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Sample records for bleomycin

  1. Bleomycin-induced flagellate dermatitis

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    Guilherme Devidé Mota

    2014-07-01

    Full Text Available A 29-year-old woman with stage IVB Hodgkin's lymphoma was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine. Two weeks after the first cycle was completed, she developed pruritic, linear erythematous lesions in a flagellate-like pattern on the trunk, neck and arms. After oral prednisone therapy and cessation of bleomycin, the lesions started to recede.

  2. Bleomycin: A worthy alternative

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    Gursev Sandlas

    2011-01-01

    Full Text Available Context : Lymphangiomas are developmental anomalies presenting mainly in the first two years of life. Surgical excision has been the mainstay of treatment; however a potentially disfiguring surgery along with presence of important structures in the vicinity and infiltration into surrounding structures makes the dissection difficult. Aims : To study the safety and efficacy of Bleomycin as a sclerosing agent for lymphatic malformations in children. Settings and Design : Prospective non comparative nonrandomized trial. Materials and Methods: The study was carried out in 15 children between Day 5 of life to 12 years of age who presented between May2008 to May 2009. Bleomycin aqueous solution was injected intralesionally at a dose not exceeding 0.6 to 0.8 mg. /kg Body wt. The response to therapy was monitored clinically by measuring the length, breadth and area as well as by measuring the two largest perpendicular dimensions. The response was graded as excellent [total disappearance], good [>50% reduction] and poor [50% reduction in the size of their swellings. 2 patients [13.33%] showed a poor response to therapy and achieved less than 50% reduction in the size of the swelling. Complications of the therapy were few and far between. 2 patients developed fever after injection, one patients reported a transient increase in size of swelling, 2 patients have developed discoloration of the overlying skin and are currently being followed up for final outcome. None of the patients developed leucopenia or leukocytosis. All of the complications were managed with conservatively. Patients are on long term follow up to evaluate long term effects, if any.

  3. Bleomycin-Induced Lung Injury

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    Tomás Reinert

    2013-01-01

    Full Text Available Bleomycin is a chemotherapeutic agent commonly used to treat curable diseases such as germinative tumors and Hodgkin’s lymphoma. The major limitation of bleomycin therapy is pulmonary toxicity, which can be life threatening in up to 10% of patients receiving the drug. The mechanism of bleomycin-induced pneumonitis (BIP involves oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and the elaboration of inflammatory cytokines. Ultimately, BIP can progress to lung fibrosis. The diagnosis of BIP is established by the combination of systemic symptoms, radiological and histological findings, and respiratory function tests abnormalities, while other disorders should be excluded. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there is no effective therapy for the disease. In general, the clinical picture is extremely complex. A greater understanding of the BIP pathogenesis may lead to the development of new agents capable of preventing or even treating the injury already present. Physicians who prescribe bleomycin must be aware of the potential pulmonary toxicity, especially in the presence of risk factors. This review will focus on BIP, mainly regarding recent advances and perspectives in diagnosis and treatment.

  4. Bleomycin clinical pharmacology by radioimmunoassay

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    Hall, S.W.; Strong, J.E.; Broughton, A.; Frazier, M.L.; Benjamin, R.S.

    1982-01-01

    Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7-30 U intravenously (IV) and eight patients who received 4-30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m/sup 2/ and the volume of distribution was 13.2 l/m/sup 2/. Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m/sup 2/ and the volume of distribution was 19.2 l/m/sup 2/. Bleomycin plasma clearance correlated well with serum creatinine (r/sup 2/=0.72). Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.

  5. Bleomycin treatment of brain tumors: an evaluation

    DEFF Research Database (Denmark)

    Linnert, Mette; Gehl, Julie

    2009-01-01

    Bleomycin has been used in the treatment of brain tumors for over 30 years. Currently, we are evaluating electrochemotherapy (the use of electric pulses to enhance uptake of bleomycin) for patients with secondary brain tumors. We, therefore, reviewed the literature with specific reference...... to the tolerability and toxicity of bleomycin. Using the keywords 'brain' and 'bleomycin', a database search without date restriction was performed and over 500 articles were found. Twenty-five articles were used for this study based on relevance determined by: (i) clinical studies, (ii) use of bleomycin, and (iii......) direct injection into brain tissue or cysts. There were two main indications for the use of bleomycin directly into the brain: (i) cystic tumors in the form of craniopharyngiomas and (ii) solid brain tumors such as glioblastomas and astrocytomas. The most frequent adverse effects reported were transient...

  6. Bleomycin induced urethral stricture in Hodgkin′s disease

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    Ritesh Tapkire

    2009-01-01

    Full Text Available Bleomycin is a glycoprotein that is extensively used in combination with other anti-cancer agents because of its relative lack of hematological and gastrointestinal toxicity. However, pulmonary toxicity is common with bleomycin and limits its therapeutic utility. Urethral stricture as a result of bleomycin toxicity has not been reported in literature. In this case report, a young male patient who developed urethral stricture after bleomycin-based chemotherapy is described and the possible effects of bleomycin on the urethra are discussed.

  7. Modeling Space Radiation with Radiomimetic Agent Bleomycin

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    Lu, Tao

    2017-01-01

    Space radiation consists of proton and helium from solar particle events (SPE) and high energy heavy ions from galactic cosmic ray (GCR). This mixture of radiation with particles at different energy levels has different effects on biological systems. Currently, majority studies of radiation effects on human were based on single-source radiation due to the limitation of available method to model effects of space radiation on living organisms. While NASA Space Radiation Laboratory is working on advanced switches to make it possible to have a mixed field radiation with particles of different energies, the radiation source will be limited. Development of an easily available experimental model for studying effects of mixed field radiation could greatly speed up our progress in our understanding the molecular mechanisms of damage and responses from exposure to space radiation, and facilitate the discovery of protection and countermeasures against space radiation, which is critical for the mission to Mars. Bleomycin, a radiomimetic agent, has been widely used to study radiation induced DNA damage and cellular responses. Previously, bleomycin was often compared to low low Linear Energy Transfer (LET) gamma radiation without defined characteristics. Our recent work demonstrated that bleomycin could induce complex clustered DNA damage in human fibroblasts that is similar to DNA damage induced by high LET radiation. These type of DNA damage is difficult to repair and can be visualized by gamma-H2Ax staining weeks after the initial insult. The survival ratio between early and late plating of human fibroblasts after bleomycin treatment is between low LET and high LET radiation. Our results suggest that bleomycin induces DNA damage and other cellular stresses resembling those resulted from mixed field radiation with both low and high LET particles. We hypothesize that bleomycin could be used to mimic space radiation in biological systems. Potential advantages and limitations of

