and enzymes simultaneously. It is therefore important to adopt models that frame these multiple processes in a mechanistic sense for quantitative DDI predictions and to deconvolute the effects of individual processes on the plasma and hepatic exposure. In vitro data-informed mechanistic static and physiologically based pharmacokinetic models are proven useful in rationalizing and predicting transporter-mediated DDIs and the complex DDIs involving transporter-enzyme interplay. PMID:27385183

  8. Modelling heating of liver tumours with heterogeneous magnetic microsphere deposition.

    PubMed

    Tsafnat, N; Tsafnat, G; Lambert, T D; Jones, S K

    2005-06-21

    Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

  9. Modelling heating of liver tumours with heterogeneous magnetic microsphere deposition

    NASA Astrophysics Data System (ADS)

    Tsafnat, N.; Tsafnat, G.; Lambert, T. D.; Jones, S. K.

    2005-06-01

    Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

  10. Malignant epithelial tumours in children: incidence and aetiology.

    PubMed

    al-Sheyyab, M; Muir, K R; Cameron, A H; Raafat, F; Pincott, J R; Parkes, S E; Mann, J R

    1993-01-01

    The purpose of this study was to establish the incidence of carcinomas in children, changes in incidence over a 30-year period, and to identify features of possible aetiological significance. A total of 173 cases were identified, but after review of the histopathology, 30 patients were excluded because they were considered to have benign epithelial tumours or malignant tumours of nonepithelial origin. Seven other cases were excluded because pathology material was not available. Overall, in 28% of cases, the diagnoses were changed by pathology review. Thus, 136 children in the West Midlands Region diagnosed 1957-1986 were included, with carcinoid tumours (44) and tumours of skin (22), nasopharynx (14), salivary gland (13), adrenal cortex (13), thyroid (9), large bowel (5), other (16). Excluding carcinoids, the age-standardised incidence rate was 2.4 x 10(6) per year. Male:female ratio was 0.7:1 and 66% were aged > 10 years. Incidence increased from 1.5 to 3.3 x 10(6) per year. Genetic factors predisposing to carcinoma included tyrosinosis, MEN II and III, congenital adrenal hyperplasia and basal cell naevus syndrome. There was a case of Li-Fraumeni syndrome and several other patients had relevant family histories. Probable "environmental" causes included antenatal exposure to stilboestrol or hydroxyprogesterone hexanoate, stilboestrol given for premature menarche, neonatal hepatitis and prior radiotherapy. The aetiology of carcinomas in children is multifactorial, both genetic and environmental factors being important. The incidence is increasing.

  11. Benign cardiac tumours, malignant arrhythmias

    PubMed Central

    Myers, Kimberley A; Wong, Kenny K; Tipple, Marion; Sanatani, Shubhayan

    2010-01-01

    Four cases of pediatric cardiac tumours (PCTs) associated with ventricular arrhythmias are reported. Sudden cardiac death attributable to the tumour occurred in two children. A third child received an implantable cardioverter defibrillator and the fourth had persistent ventricular arrhythmia despite medical therapy. Most PCTs are considered benign; however, the development of malignant arrhythmias may complicate the management of these tumours in some patients. The literature regarding the arrhythmogenic potential of PCTs and the use of implantable cardioverter defibrillators in these patients is reviewed. The series highlights the deficiency of prognostic information for this cohort. PMID:20151061

  12. Malignant tumours of the duodenum.

    PubMed

    Ryska, M; Hrabal, P

    2015-12-01

    No comprehensive knowledge of duodenal tumours exists in the current literature; individual types of malignant tumours may be described within malignancies of the small bowel, sets of case reports, or individual cases. Ampullary carcinomas are the exception and they are detailed in the current WHO histological classification of tumours of digestive system. Neither national nor international literature sources provide a comprehensive review of their therapy. The situation is similar when searching for surgical procedures. Resection procedures on the duodenum should thus be performed in specialized centres with sufficient experience with hepato-pancreato-biliary surgery. PMID:26767899

  13. [First pass effect by infusing 99mTc-human serum albumin into the hepatic artery].

    PubMed

    Ozawa, T; Kimura, K; Koyanagi, Y; Aoki, T; Kusama, M; Takagi, S; Kakuta, T; Yoshimatsu, A; Ishikawa, M; Yasuda, D

    1988-08-01

    The fundamental principles of intra-arterial infusion chemotherapy are thought to be increased local drug concentration and the "first-pass" effect. The concentration in the rest of the body can only be decreased if there is local elimination of the infused drug before reaching the systemic circulation. This is referred to as the "first-pass" effect. In the evaluation of "first-pass" effect, the uptake of liver after infusing 99mTc-human serum albumin (99mTc-HSA) in the hepatic artery by injecting the subcutaneously implanted silicon reservoir was compared with that obtained after intravenous administration of 99mTc-HSA. In order to remove the factor of portal infusion, each count of liver up take had been continued for only 24 seconds after starting the liver uptake. The results are as follows: for 24 cases excepting 6 cases with catheter obstruction, the mean i.a./i.v. ratio was 7.92 +/- 3.34 (range 3.25 to 17.25). Although the elimination rate of drugs in the liver varies with each drug, the infusion of intraarterial chemotherapy should be about 8 times more concentrative than intravenous administration on the "first-pass" effect.