  8. Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice

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    OU Xue-mei; FENG Yu-lin; WEN Fu-qiang; HUANG Xiang-yang; XIAO Jun; WANG Ke; WANG Tao

    2008-01-01

    Background Bleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.Methods Bleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days.We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.Results Simvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (Ⅰand Ⅲ) mRNA expression induced by bleomycin. Moreover,simvastatin down-regulated the increased expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-(] (TNF-a) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore,the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.Conclusions Simvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-βI and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.

  9. The effects of Bleomycin A5 on infantile maxillofacial haemangioma

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    Zhao Fu-yun

    2011-07-01

    Full Text Available Abstract Objective To examine the effects of bleomycin A5 on infantile maxillofacial haemangiomas. Methods Bleomycin A5 was given by multiple intralesinoal injections and the dosage was given according to the age of the patient and size of the lesion. Parts of patients were accompanied by prednisone treatment(2-5 mg/kg, po, QOD. Results All the haemangiomas involuted completely after treated with bloemycin A5 with better recovery of skin color and less scar forming in small haemangiomas. Conclusion Infantile haemangioma could be effectively treated with bleomycin A5 without serious side effects.

  10. Bleomycin lung toxicity: who are the patients with increased risk?

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    Azambuja, E; Fleck, J F; Batista, R G; Menna Barreto, S S

    2005-01-01

    Bleomycin is an antibiotic drug with anticancer properties produced by Streptomyces verticillus [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459]. It was isolated in 1966 by Umezawa et al. and its mechanism of action is breaking the DNA double helix by the production of free radicals, which is oxygen and iron dependent [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin may be inactivated by bleomycin hidrolase presents in normal and tumoral cells [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94; Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clinics Chest Med 1990;11:1-20]. The complex bleomycin-Fe has been the most studied because bleomycin joins the DNA and Fe at the same time, and release of free radicals happens in the presence of molecular oxygen [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin has a renal metabolism with 50% of dose eliminated in 4h after its administration and 70% in the next 24h. Its half-life (T 1/2) is not altered, although the creatinine clearance drops to 25-35 ml/min [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg

  11. Erdosteine prevents bleomycin-induced pulmonary fibrosis in rats.

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    Sogut, Sadik; Ozyurt, Huseyin; Armutcu, Ferah; Kart, Levent; Iraz, Mustafa; Akyol, Omer; Ozen, Suleyman; Kaplan, Suleyman; Temel, Ismail; Yildirim, Zeki

    2004-06-28

    Oxidative stress plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. Therefore, erdosteine, an antioxidant, is expected to have an inhibitor potential against the disease. Rats were given one dose of bleomycin in pulmonary fibrosis groups and saline in controls. The first dose of oral erdosteine (10 mg/kg/day) was given 2 days before the bleomycin injection to achieve the plateau level in blood and continued until killing. At day 14, fibrotic changes were evaluated, using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a fivefold increase in fibrosis score that was decreased by 87% by erdosteine (P>0.001) and almost twofold increases in hydroxyproline content which were completely prevented by erdosteine. Myeloperoxidase activities and MDA levels, which were significantly higher in the bleomycin group, were then significantly attenuated by erdosteine. These results revealed that oral erdosteine may prevent the development of acute pulmonary inflammation caused by bleomycin injection via the repression of neutrophil accumulation and lipid peroxidation, resulting in the inhibition of subsequent lung fibrosis.

  12. Bleomycin and radiation-induced lung damage in mice

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    Collis, C.H.; Down, J.D.; Pearson, A.E.; Steel, G.G. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1983-01-01

    Bleomycin-induced lung damage was assessed using both a functional end-point and mortality. The extent of lung damage was found to depend on the schedule, mode of administration and dose of the drug. Greater damage occurred following twice-weekly administration than when the same dose was given as a single injection. Intravenous administration resulted in greater damage than intraperitoneal administration. When bleomycin was given with thoracic irradiation lung damage occurred earlier and at lower radiation doses than with radiation alone. Similar responses were obtained whether bleomycin was given four weeks before, with or four weeks after irradiation. Thus although there was enhanced damage from the combined treatment, there was no evidence of a time-dependent interaction.

  13. Detection of lung cancer with /sup 55/Co-bleomycin using a positron camera

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    Nieweg, O.E.; Beekhuis, H.; Paans, A.M.J.; Piers, D.A.; Vaalburg, W.; Welleweerd, J.; Wiegman, T.; Woldring, M.G.

    1982-03-01

    /sup 57/Co-bleomycin is useful in the detection and staging of lung cancer, but the long half-life of /sup 57/Co(270 days) has discouraged its widespread acceptance. We investigated the shorter living positron emitting /sup 55/Co(half-life 18.2 h) as a label for bleomycin. In eleven patients with proven lung cancer scintigraphy with /sup 55/Co-bleomycin, using a positron camera, demonstrated the tumor in ten cases. Tumor to lung ratios were calculated. The results were superior to those obtained with /sup 55/Co-bleomycin single photon imaging but inferior to those obtained with /sup 57/Co-bleomycin scintigraphy.

  14. Effects of aminoguanidine and antioxidant erdosteine on bleomycin-induced lung fibrosis in rats.

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    Yildirim, Zeki; Turkoz, Yusuf; Kotuk, Mahir; Armutcu, Ferah; Gurel, Ahmet; Iraz, Mustafa; Ozen, Suleyman; Aydogdu, Ismet; Akyol, Omer

    2004-09-01

    Reactive oxygen and nitrogen species have been implicated in the pathogenesis of bleomycin-induced lung fibrosis. The effects of aminoguanidine and erdosteine on the bleomycin-induced lung fibrosis were evaluated in rats. The animals were placed into five groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + aminoguanidine (200 mg/kg), bleomycin + erdosteine (10 mg/kg), and bleomycin + erdosteine + aminoguanidine. Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology, which is completely prevented by erdosteine and aminoguanidine. A strong staining for nitro tyrosine antibody in lung tissue and increased levels of lung NO were found in bleomycin group, that were significantly reduced by aminoguanidine and erdosteine. Aminoguanidine and erdosteine significantly prevented depletion of superoxide dismutase and glutathione peroxidase and elevated myeloperoxidase activities, malondialdehyde level in lung tissue produced by bleomycin. Data presented here indicate that aminoguanidine and erdosteine prevented bleomycin-induced lung fibrosis and that nitric oxide mediated tyrosine nitration of proteins plays a significant role in the pathogenesis of bleomycin-induced lung fibrosis. Also our data suggest that antifibrotic affect of antioxidants may be due to their inhibitory effect on nitric oxide generation in this model.

  15. Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice

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    Fujita, Masaki; Ye, Qing; Ouchi, Hiroshi; Harada, Eiji; Inoshima, Ichiro; Kuwano, Kazuyoshi; Nakanishi, Yoichi

    2006-01-01

    The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

  16. [Bleomycin and pulmonary function changes in children with malignant lymphomas].

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    Kuijten, R R; Voûte, P A; van Nierop, J C; van Leeuwen, E F; Griffioen, R W; Wagner-Soeters, R E

    1991-02-09

    In 25 patients under 18 years of age with Hodgkin's disease or non-Hodgkin lymphoma treated with bleomycin as part of the treatment with several cytostatics, the diffusion capacity of the lung for carbon monoxide (DLCO) was determined before, during and after this treatment to investigate the damaging effect of bleomycin on the lungs. The DLCO decreased in 18 of the 25 children; the degree of decrease depended both on the total dosage (max. 120 mg/sq.m body surface) and on the dose per administration (5 or 10 mg/sq.m). Eight of these 18 children were followed up for some time after discontinuation of bleomycin treatment. During the relatively brief follow-up period of one year on average, complete recovery of pulmonary function was seen in none of these children; in two, partial recovery occurred. It is necessary to study the changes of DLCO for a longer period after bleomycin treatment, as well as the factors that influence recovery of pulmonary function in children.

  17. Gefitinib attenuates murine pulmonary fibrosis induced by bleomycin

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    WANG Ping; TIAN Qing; LIANG Zhi-xin; YANG Zhen; XU Shu-feng; SUN Ji-ping; CHEN Liang-an

    2010-01-01

    Background Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is an effective treatment for epithelial tumors, including non-small cell lung cancer (NSCLC), and is generally well tolerated.However, some clinical trials revealed that gefitinib exposure caused lung fibrosis, a severe adverse reaction.This study investigated the effect of gefitinib on lung fibrosis in mice.Methods We generated a mouse model of lung fibrosis induced by bleomycin to investigate the fibrotic effect of gefitinib.C57BL/6 mice were injected intratracheally with bleomycin or saline, with intragastric administration of gefitinib or saline.Lung tissues were harvested on day 14 or 21 for histology and genetic analysis.Results The histological results showed that bleomycin successfully induced lung fibrosis in mice, and gefitinib prevented lung fibrosis and suppressed the proliferation of S100A4-positive fibroblast cells.In addition, Western blotting analysis revealed that gefitinib decreased the expression of phosphorylated EGFR (p-EGFR).Furthermore, quantitative real-time PCR (qRT-PCR) demonstrated that gefitinib inhibited the accumulation of collagens Ⅰ and Ⅲ.Conclusions These results reveal that gefitinib reduces pulmonary fibrosis induced by bleomycin in mice and suggest that administration of small molecule EGFR tyrosine kinase inhibitors has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that targeting tyrosine kinase receptors might be useful for the treatment of pulmonary fibrosis in humans.

  18. DECREASE IN PULMONARY-FUNCTION DURING BLEOMYCIN-CONTAINING COMBINATION CHEMOTHERAPY FOR TESTICULAR CANCER - NOT ONLY A BLEOMYCIN EFFECT

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    SLEIJFER, S; VANDERMARK, TW; KOOPS, HS; MULDER, NH

    1995-01-01

    This study was performed to determine the changes in pulmonary function in patients randomised to receive treatment with four cycles of bleomycin, etoposide and cisplatin (BEP) (27 patients) or with four cycles of etoposide and cisplatin (EP) (27 patients) for disseminated non-seminomatous testicula

  19. Effects of bleomycin and antioxidants on the fatty acid profile of testicular cancer cell membranes.

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    Cort, A; Ozben, T; Melchiorre, M; Chatgilialoglu, C; Ferreri, C; Sansone, A

    2016-02-01

    Bleomycin is used in chemotherapy regimens for the treatment of patients having testicular germ-cell tumor (TGCT). There is no study in the literature investigating the effects of bleomycin on membrane lipid profile in testicular cancer cells. We investigated membrane fatty acid (FA) profiles isolated, derivatized and analyzed by gas chromatography of NTera-2 testicular cancer cells incubated with bleomycin (Bleo) for 24 h in the absence and presence of N-Acetyl-L-Cysteine (NAC) and curcumin (Cur) as commonly used antioxidant adjuvants. At the same time the MAPK pathway and EGFR levels were followed up. Bleomycin treatment increased significantly saturated fatty acids (SFA) of phospholipids at the expense of monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). Bleomycin also led to a significant increase in the trans lipid isomers of oleic and arachidonic acids due to its free radical producing effect. Incubation with bleomycin increased the p38 MAPK and JNK levels and downregulated EGFR pathway. Coincubation of bleomycin with NAC reversed effects caused by bleomycin. Our results highlight the important role of membrane fatty acid remodeling occurring during the use of bleomycin and its concurrent use with antioxidants which can adjuvate the cytotoxic effects of the chemotherapeutic agents.