  14. Effect of bovine lactoferrin in a therapeutic hamster model of hepatic amoebiasis.

    PubMed

    Ordaz-Pichardo, Cynthia; León-Sicairos, Nidia; Hernández-Ramírez, Verónica Ivonne; Talamás-Rohana, Patricia; de la Garza, Mireya

    2012-06-01

    Entamoeba histolytica is the causative agent of amoebiasis, a disease that produces dysentery as a result of the perforation of the large intestine. This parasite often invades other organs, primarily the liver, leading to an amoebic liver abscess (ALA), which can cause death. Metronidazole is the drug of choice for the treatment of ALA; however, it produces toxic side effects in patients. Lactoferrin (Lf) is a glycoprotein of the innate immune response that sequesters iron in the mucosae. Lf possesses immune-regulatory properties, such as antiinflammatory and antioxidant activities. Moreover, the microbicidal activity of apoLf, which lacks bound iron, has been shown. In this study, we evaluated the therapeutic effect of bovine Lf (bLf) against ALA in a model of hepatic amoebiasis in hamsters. Interestingly, hamsters treated intragastrically with Lf (2.5 mg/100 g mass) over a period of 8 days showed no clinical signs of disease and ALA was effectively decreased, with only 0.63% detectable lesion, compared with 63% in untreated animals. Furthermore, liver function and blood cells approached normal levels among those receiving bLf treatment. These results suggest that bLf may aid in the therapy of amoebiasis, likely without producing undesirable effects in patients. PMID:22332957

  15. Effect of bovine lactoferrin in a therapeutic hamster model of hepatic amoebiasis.

    PubMed

    Ordaz-Pichardo, Cynthia; León-Sicairos, Nidia; Hernández-Ramírez, Verónica Ivonne; Talamás-Rohana, Patricia; de la Garza, Mireya

    2012-06-01

    Entamoeba histolytica is the causative agent of amoebiasis, a disease that produces dysentery as a result of the perforation of the large intestine. This parasite often invades other organs, primarily the liver, leading to an amoebic liver abscess (ALA), which can cause death. Metronidazole is the drug of choice for the treatment of ALA; however, it produces toxic side effects in patients. Lactoferrin (Lf) is a glycoprotein of the innate immune response that sequesters iron in the mucosae. Lf possesses immune-regulatory properties, such as antiinflammatory and antioxidant activities. Moreover, the microbicidal activity of apoLf, which lacks bound iron, has been shown. In this study, we evaluated the therapeutic effect of bovine Lf (bLf) against ALA in a model of hepatic amoebiasis in hamsters. Interestingly, hamsters treated intragastrically with Lf (2.5 mg/100 g mass) over a period of 8 days showed no clinical signs of disease and ALA was effectively decreased, with only 0.63% detectable lesion, compared with 63% in untreated animals. Furthermore, liver function and blood cells approached normal levels among those receiving bLf treatment. These results suggest that bLf may aid in the therapy of amoebiasis, likely without producing undesirable effects in patients.

  16. A comparative study of the effects of anti-tumour and immunosuppressive drugs on antibody-forming and erythropoietic cells

    PubMed Central

    Floersheim, G. L.

    1970-01-01

    Immunosuppressive and erythroid cell line depressing activities of various agents used in cancer chemotherapy were investigated simultaneously in the same mice and compared to X-Rays. Vincristine, vinblastine, mitomycin C and actinomycin D had greater effects on erythropoiesis than on antibody-forming cells. By contrast, the immunosuppressive effects of cyclophosphamide, demecolcine and methotrexate exceeded markedly their erythropoietic toxicity. The Vinca alkaloids stimulated the secondary immune response, whereas X-Rays, antilymphocytic serum and the methylhydrazine derivatives inhibited the anamnestic response to a greater extent than the primary immune response. PMID:5529340

  17. Fountain of steroid from an ectopic ACTH-producing tumour

    PubMed Central

    Lo, Tom Edward Ngo; Jimeno, Cecilia Alegado

    2013-01-01

    This case is of a 39-year-old Filipino woman who within 2 months developed, Cushing's features she had no known comorbidities and no history of steroid intake. The patient also presented with hyperpigmentation of knuckles and toes, metabolic alkalosis and persistent hypokalaemia noted as proximal muscle weakness. The patient was referred to our institution for acutely worsening behavioural and psychiatric changes. Work-up for endogenous Cushing's syndrome revealed a significant adrenocorticotropic hormone production from an ectopic source. Further imaging was requested to locate the tumour, but the patient eventually succumbed to the drastic complications of hypercortisolism. On autopsy, the patient was found to have an ectopic well-differentiated neuroendocrine tumour located at the pancreatic head with metastasis to the right hepatic lobe. PMID:23861274

  18. Effectiveness of daily versus non-daily granulocyte colony-stimulating factors in patients with solid tumours undergoing chemotherapy: a multivariate analysis of data from current practice

    PubMed Central

    Almenar Cubells, D; Bosch Roig, C; Jiménez Orozco, E; Álvarez, R; Cuervo, JM; Díaz Fernández, N; Sánchez Heras, AB; Galán Brotons, A; Giner Marco, V; Codes M De Villena, M