  20. Cisplatin, vindesine, and bleomycin (DVB) combination chemotherapy for esophageal carcinoma.

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    Kelsen, D P; Bains, M; Chapman, R; Golbey, R

    1981-01-01

    Forty-six patients with epidermoid carcinoma of the esophagus have been treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Of the 40 patients currently evaluable for response, 21 have had partial remissions (52%). At least four of these responses were almost complete, with only microscopic disease found on endoscopy or review of the resected specimen. Toxic effects have, in general, been manageable. The major toxic effects included nausea and vomiting, nephrotoxicity, and myelosuppression. There were two drug-related deaths: one due to renal failure and one due to sepsis. The three-drug combination appears to be substantially more effective than either the two-drug combination of cisplatin and bleomycin or vindesine alone. Effects on survival cannot yet be evaluated.

  1. Bleomycin induced epithelial–mesenchymal transition (EMT) in pleural mesothelial cells

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    Chen, Li-Jun [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Ye, Hong [Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Zhang, Qian; Li, Feng-Zhi; Song, Lin-Jie; Yang, Jie; Mu, Qing [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Rao, Shan-Shan [Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Cai, Peng-Cheng [Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Xiang, Fei; Zhang, Jian-Chu [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Su, Yunchao [Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA (United States); Xin, Jian-Bao, E-mail: 814643835@qq.com [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China); Ma, Wan-Li, E-mail: whmawl@aliyun.com [Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei (China); Key Laboratory of Pulmonary Diseases, Ministry of Health of China, Wuhan, Hubei (China)

    2015-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis. Recent studies revealed that pleural mesothelial cells (PMCs) undergo epithelial–mesenchymal transition (EMT) and play a pivotal role in IPF. In animal model, bleomycin induces pulmonary fibrosis exhibiting subpleural fibrosis similar to what is seen in human IPF. It is not known yet whether bleomycin induces EMT in PMCs. In the present study, PMCs were cultured and treated with bleomycin. The protein levels of collagen-I, mesenchymal phenotypic markers (vimentin and α-smooth muscle actin), and epithelial phenotypic markers (cytokeratin-8 and E-cadherin) were measured by Western blot. PMC migration was evaluated using wound-healing assay of culture PMCs in vitro, and in vivo by monitoring the localization of PMC marker, calretinin, in the lung sections of bleomycin-induced lung fibrosis. The results showed that bleomycin induced increases in collagen-I synthesis in PMC. Bleomycin induced significant increases in mesenchymal phenotypic markers and decreases in epithelial phenotypic markers in PMC, and promoted PMC migration in vitro and in vivo. Moreover, TGF-β1-Smad2/3 signaling pathway involved in the EMT of PMC was demonstrated. Taken together, our results indicate that bleomycin induces characteristic changes of EMT in PMC and the latter contributes to subpleural fibrosis. - Highlights: • Bleomycin induces collagen-I synthesis in pleural mesothelial cells (PMCs). • Bleomycin induces increases in vimentin and α-SMA protein in PMCs. • Bleomycin induces decreases in cytokeratin-8 and E-cadherin protein in PMCs • TGF-β1-Smad2/3 signaling pathway is involved in the PMC EMT induced by bleomycin.

  2. Extensive pneumothorax, pneumomediastinum and surgical emphysema as a complication of bleomycin therapy

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    Jain, Tarun P.; Thulkar, Sanjay; Saha, Sanchita [All India Institute of Medical Sciences, Department of Radiology, New Delhi (India); Bakhshi, Sameer; Dominic, Joseph [All India Institute of Medical Sciences, Department of Medical Oncology, New Delhi (India)

    2005-12-01

    Bleomycin is a commonly used chemotherapeutic agent and one of the commonest cytotoxic drugs leading to pulmonary parenchymal damage. It generally leads to interstitial pneumonitis and fibrosis, hypersensitivity reactions and acute respiratory distress syndrome. We describe an 8-year-old boy who, following prolonged bleomycin therapy, demonstrated extensive air dissection and extrapulmonary air, an unusual and fatal complication. (orig.)

  3. Bleomycin-Induced Flagellate Erythema in a Patient Diagnosed with Ovarian Yolk Sac Tumor

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    Stergios Boussios

    2015-01-01

    Full Text Available Flagellate linear hyperpigmentation can rarely be caused by the chemotherapy agent, bleomycin. Herein, we describe the case of a 20-year-old woman treated with bleomycin for an ovarian yolk sac tumor and review the prominent features of this form of dermatitis.

  4. Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats.

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    Verma, Ramesh; Brahmankar, Mahesh; Kushwah, Lokendra; Suresh, Balakrishnan

    2013-11-01

    The present study examined the protective effect of sulindac on bleomycin-induced lung fibrosis in rats. Animals were divided into saline group, bleomycin group (single intra-tracheal instillation of bleomycin) and bleomycin+sulindac (orally from day 1 to day 20). Bleomycin administration reduced the body weight, altered antioxidant status (such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione) while it increased the lung weight, hydroxyproline content, collagen deposition and lipid peroxidation. However, simultaneous administration of sulindac improved the body weight, antioxidant status and decreased the collagen deposition in lungs. Moreover, the levels of inflammatory cytokine tumour necrosis factor-α increased in bleomycin-induced group, whereas, on treatment with sulindac the levels of tumour necrosis factor-α were found reduced. Finally, histological evidence also supported the ability of sulindac to inhibit bleomycin-induced lung fibrosis. The results of the present study indicate that sulindac can be used as an agent against bleomycin-induced pulmonary fibrosis.

  5. Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice.

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    Li, Xinping; Li, Shengli; Zhang, Miaotao; Li, Xiukun; Zhang, Xiaoming; Zhang, Wenlong; Li, Chuanghong

    2010-08-01

    Current evidence suggests that the keratinocyte growth factor (KGF) and the polymorphonuclear leukocyte may play key roles in the development of lung fibrosis. Here we describe the construction, expression, purification, and identification of a novel NIF (neutrophil inhibitory factor)-KGF mutant fusion protein (NKM). The fusion gene was ligated via a flexible octapeptide hinge and expressed as an insoluble protein in Escherichia coli BL21 (DE3). The fusion protein retained the activities of KGF and NIF, as it inhibited both fibroblast proliferation and leukocyte adhesion. Next, the effects of NKM on bleomycin-induced lung fibrosis in mice were examined. The mice were divided into the following four groups: (i) saline group; (ii) bleomycin group (instilled with 5 mg/kg bleomycin intratracheally); (iii) bleomycin plus dexamethasone (Dex) group (Dex was given intraperitoneally (i.p.) at 1 mg/kg/day 2 days prior to bleomycin instillation and daily after bleomycin instillation until the end of the treatment); and (iv) bleomycin plus NKM group (NKM was given i.p. at 2 mg/kg/day using the same protocol as the Dex group). NKM significantly improved the survival rates of mice exposed to bleomycin. The marked morphological changes and increased hydroxyproline levels resulted from the instillation of bleomycin (on Day 17) in the lungs were significantly inhibited by NKM. These results revealed that NKM can attenuate bleomycin-induced lung fibrosis, suggesting that NKM could be used to prevent bleomycin-induced lung damage or other interstitial pulmonary fibrosis.

  6. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice

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    Choi, Sun Mi; Jang, An-Hee; Kim, Hyojin; Lee, Kyu Hwa; Kim, Young Whan

    2016-01-01

    Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lu...

  7. Intralesional bleomycin for the treatment of periocular capillary hemangiomas

    Directory of Open Access Journals (Sweden)

    Derrick P Smit

    2012-01-01

    Full Text Available Periocular infantile capillary hemangiomas do not always respond well to conventional treatment modalities such as systemic or intralesional corticosteroids, radiotherapy or debulking surgery. The authors describe the use of intralesional bleomycin injections (IBIs to treat potentially amblyogenic lesions in two cases where other modalities have failed. In both cases monthly IBIs successfully cleared the visual axis of the affected eye before the age of 1 year thus preventing permanent sensory deprivation amblyopia. A total of five and nine injections, respectively, were used and no significant side effects were noted. IBI appears to be a useful alternative in the treatment of periocular capillary hemangiomas refractory to more conventional modalities.

  8. Prostaglandin E₂ protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction.

    Science.gov (United States)

    Dackor, Ryan T; Cheng, Jennifer; Voltz, James W; Card, Jeffrey W; Ferguson, Catherine D; Garrett, Ryan C; Bradbury, J Alyce; DeGraff, Laura M; Lih, Fred B; Tomer, Kenneth B; Flake, Gordon P; Travlos, Gregory S; Ramsey, Randle W; Edin, Matthew L; Morgan, Daniel L; Zeldin, Darryl C

    2011-11-01

    Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered

  9. Synthesis of samarium binding bleomycin - a possible NCT radiosensitizer

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, B.M., E-mail: bmm@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Mendes, T.M.; Campos, T.P.R., E-mail: campos@nuclear.ufmg.b [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil)

    2011-07-01

    Bleomycin (BLM) is a drug that has attractive features for the development of a new radiopharmaceutical, particularly with regard to neutron capture therapy (NCT) sensitized by Sm-149. It has the ability to chelate many metal ions. In vitro studies have shown that up to 78% of BLM present in a cell is accumulated inside the nucleus or in the nuclear membrane. In addition, this drug has higher affinity for tumor tissues than for normal tissues. Radioactive isotopes carried by this antibiotic would be taken preferentially to one important cellular targets DNA. Besides, BLM displays intrinsic anti-tumor activity - it is a chemotherapic antibiotic clinically used against some cancers. This study aimed to obtain bleomycin molecules bound to samarium (BLM-Sm) for NCT studies in vitro and in vivo. The binding technique employed in this work has great simplicity and low cost. Thin layer chromatography, high performance liquid chromatography, fast protein liquid chromatography and analysis by ICP-AES were applied to verify the binding molecule. ICP-AES results showed the presence of samarium in the sample peaks related to BLM-Sm. However, efficiency and stability of this bond needs to be investigated. (author)

  10. Pingyangmycin and Bleomycin Share the Same Cytotoxicity Pathway

    Directory of Open Access Journals (Sweden)

    Yanli He

    2016-06-01

    Full Text Available Pingyangmycin is an anticancer drug known as bleomycin A5 (A5, discovered in the Pingyang County of Zhejiang Province of China. Bleomycin (BLM is a mixture of mainly two compounds (A2 and B2, which is on the World Health Organization’s list of essential medicines. Both BLM and A5 are hydrophilic molecules that depend on transporters or endocytosis receptors to get inside of cells. Once inside, the anticancer activities rely on their abilities to produce DNA breaks, thus leading to cell death. Interestingly, the half maximal inhibitory concentration (IC50 of BLMs in different cancer cell lines varies from nM to μM ranges. Different cellular uptake, DNA repair rate, and/or increased drug detoxification might be some of the reasons; however, the molecules and signaling pathways responsible for these processes are largely unknown. In the current study, we purified the A2 and B2 from the BLM and tested the cytotoxicities and the molecular mechanisms of each individual compound or in combination with six different cell lines, including a Chinese hamster ovary (CHO cell line defective in glycosaminoglycan biosynthesis. Our data suggested that glycosaminoglycans might be involved in the cellular uptake of BLMs. Moreover, both BLM and A5 shared similar signaling pathways and are involved in cell cycle and apoptosis in different cancer cell lines.