    2013-01-01

    We conducted a multicentre, retrospective, observational study including patients with solid tumours (excluding breast cancer) that received granulocyte colony-stimulating factors (G-CSF) and chemotherapy. We investigated the effectiveness of daily vs. non-daily G-CSFs (pegfilgrastim) adjusting by potential confounders. The study included 391 patients (211 daily G-CSF; 180 pegfilgrastim), from whom 47.3% received primary prophylaxis (PP) (57.8% pegfilgrastim), 26.3% secondary prophylaxis (SP: initiation after cycle 1 and no reactive treatment in any cycle) (51.5% pegfilgrastim) and 26.3% reactive treatment (19.4% pegfilgrastim). Only 42.2% of patients with daily G-CSF and 46.2% with pegfilgrastim initiated prophylaxis within 72 h after chemotherapy, and only 10.5% of patients with daily G-CSF received it for ≥7 days. In the multivariate models, daily G-CSF was associated with higher risk of grade 3-4 neutropenia (G3-4N) vs. pegfilgrastim [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.004–2.97]. Relative to SP, PP protected against G3-4N (OR for SP vs. PP: 6.0, 95%CI: 3.2–11.4) and febrile neutropenia (OR: 3.1, 95%CI: 1.1–8.8), and was associated to less chemotherapy dose delays and reductions (OR for relative dose intensity <85% for SP vs. PP: 3.1, 95%CI: 1.7–5.4) and higher response rate (OR: 2.1, 95%CI: 1.2–3.7). Data suggest that pegfilgrastim, compared with a daily G-CSF, and PP, compared with SP, could be more effective in preventing neutropenia and its related events in the clinical practice. PMID:23331323

  19. Effectiveness of daily versus non-daily granulocyte colony-stimulating factors in patients with solid tumours undergoing chemotherapy: a multivariate analysis of data from current practice.

    PubMed

    Almenar Cubells, D; Bosch Roig, C; Jiménez Orozco, E; Álvarez, R; Cuervo, J M; Díaz Fernández, N; Sánchez Heras, A B; Galán Brotons, A; Giner Marco, V; Codes M De Villena, M

    2013-05-01

    We conducted a multicentre, retrospective, observational study including patients with solid tumours (excluding breast cancer) that received granulocyte colony-stimulating factors (G-CSF) and chemotherapy. We investigated the effectiveness of daily vs. non-daily G-CSFs (pegfilgrastim) adjusting by potential confounders. The study included 391 patients (211 daily G-CSF; 180 pegfilgrastim), from whom 47.3% received primary prophylaxis (PP) (57.8% pegfilgrastim), 26.3% secondary prophylaxis (SP: initiation after cycle 1 and no reactive treatment in any cycle) (51.5% pegfilgrastim) and 26.3% reactive treatment (19.4% pegfilgrastim). Only 42.2% of patients with daily G-CSF and 46.2% with pegfilgrastim initiated prophylaxis within 72 h after chemotherapy, and only 10.5% of patients with daily G-CSF received it for ≥ 7 days. In the multivariate models, daily G-CSF was associated with higher risk of grade 3-4 neutropenia (G3-4N) vs. pegfilgrastim [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.004-2.97]. Relative to SP, PP protected against G3-4N (OR for SP vs. PP: 6.0, 95%CI: 3.2-11.4) and febrile neutropenia (OR: 3.1, 95%CI: 1.1-8.8), and was associated to less chemotherapy dose delays and reductions (OR for relative dose intensity <85% for SP vs. PP: 3.1, 95%CI: 1.7-5.4) and higher response rate (OR: 2.1, 95%CI: 1.2-3.7). Data suggest that pegfilgrastim, compared with a daily G-CSF, and PP, compared with SP, could be more effective in preventing neutropenia and its related events in the clinical practice.

  20. Effect of Olea oleaster and Juniperus procera leaves extracts on thioacetamide induced hepatic cirrhosis in male albino mice.

    PubMed

    Al-Attar, Atef M; Alrobai, Ali A; Almalki, Daklallah A

    2016-05-01

    The effect of Olea oleaster and Juniperus procera leaves extracts and their combination on thioacetamide (TAA)-induced hepatic cirrhosis were investigated in male albino mice. One hundred sixty mice were used in this study and were randomly distributed into eight groups of 20 each. Mice of group 1 served as controls. Mice of group 2 were treated with TAA. Mice of group 3 were exposed to TAA and supplemented with O. oleaster leaves extracts. Mice of group 4 were treated with TAA and supplemented with J. procera leaves extracts. Mice of group 5 were subjected to TAA and supplemented with O. oleaster and J. procera leaves extracts. Mice of groups 6, 7 and 8 were supplemented with O. oleaster, J. procera, and O. oleaster and J. procera leaves extracts respectively. Administration of TAA for six and twelve weeks resulted in a decline in body weight gain and increased the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Histopathological evaluations of hepatic sections from mice treated with TAA showed severe alterations including increase of fibrogenesis processes with structural damage. Treatment of mice with these extracts showed a pronounced attenuation in TAA induced hepatic cirrhosis associated with physiological and histopathological alterations. Finally, this study suggests that the supplementation of these extracts may act as antioxidant agents and could be an excellent adjuvant support in the therapy of hepatic cirrhosis.