  11. Complete Resolution of Cystic Hygroma with Single Session of Intralesional Bleomycin

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    Fadi Atwan

    2012-07-01

    Full Text Available Intralesional sclerotherapy as a primary modality of management for cystic hygroma is successfully described in literature. It has many benefits over surgical approach; recurrence being the concern of as much as 20% of patients in which apparent complete excision has been performed. Bleomycin is one of sclerosing agents used as intralesional therapy in cystic hygroma. Complete response usually occurs in multiple sessions of sclerotherapy. Rarely, complete resolution occurs with single session of bleomycin sclerotherapy. We share our experience of managing a case of cystic hygroma of neck that completely resolved with single session of bleomycin sclerotherapy.

  12. The genome-wide DNA sequence specificity of the anti-tumour drug bleomycin in human cells.

    Science.gov (United States)

    Murray, Vincent; Chen, Jon K; Tanaka, Mark M

    2016-07-01

    The cancer chemotherapeutic agent, bleomycin, cleaves DNA at specific sites. For the first time, the genome-wide DNA sequence specificity of bleomycin breakage was determined in human cells. Utilising Illumina next-generation DNA sequencing techniques, over 200 million bleomycin cleavage sites were examined to elucidate the bleomycin genome-wide DNA selectivity. The genome-wide bleomycin cleavage data were analysed by four different methods to determine the cellular DNA sequence specificity of bleomycin strand breakage. For the most highly cleaved DNA sequences, the preferred site of bleomycin breakage was at 5'-GT* dinucleotide sequences (where the asterisk indicates the bleomycin cleavage site), with lesser cleavage at 5'-GC* dinucleotides. This investigation also determined longer bleomycin cleavage sequences, with preferred cleavage at 5'-GT*A and 5'- TGT* trinucleotide sequences, and 5'-TGT*A tetranucleotides. For cellular DNA, the hexanucleotide DNA sequence 5'-RTGT*AY (where R is a purine and Y is a pyrimidine) was the most highly cleaved DNA sequence. It was striking that alternating purine-pyrimidine sequences were highly cleaved by bleomycin. The highest intensity cleavage sites in cellular and purified DNA were very similar although there were some minor differences. Statistical nucleotide frequency analysis indicated a G nucleotide was present at the -3 position (relative to the cleavage site) in cellular DNA but was absent in purified DNA.

  13. Bleomycin sensitivity in Escherichia coli is medium-dependent.

    Directory of Open Access Journals (Sweden)

    Tao Xu

    Full Text Available Bleomycin (BLM is a glycopeptide antibiotic and anti-tumor agent that targets primarily the furanose rings of DNA and in the presence of ferrous ions produces oxidative damage and DNA strand breaks. Escherichia coli cells growing in broth medium and exposed to low concentrations of BLM contain double-strand breaks and require homologous recombination to survive. To a lesser extent, the cells also require the abasic (AP endonucleases associated with base excision repair, presumably to repair oxidative damage. As expected, there is strong induction of the SOS system in treated cells. In contrast, E. coli cells growing in glucose or glycerol minimal medium are resistant to the lethal action of BLM and do not require either homologous recombination functions or AP-endonucleases for survival. DNA ligase activity, however, is needed for cells growing in minimal medium to resist the lethal effects of BLM. There is weak SOS induction in such treated cells.

  14. Intralesional bleomycin in the treatment of cutaneous warts: A randomized clinical trial comparing it with cryotherapy

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    Dhar S

    2009-01-01

    Full Text Available Background: Though not in regular practice, intralesional (IL bleomycin has been used for the treatment of warts since the 1970s and on the other hand, till now cryotherapy is quite regularly used to treat warts. Aim: Our aim was to assess the evidence for the efficacy of IL bleomycin, in comparison with a control group of similar sample receiving cryotherapy, in the treatment of cutaneous warts. Methods: Patients were randomized using computer-generated codes to receive either cryotherapy (double freeze-thaw cycle or IL bleomycin (0.1% solution with concurrent anesthesia for a maximum of four treatments 3 weeks apart and a maximum of five warts treated in each visit for both groups. Patients had their warts measured at base-line and with each return visit including a post treatment follow-up that was 8 weeks apart from last treatment taken. Results: Of the 73 patients completing the study, 39 (53% were treated with IL bleomycin and 34 (47% were treated with cryotherapy. Out of 155 treated warts, 87 (56% were treated with IL beomycin and 68 (44% were treated with cryotherapy. The clearance rates in context of number of patients and number of warts were 94.9% and 97% for bleomycin and 76.5% and 82% for cryotherapy respectively ( P < 0.05 by x 2 analysis and RR = 7.67. Conclusion: IL bleomycin injection was significantly more effective than cryotherapy for treatment of cutaneous wart.

  15. Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats.

    Science.gov (United States)

    Cortijo, J; Cerdá-Nicolás, M; Serrano, A; Bioque, G; Estrela, J M; Santangelo, F; Esteras, A; Llombart-Bosch, A; Morcillo, E J

    2001-06-01

    Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study examines the effect of N-acetylcysteine (NAC) on bleomycin-induced lung fibrosis in rats. NAC (3 mmol x kg(-1); oral) was given daily from 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) or saline, until 14 days postinstillation. NAC partially decreased the augmented collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,354+/-386 and 3,416+/-326 microg x lung(-1) in vehicle-treated and NAC-treated rats, respectively; p < 0.05). The histological assessment using a semiquantitative score showed less collagen deposition and inflammatory cells in NAC-treated rats compared to those receiving bleomycin alone. NAC failed to inhibit the bleomycin-induced increases in lung wet weight and in cell counts and protein levels of bronchoalveolar lavage fluid, but significantly increased total glutathione and taurine levels in bronchoalveolar lavage fluid. These results indicate that oral N-acetylcysteine improves the pulmonary antioxidant protection and may be useful in reducing lung damage produced by bleomycin.

  16. Micronuclei frequency induced by bleomycin in human peripheral lymphocytes: correlating BLHX polymorphism with mutagen sensitivity.