  1. Effect of antioxidant therapy on hepatic fibrosis and liver iron concentrations in β-thalassemia major patients.

    PubMed

    Elalfy, Mohsen S; Adly, Amira A M; Attia, Atef A M; Ibrahim, Fatma A; Mohammed, Amer S; Sayed, Abdelbasset M

    2013-01-01

    To assess the effects of combined vitamin therapy on oxidant-antioxidant hepatic status and hemoglobin (Hb) derivatives on β-thalassemia major (β-TM), a prospective study of 60 β-TM patients aged 4 to 17 years, was conducted. Thirty-nine patients with initial low serum vitamins E, C and A, were treated with oral combined vitamins for 1 year compared to 21 patients with normal vitamin levels. Serum transaminases, serum ferritin, hepatic fibroscan elastography (TE) and magnetic resonance imaging R2* (MRI R2*) for liver iron concentration (LIC), were assessed before and after 6 and 12 months of therapy. Antioxidant capacity was assessed by levels of reduced glutathione (GSH), malondialdehyde (MDA), catalase, superoxide dismutase and GSH enzymes. The studied vitamins, reduced GSH and Hb levels were significantly elevated and paralleled by progressive decline in MDA and ferritin during therapy (p <0.001). Serum transaminase and superoxide dismutase were significantly decreased, while GSH reductase was significantly elevated during therapy (p <0.001). Improvement of hepatic fibrosis as 23.0% had TE (>12 kPa) at baseline compared to 20.5% after therapy (p >0.05), although LIC values were significantly decreased (p <0.001). Combined vitamin therapy improves the antioxidant/oxidant balance, LIC and hepatic fibrosis in young β-TM patients.

  2. Hepatoprotective effects of polysaccharide isolated from Agaricus bisporus industrial wastewater against CCl₄-induced hepatic injury in mice.

    PubMed

    Huang, Jiafu; Ou, Yixin; Yew, Tai Wai David; Liu, Jingna; Leng, Bo; Lin, Zhichao; Su, Yi; Zhuang, Yuanhong; Lin, Jiaofen; Li, Xiumin; Xue, Yu; Pan, Yutian

    2016-01-01

    During the industrial production of canned mushroom (Agaricus bisporus), a large quantity of wastewater is produced. In this study, the wastewater generated during the canning of mushroom was analyzed. From this wastewater, four polysaccharide components (Abnp1001, Abnp1002, Abap1001, and Abap1002) with hepatic-protective activity were isolated by ultrafiltration, DEAE cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography. Results of ultraviolet spectra analysis and molecular weight determination showed that Abnp1001, Abnp1002, Abap1001 and Abap1002 were uniform with average molecular weights of 336, 12.8, 330 and 15.8kDa, respectively. The monosaccharide composition analysis using gas chromatography (GC) showed that the four fractions were heteropolysaccharides and mainly composed of glucose. Fourier transform-infrared (FT-IR) analysis showed that the isolated fractions were all composed of β-glycoside linkages. Additionally, the potential hepatoprotective activities of these polysaccharides against CCl4-induced hepatic injury in mice were studied. Notably, Abnp1002 and Abap1002 could lower the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in serum in a dose dependent manner and reduce the hepatocellular degeneration and necrosis, as well as inflammatory infiltration. These results indicate that these two polysaccharides had protective effects on acute hepatic injury induced by CCl4 in mice and suggest that the polysaccharides extracted from A. bisporus industrial wastewater might have potential in therapeutics of acute hepatic injury.

  3. Effect of Olea oleaster and Juniperus procera leaves extracts on thioacetamide induced hepatic cirrhosis in male albino mice

    PubMed Central

    Al-Attar, Atef M.; Alrobai, Ali A.; Almalki, Daklallah A.

    2015-01-01

    The effect of Olea oleaster and Juniperus procera leaves extracts and their combination on thioacetamide (TAA)-induced hepatic cirrhosis were investigated in male albino mice. One hundred sixty mice were used in this study and were randomly distributed into eight groups of 20 each. Mice of group 1 served as controls. Mice of group 2 were treated with TAA. Mice of group 3 were exposed to TAA and supplemented with O. oleaster leaves extracts. Mice of group 4 were treated with TAA and supplemented with J. procera leaves extracts. Mice of group 5 were subjected to TAA and supplemented with O. oleaster and J. procera leaves extracts. Mice of groups 6, 7 and 8 were supplemented with O. oleaster, J. procera, and O. oleaster and J. procera leaves extracts respectively. Administration of TAA for six and twelve weeks resulted in a decline in body weight gain and increased the levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Histopathological evaluations of hepatic sections from mice treated with TAA showed severe alterations including increase of fibrogenesis processes with structural damage. Treatment of mice with these extracts showed a pronounced attenuation in TAA induced hepatic cirrhosis associated with physiological and histopathological alterations. Finally, this study suggests that the supplementation of these extracts may act as antioxidant agents and could be an excellent adjuvant support in the therapy of hepatic cirrhosis. PMID:27081362

  4. Modeling toxicodynamic effects of trichloroethylene on liver in mouse model of autoimmune hepatitis

    SciTech Connect

    Gilbert, Kathleen M.; Reisfeld, Brad; Zurlinden, Todd J.; Kreps, Meagan N.; Erickson, Stephen W.; Blossom, Sarah J.