    Science.gov (United States)

    Maffei, Francesca; Carbone, Fabio; Angelini, Sabrina; Forti, Giorgio Cantelli; Norppa, Hannu; Hrelia, Patrizia

    2008-03-01

    Mutagen sensitivity assay, by measuring chromosome damage induced by an in vitro treatment of peripheral lymphocytes with bleomycin, has been proposed as a biomarker for assessing cancer susceptibility. Recently, a single nucleotide polymorphism (SNP A1450G) of the gene for bleomycin hydrolase (BLHX), a specific neutral cysteine protease able to metabolise bleomycin, was proposed as a plausible candidate to variation in mutagen sensitivity. To shed more light on the effect of BLHX genotype on the expression of chromosome damage induced in vitro by bleomycin, we determined mutagen sensitivity for 45 non-smoker healthy volunteers. The level of bleomycin-induced chromosome damage was assessed as frequencies of micronuclei (MN) in cytokinesis-blocked lymphocytes. The subjects were genotyped for the BLHX gene, to determine the possible effect of this polymorphism on mutagen sensitivity. No difference in the spontaneous value of MN was detected between the homozygotes wild-type (A/A) and the carriers of variant alleles A/G heterozygotes or G/G homozygotes (MN/1000 binucleated (BN) cells: 6.69+/-2.53 and 6.37+/-4.87, respectively). A substantial effect of BLHX polymorphism in predetermining individual mutagen sensitivity status was observed: subjects with the BLHX A/A genotype displayed significantly lower mean levels of bleomycin-induced MN frequency than the carriers of A/G or G/G variant alleles combined (12.00+/-3.76 MN/1000 BN vs. 16.37+/-8.86 MN/1000 BN, respectively; P=0.029). The multiple regression analysis, including BLHX genotype and age, confirmed the significant effect of BLHX variant alleles (A/G, G/G) on the chromosome damage induced by bleomycin (P=0.01), whereas age correlated only with the spontaneous MN frequency.

  17. Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer

    DEFF Research Database (Denmark)

    de Wit, Ronald; Skoneczna, Iwona; Daugaard, Gedske

    2012-01-01

    To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC).......To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC)....

  18. Static and dynamic mechanics of the murine lung after intratracheal bleomycin

    Directory of Open Access Journals (Sweden)

    Papiris Spyridon

    2011-05-01

    Full Text Available Abstract Background Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure. Methods Single intratracheal injections of saline (50 μL or bleomycin (2 mg/Kg in 50 μL saline were administered to C57BL/6 (n = 40 and Balb/c (n = 32 mice. Injury/fibrosis score, tissue volume density (TVD, collagen content, airway resistance (RN, tissue damping (G and elastance coefficient (H, hysteresivity (η, and area of pressure-volume curve (PV-A were determined after 7 and 21 days (inflammation and fibrosis stage, respectively. Statistical hypothesis testing was performed using one-way ANOVA with LSD post hoc tests. Results Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and G and H non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. G and H, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, H and G was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls. Conclusions Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than

  19. A Highly Sensitive Spectrophotometric Assay of Bleomycins Based on the Fading Reaction of Some Halofluorescein Dyes

    Institute of Scientific and Technical Information of China (English)

    LIU,Jiang-Tao; LIU,Zhong-Fang; HU,Xiao-Li; Kong,Ling; LIU,Shao-Pu

    2007-01-01

    In weak acidic medium, anticancer antibiotics bleomycin A5 (BLMA5) and bleomycin A2 (BLMA2) can react with halofluorescein dyes such as erythrosin (Ery), eosin Y (EY), eosin B (EB) and rose bengal (RB) by virtue of electrostatic attraction and hydrophobic force to form the ion-association complexes, which can result in the fading reactions of four halofluorescein dyes. The maximum fading wavelengths of these four dyes were located at 527 nm for Ery, 515 nm for EY, 517 nm for EB and 546 nm for RB, respectively. The decrements of absorbance (△A) were directly proportional to the concentrations of bleomycin in a certain range. A new method for the determination of bleomycins anticancer drugs based on fading reactions of halofluorescein dyes has been developed. The method was not only highly sensitive but also simple and rapid. The molar absorptivities (ε) ranged from 1.5 × 105 to 7.5 ×105 L·mol-1·cm-1. It was applied to determination of the bleomycins in human serum, urine and rabbit serum samples. In this work, the spectral properties and the optimum reaction conditions were investigated. The structure of ion-association complexes and the reaction mechanism were discussed.

  20. Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

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    Satish K. Madala

    2011-01-01

    Full Text Available Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD and interstitial pulmonary fibrosis (IPF. Gene-targeted mice that lack SP-C (−/− develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of −/− mice. +/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated +/+ and −/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated −/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF.

  1. Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine.

    Science.gov (United States)

    Yildirim, Zeki; Kotuk, Mahir; Iraz, Mustafa; Kuku, Irfan; Ulu, Ramazan; Armutcu, Ferah; Ozen, Suleyman

    2005-01-01

    Antioxidant therapy may be useful in diseases with impaired oxidant antioxidant balance such as lung fibrosis. The effects of sulfhydryl-containing antioxidant agents N-acetylcysteine (NAC) and erdosteine on the bleomycin-induced lung fibrosis were compared in rats. The animals were divided into four groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + (10 mg/kg), and bleomycin + NAC (3 mmol/kg). Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology which is almost completely prevented by erdosteine and NAC. Hydroxyproline content was 18.7 +/- 3.5 and 11.2 +/- 0.6 mg/g dried tissue in bleomycin and saline treated rats, respectively (P erdosteine and NAC pretreated, respectively. Erdosteine and NAC significantly reduced depletion of glutathione peroxidase, and prevented increases in myeloperoxidase activities, nitric oxide, and malondialdehyde levels in lung tissue produced by bleomycin. Data presented here indicate that erdosteine and NAC similarly prevented bleomycin-induced lung fibrosis and their antioxidant effects were also similar in this experiment.

  2. Enhanced effects of bleomycin on pulmonary function disturbances in patients with decreased renal function due to cisplatin

    NARCIS (Netherlands)

    Sleijfer, S; vanderMark, TW; Mulder, NH; Schraffordt Koops, H.