    2014-09-15

    Chronic exposure to industrial solvent and water pollutant trichloroethylene (TCE) in female MRL +/+ mice generates disease similar to human autoimmune hepatitis. The current study was initiated to investigate why TCE-induced autoimmunity targeted the liver. Compared to other tissues the liver has an unusually robust capacity for repair and regeneration. This investigation examined both time-dependent and dose-dependent effects of TCE on hepatoprotective and pro-inflammatory events in liver and macrophages from female MRL +/+ mice. After a 12-week exposure to TCE in drinking water a dose-dependent decrease in macrophage production of IL-6 at both the transcriptional and protein level was observed. A longitudinal study similarly showed that TCE inhibited macrophage IL-6 production. In terms of the liver, TCE had little effect on expression of pro-inflammatory genes (Tnfa, Saa2 or Cscl1) until the end of the 40-week exposure. Instead, TCE suppressed hepatic expression of genes involved in IL-6 signaling (Il6r, gp130, and Egr1). Linear regression analysis confirmed liver histopathology in the TCE-treated mice correlated with decreased expression of Il6r. A toxicodynamic model was developed to estimate the effects of TCE on IL-6 signaling and liver pathology under different levels of exposure and rates of repair. This study underlined the importance of longitudinal studies in mechanistic evaluations of immuntoxicants. It showed that later-occurring liver pathology caused by TCE was associated with early suppression of hepatoprotection rather than an increase in conventional pro-inflammatory events. This information was used to create a novel toxicodynamic model of IL-6-mediated TCE-induced liver inflammation. - Highlights: • We developed a toxicodynamic model to study effects of trichloroethylene on liver. • We examined protective as well as pro-inflammatory events in the liver. • Trichloroethylene inhibits IL-6 production by macrophages. • Trichloroethylene

  5. Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review

    PubMed Central

    Golabi, Pegah; Locklear, Cameron T; Austin, Patrick; Afdhal, Sophie; Byrns, Melinda; Gerber, Lynn; Younossi, Zobair M

    2016-01-01

    AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease (NAFLD) patients. METHODS: Ovid-Medline, PubMed, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: “NASH”, “NAFLD”, “non-alcoholic steatohepatitis”, “non-alcoholic fatty liver disease”, “fat”, “steatosis”, “diet”, “exercise”, “MR spectroscopy” and “liver biopsy”. NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy (H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria (6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared the two interventions. The beneficial effects of exercise on intrahepatic triglyceride (IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents

  6. Effects of guar gum and cellulose on glucose absorption, hormonal release and hepatic metabolism in the pig

    NASA Technical Reports Server (NTRS)

    Nunes, C. S.; Malmlof, K.

    1992-01-01

    Six Large White pigs (mean body-weight 59 (SE 1.7) kg) were surgically fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein, as well as with electromagnetic flow probes around the portal vein and the hepatic artery, and allowed to recover. The non-anaesthetized animals were given a basal non-fibre diet (diet A) alone or together with 60 g guar gum/kg (diet B) or 150 g purified cellulose/kg (diet C) by substitution for mica. The diets were given for weekly periods and according to a replicated 3 x 3 Latin square design. On the last day of each such adaptation period, test meals of 800 g were given before blood sampling. Sampling was continued for 8 h. Guar gum strongly reduced glucose apparent absorption without changing the absorption and the hepatic uptake profiles. Production rates of insulin, gastric inhibitory polypeptide and insulin-like growth factor-1 (IGF-1) were lowest after guar gum ingestion. However, the reductions in peripheral blood insulin levels caused by guar gum were not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly secreted by the gut, whereas the liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut-produced IGF-1. Guar gum ingestion appeared also to decrease glucagon secretion. Cellulose at the level consumed had very few effects on the variables considered. It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the metabolic effects described.

  7. Effect of hepatocyte-specific gadolinium-based contrast agents on hepatic fat-fraction and R2(⁎).

    PubMed

    Hernando, Diego; Wells, Shane A; Vigen, Karl K; Reeder, Scott B

    2015-01-01

    The purpose of this work was to investigate the effect of a hepatocyte-specific gadolinium based contrast agent (GBCA) on quantitative hepatic fat-fraction (FF) and R2* measurements. Fifty patients were imaged at 1.5T, using chemical-shift encoded water-fat MRI with low (5°) and high (15°) flip angles (FA), both before and after administration of a hepatocyte-specific GBCA (gadoxetic acid). Low and high FA, pre- and post-contrast FF and R2* values were measured for each subject. Available serum laboratory studies related to liver disease were also recorded. Linear regression and Bland-Altman analysis were performed to compare measurements. Hepatic FF was unaffected by GBCA at low FA (slope=1.02±0.02, p=0.32). FF was overestimated at high FA pre-contrast (slope=1.33±0.03, p<10(-10)), but underestimated post-contrast (slope=0.81±0.02, p<10(-10)). Hepatic R2* was unaffected by FA (mean difference±95% CI pre-contrast:2.2±4.9s(-1), post-contrast:2.8±3.6s(-1)), but increased post-contrast in patients with total bilirubin <2.5mg/dL (ΔR2*=13.4±12.7s(-1)). Regression analysis of serum values demonstrated a correlation of post-contrast change in R2* with total bilirubin (p<0.01) and model for end-stage liver disease (MELD) score (p≈0.01). In conclusion, GBCA has no effect on hepatic FF at low FA due to a lack of T1-weighting, potentially allowing flexibility for FF imaging with hepatobiliary imaging protocols. Hepatic R2* increased significantly after GBCA administration, particularly in the biliary tree. Therefore, R2* maps should be obtained prior to contrast administration.

  8. Intra-tumoural microvessel density in human solid tumours

    PubMed Central

    Hasan, J; Byers, R; Jayson, G C

    2002-01-01

    Over the last decade assessment of angiogenesis has emerged as a potentially useful biological prognostic and predictive factor in human solid tumours. With the development of highly specific endothelial markers that can be assessed in histological archival specimens, several quantitative studies have been performed in various solid tumours. The majority of published studies have shown a positive correlation between intra-tumoural microvessel density, a measure of tumour angiogenesis, and prognosis in solid tumours. A minority of studies have not demonstrated an association and this may be attributed to significant differences in the methodologies employed for sample selection, immunostaining techniques, vessel counting and statistical analysis, although a number of biological differences may account for the discrepancy. In this review we evaluate the quantification of angiogenesis by immunohistochemistry, the relationship between tumour vascularity and metastasis, and the clinicopathological studies correlating intra-tumoral microvessel density with prognosis and response to anti-cancer therapy. In view of the extensive nature of this retrospective body of data, comparative studies are needed to identify the optimum technique and endothelial antigens (activated or pan-endothelial antigens) but subsequently prospective studies that allocate treatment on the basis of microvessel density are required. British Journal of Cancer (2002) 86, 1566–1577. DOI: 10.1038/sj/bjc/6600315 www.bjcancer.com © 2002 Cancer Research UK PMID:12085206

  9. Rapid recruitment of macrophages in interleukin-12-mediated tumour regression.

    PubMed Central

    Ha, S J; Lee, S B; Kim, C M; Shin, H S; Sung, Y C

    1998-01-01

    In order to study the mechanism of interleukin-12 (IL-12) antitumour activity, RH7777 rat hepatoma cells were engineered to express mouse IL-12 (mIL-12) (RH7777/mIL-12) under the tight control of doxycycline (dox). The production of the mIL-12 protein was regulated by the concentration of dox that was present in the culture medium. RH7777/mIL-12 cells appeared to have the same tumorigenic activity as did parental RH7777 cells, when subcutaneously injected into syngeneic rat (BUF/N) in the absence of dox. However, the tumorigenicity of RH7777/mIL-12, but not RH7777, cells were significantly decreased when dox was administrated to the animals. In addition, established tumours of RH7777/mIL-12 cells gradually disappeared upon the induction of mIL-12 by dox. To elucidate the kinetic profile of immune cells involved in the mIL-12-induced tumour regression, both histological and immunohistochemical analyses were performed 1, 3 and 14 days after the dox treatment on rats bearing tumours that were approximately 0. 5 cm in diameter. Tumour-infiltrating macrophages began to appear at the tumour site one day after dox treatment. As time elapsed, the number of tumour infiltrates including CD4+, CD8+, natural killer (NK) cells and macrophages gradually increased. In particular, CD8+ and NK cells constituted the major population of the tumour-infiltrated cells. Furthermore, it was found that resting peritoneal macrophages (PM) from rats were chemoattracted in response to mIL-12. The effects of mIL-12 on PM chemotaxis were reproducibly observed in concentrations as low as 0.1 ng/ml. These findings suggest that IL-12 can directly recruit macrophages into tumour sites which, in turn, leads to a broad and intense immunological response against tumour. Images Figure 3 Figure 4 PMID:9767471

  10. A Hepatitis C Virus Infection Model with Time-Varying Drug Effectiveness: Solution and Analysis

    PubMed Central

    Conway, Jessica M.; Perelson, Alan S.

    2014-01-01

    Simple models of therapy for viral diseases such as hepatitis C virus (HCV) or human immunodeficiency virus assume that, once therapy is started, the drug has a constant effectiveness. More realistic models have assumed either that the drug effectiveness depends on the drug concentration or that the effectiveness varies over time. Here a previously introduced varying-effectiveness (VE) model is studied mathematically in the context of HCV infection. We show that while the model is linear, it has no closed-form solution due to the time-varying nature of the effectiveness. We then show that the model can be transformed into a Bessel equation and derive an analytic solution in terms of modified Bessel functions, which are defined as infinite series, with time-varying arguments. Fitting the solution to data from HCV infected patients under therapy has yielded values for the parameters in the model. We show that for biologically realistic parameters, the predicted viral decay on therapy is generally biphasic and resembles that predicted by constant-effectiveness (CE) models. We introduce a general method for determining the time at which the transition between decay phases occurs based on calculating the point of maximum curvature of the viral decay curve. For the parameter regimes of interest, we also find approximate solutions for the VE model and establish the asymptotic behavior of the system. We show that the rate of second phase decay is determined by the death rate of infected cells multiplied by the maximum effectiveness of therapy, whereas the rate of first phase decline depends on multiple parameters including the rate of increase of drug effectiveness with time. PMID:25101902

  11. Accounting for treatment delays when treating highly proliferative tumours

    NASA Astrophysics Data System (ADS)

    Jones, Lois; Metcalfe, Peter; Hoban, Peter

    1999-01-01

    This study was undertaken to investigate the possibility of increasing the dose per fraction or increasing the number of fractions to account for treatment delays occurring during radiotheraphy treatments for highly proliferative tumours. The linear quadratic model with time was used to determine the difference in biological effective dose (BED) for the original schedule and the schedule including a treatment delay. Tables of extra fractions and extra dose per fraction required to account for a number of possible delays have been determined. It has been shown that for tumours with very short potential doubling times it is best to deliver the extra dose as an increase in dose per fraction rather than an increase in the number of fractions, while for tumours with moderately short potential doubling times (above 7 days) the reverse is true. The equivalent uninterrupted schedules, which would have delivered the same effects to the tumour, have also been determined.

  12. Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs.

    PubMed

    Regmi, N L; Abd El-Aty, A M; Kuroha, M; Nakamura, M; Shimoda, M

    2005-12-01

    We examined inhibitory effects of ofloxacin (OFX), orbifloxacin (OBFX), ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX) on cytochrome P-450 1A (CYP1A) activities using hepatic microsomes from four beagle dogs. Ethoxyresorufin O-de-ethylation was referred as CYP1A activities. All the fluoroquinolones inhibited the reaction in a noncompetitive manner. The determined inhibitory constants were the followings; 10.1 +/- 3.8 mM for OFX, 6.43 +/- 2.01 mM for OBFX, 0.726 +/- 0.134 mM for CFX, 4.06 +/- 1.19 mM for EFX and 4.75 +/- 1.63 mM for NFX respectively. As these values are >100-fold of plasma concentrations after a clinical single dose of the fluoroquinolones, it is suggested that the inhibitory effect on CYP1A activities is not so high to elicit drug-drug interaction with CYP1A substrates, when these fluoroquinolones are co-administered. Mechanism based inhibition was also examined in this study. Of the five fluoroquinolones examined, OFX, OBFX and CFX had this inhibition manner. As this inhibition is irreversible, inhibitory effects of the three fluoroquinolones may accumulate, when they are repeatedly administered. Therefore, OFX, OBFX and CFX may result in substantial drug-drug interaction with a CYP1A substrate even in clinical states. As EFX is metabolized to CFX in the body, it may also have the same possibility.

  13. Danshensu-mediated protective effect against hepatic fibrosis induced by carbon tetrachloride in rats.

    PubMed

    Qu, W; Huang, H; Li, K; Qin, C

    2014-12-01

    The culprit of hepatic fibrosis (HF) is linked to suprathreshold deposition of collagen. Thus, collagen reduction by improved metabolism contributes to HF management. In this study, we aimed to investigate the hepatoprotective effects of Danshensu (DSS) against carbon tetrachloride (CCl4)-induced HF rats. The results showed that DSS-administrated rats resulted in decreasing in hepatosomatic indexes, and lowering serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Meanwhile, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were increased, while the content of malonaldehyde (MDA) was lessened in liver tissue of DSS administration group. In addition, the pro-fibrotic markers of hydroxyproline (Hyp), type III procollagen (PCIII) and hyaluronic acid (HA) contents were decreased. Histopathological examination confirmed that the hepatotoxicity in CCl4-injured rats was alleviated following the DSS administration. Furthermore, intrahepatic protein expressions of alpha-smooth muscle actin (α-SMA), phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) were effectively down-regulated, respectively. Overall, this work demonstrates that DSS played the protective effect against CCl4-induced cytotoxicity in liver tissue, which the probable mechanism is associated with attenuation of lipid peroxidation, collagen accumulation and enhancement of anti-oxidative defense capability, as well as regulation of intrahepatic JAK/STAT pathway for maintaining collagenic homoeostasis. PMID:25201143

  14. Differential effects of krill oil and fish oil on the hepatic transcriptome in mice.

    PubMed

    Burri, Lena; Berge, Kjetil; Wibrand, Karin; Berge, Rolf K; Barger, Jamie L

    2011-01-01

    Dietary supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs), specifically the fatty acids docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapentaenoic acid (EPA; 20:5 ω-3), is known to have beneficial health effects including improvements in glucose and lipid homeostasis and modulation of inflammation. To evaluate the efficacy of two different sources of ω-3 PUFAs, we performed gene expression profiling in the liver of mice fed diets supplemented with either fish oil (FO) or krill oil (KO). We found that ω-3 PUFA supplements derived from a phospholipid krill fraction (KO) downregulated the activity of pathways involved in hepatic glucose production as well as lipid and cholesterol synthesis. The data also suggested that KO-supplementation increases the activity of the mitochondrial respiratory chain. Surprisingly, an equimolar dose of EPA and DHA derived from FO modulated fewer pathways than a KO-supplemented diet and did not modulate key metabolic pathways regulated by KO, including glucose metabolism, lipid metabolism and the mitochondrial respiratory chain. Moreover, FO upregulated the cholesterol synthesis pathway, which was the opposite effect of krill-supplementation. Neither diet elicited changes in plasma levels of lipids, glucose, or insulin, probably because the mice used in this study were young and were fed a low-fat diet. Further studies of KO-supplementation using animal models of metabolic disorders and/or diets with a higher level of fat may be required to observe these effects.

  15. [Predicting side effects of the treatment of chronic hepatitis with peginterferon alpha-2A with ribaverin].

    PubMed

    Sarkisiants, N K; Grigorian, É G

    2013-01-01

    The aim of the study was to monitor the commonest side effects of the treatment of chronic hepatitis with peginterferon alpha-2A (PEG-IFN) and ribaverin (RBV) and the influence of various factors on their development. The work was done in the Department of Infectious Disease, Erevan State Medical University. Monitoring 16 adverse reactions was carried out with the use of special tables within 1, 2, 4 and 6 months after the onset of therapy in patients with genotypes 2 and 3 and in addition after 8, 10 and 12 months in patients with genotype 1. The influence of independent prognostic factors was estimated by logistic regression analysis. The commonest side effects of PEG-IFN plus RBV therapy were leukopenia, thrombocytopenia, weight loss, depression, fatigue, and insomnia that occurred at one time or another in more than half of the patients. Weight loss during therapy amounted to 8.36 kg (95% CI 6.7-10) (maximum 21 kg). Myalgia, anorexia, arthralgia, headache, alopecia, and vomiting were documented in 20-50% of the cases. Anemia, pruritis, eruption, erythema, and hair shedding at injection sites occurred in 1/4 of the patients. It is concluded that logistic regression analysis with matching selected prognostic factors permits to estimate the probability of such side effects as weight loss, flu-like syndrome, and myalgia. PMID:24159787

  16. Antioxidant effects of proanthocyanidin from grape seed on hepatic tissue injury in diabetic rats

    PubMed Central

    Mansouri, Esrafil; Khorsandi, Layasadat; Abedi, Hassan Ali

    2014-01-01

    Objective(s): Diabetes plays an important role in the induction of the liver injury. Grape seed proanthocyanidin (GSP) have a wide range of medicinal properties against oxidative stress. In this study we evaluated antioxidant effects of GSP on liver in streptozotocin-induced diabetic rats. Materials and Methods: Thirty male Sprague–Dawley rats were divided into three groups: control, untreated diabetic and diabetic rats treated with GSP. Diabetes was induced in rats by intraperitoneal injection of streptozotocin (50 mg/kg). GSP were administered via oral gavage (200 mg/kg) for 4 weeks. Results: GSP produced significant hepatoprotective effects by decreasing activities of serum aminotransferases and alkaline phosphatase, and decreasing liver malondialdehyde and bilirubin (P<0.05) levels. It increased liver superoxide dismutase, catalase and glutathione peroxidase activities and albumin level (P<0.05). Administration of GSP significantly ameliorated structural changes induced in liver of diabetic rats. Conclusion: GSP have protective effects against hepatic tissue injury due to antioxidant properties. PMID:25140209

  17. Rewiring macrophages for anti-tumour immunity.

    PubMed

    Lee, Yunqin; Biswas, Subhra K

    2016-06-28

    Tumour-associated macrophages facilitate cancer progression, but whether they can be reprogrammed to elicit an anti-tumour response remains unclear. Deletion of the microRNA-processing enzyme Dicer is now shown to rewire macrophages to an anti-tumour mode, leading to an enhanced response to immunotherapy and inhibition of tumour progression. PMID:27350442

  18. Chemotherapy for desmoid tumours in association with familial adenomatous polyposis: a report of three cases

    PubMed Central

    Hamilton, Lisa; Blackstein, Martin; Berk, Terri; McLeod, Robin S.; Gallinger, Steven; Madlensky, Lisa; Cohen, Zane

    1996-01-01

    Objective To determine the efficacy of chemotherapy for inoperable desmoid tumours associated with familial adenomatous polyposis. Design A review of three cases of unresectable desmoid tumours and of the literature on the subject. Setting The Steven Atanas Stavro Polyposis Registry at Mount Sinai Hospital in Toronto. Patients Three patients with symptomatic, unresectable desmoid tumours associated with familial adenomatous polyposis and unresponsive to conventional hormone therapy. Intervention A chemotherapy regimen of seven cycles of doxorubicin (dose ranging from 60 to 90 mg/m2) and dacarbazine (1000 mg/m2), followed by carboplatin (400 mg/m2) and dacarbazine. Outcome Measures Clinical improvement and tumour regression demonstrated by computed tomography. Results In each of the three cases significant tumour regression was seen clinically and radiologically. Conclusions Cytotoxic chemotherapy is an effective treatment for desmoid tumours associated with familial adenomatous polyposis. The chemotherapy should be started early in cases of symptomatic desmoid tumour unresponsive to conventional medical therapy. PMID:8640627

  19. [Patient education of hepatitis].

    PubMed

    Boyer, Dominique; Faillebin, Françoise; de la Brière, Aice

    2013-11-01

    The therapeutic education of patients with hepatitis C helps to improve their health and quality of life. The aim is to encourage compliance with the treatment and the fight against side effects, through to the patient's recovery. PMID:24409616

  20. Stevia rebaudiana ethanolic extract exerts better antioxidant properties and antiproliferative effects in tumour cells than its diterpene glycoside stevioside.

    PubMed

    López, Víctor; Pérez, Sergio; Vinuesa, Arturo; Zorzetto, Christian; Abian, Olga

    2016-04-01

    Steviol glycosides are currently being used as natural sweeteners by the food industry and Stevia rebaudiana has long been used as a sweet plant in South America for patients suffering from diabetes. In this study, a Stevia rebaudiana ethanolic extract (SREE) was prepared, analysed and tested for antioxidant activity in terms of free radical scavenging properties and antiproliferative effects in cervix (HeLa), pancreatic (MiaPaCa-2) and colonic (HCT116) cancer cells. The antiproliferative mechanism wa