    1996-01-01

    We examined whether cisplatin-induced nephrotoxicity augmented bleomycin-induced pulmonary toxicity in patients with testicular cancer treated with etoposide and cisplatin with (BEP) or without bleomycin (EP). Before and at 3-week intervals during chemotherapy, creatinine clearance and lung function

  3. Effects of N-acetyl-L-cysteine on bleomycin induced oxidative stress in malignant testicular germ cell tumors.

    Science.gov (United States)

    Cort, Aysegul; Ozdemir, Evrim; Timur, Mujgan; Ozben, Tomris

    2012-12-01

    Testicular cancer is a very common cancer in males aged 15-44 years. Bleomycin is used in chemotherapy regimens in the treatment of patients having testicular germ-cell tumor. Bleomycin generates oxygen radicals, induces oxidative cleavage of DNA strand and induces apoptosis in cancer cells. There is no study in the literature investigating effects of N-Acetyl-L-Cysteine (NAC) on bleomycin-induced oxidative stress in testicular germ cell tumors. For this reason, we studied effects of NAC on oxidative stress produced in wild-type NTera-2 and p53-mutant NCCIT testis cancer cells incubated with bleomycin and compared the results with H(2)O(2) which directly produces oxidative stress. We determined protein carbonyl content, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), 8-isoprostane, lipid hydroperoxide levels and total antioxidant capacity in both testicular cancer cells. Bleomycin and H(2)O(2) significantly increased 8-isoprostane, TBARS, protein carbonyl and lipid hydroperoxide levels in NTera-2 and NCCIT cells. Bleomycin and H(2)O(2) significantly decreased antioxidant capacity and GSH levels in both cell lines. Co-incubation with NAC significantly decreased lipid hydroperoxide, 8-isoprostane, protein carbonyl content and TBARS levels increased by bleomycin and H(2)O(2). NAC enhanced GSH levels and antioxidant capacity in the NTera-2 and NCCIT cells. It can be concluded that NAC diminishes oxidative stress in human testicular cancer cells induced by bleomycin and H(2)O(2).

  4. Protective Effect of Pistacia lentiscus Oil Against Bleomycin-Induced Lung Fibrosis and Oxidative Stress in Rat.

    Science.gov (United States)

    Abidi, Anouar; Aissani, Nadhem; Sebai, Hichem; Serairi, Raja; Kourda, Nadia; Ben Khamsa, Saloua

    2017-04-01

    We aimed in the present study to investigate the protective effect of Pistacia lentiscus oil against bleomycin-induced lung fibrosis as well as the involvement of oxidative stress in such protection. In this respect, adult male Wistar rats were used and divided into three groups of twenty each: control (NaCl, 0.9%), bleomycin, and bleomycin (4 mg/kg b.w.) + P. lentiscus oil (3 g/kg, b.w.). Animals were pretreated for 30 days before the induction of fibrosis by bleomycin and 1 wk after the induction of fibrosis. The oil principal compounds detected by gas chromatography analysis are: Linoleic and palmitic acids (70.6 and 24.7%, respectively). Our data demonstrated that P. lentiscus oil protected against bleomycin-induced fibrosis as evidenced by TGFβ immunostaining increase in lungs fibrocytes as well as inflammatory infiltrate. We also showed that acute bleomycin-induced fibrosis was accompanied by an oxidative stress in lung tissue as assessed by an increase of lipid peroxidation as well as antioxidant enzyme activities depletion such as superoxide dismutase (SOD) and catalase (CAT). More importantly, P. lentiscus oil treatment reversed all bleomycin-induced oxidative stress parameters disturbances. In conclusion, we suggest that P. lentiscus oil had potent protective effects against bleomycin-induced fibrosis due in part to its antioxidant properties.

  5. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

    Directory of Open Access Journals (Sweden)

    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  6. Aerobic Exercise Attenuated Bleomycin-Induced Lung Fibrosis in Th2-Dominant Mice

    Science.gov (United States)

    Oliveira-Junior, Manoel Carneiro; Assumpção-Neto, Erasmo; Brandão-Rangel, Maysa Alves Rodrigues; Damaceno-Rodrigues, Nilsa Regina; Garcia Caldini, Elia; Velosa, Ana Paula Pereira; Teodoro, Walcy Rosolia; Ligeiro de Oliveira, Ana Paula; Dolhnikoff, Marisa; Eickelberg, Oliver; Vieira, Rodolfo Paula

    2016-01-01

    Introduction The aim of this study was to investigate the effect of aerobic exercise (AE) in reducing bleomycin-induced fibrosis in mice of a Th2-dominant immune background (BALB/c). Methods BALB/c mice were distributed into: sedentary, control (CON), Exercise-only (EX), sedentary, bleomycin-treated (BLEO) and bleomycin-treated+exercised (BLEO+EX); (n = 8/group). Following treadmill adaptation, 15 days following a single, oro-tracheal administration of bleomycin (1.5U/kg), AE was performed 5 days/week, 60min/day for 4 weeks at moderate intensity (60% of maximum velocity reached during a physical test) and assessed for pulmonary inflammation and remodeling, and cytokine levels in bronchoalveolar lavage (BAL). Results At 45 days post injury, compared to BLEO, BLEO+EX demonstrated reduced collagen deposition in the airways (p<0.001) and also in the lung parenchyma (p<0.001). In BAL, a decreased number of total leukocytes (p<0.01), eosinophils (p<0.001), lymphocytes (p<0.01), macrophages (p<0.01), and neutrophils (p<0.01), as well as reduced pro-inflammatory cytokines (CXCL-1; p<0.01), (IL-1β; p<0.001), (IL-5; p<0.01), (IL-6; p<0.001), (IL-13; p<0.01) and pro-fibrotic growth factor IGF-1 (p<0.001) were observed. Anti-inflammatory cytokine IL-10 was increased (p<0.001). Conclusion AE attenuated bleomycin-induced collagen deposition, inflammation and cytokines accumulation in the lungs of mice with a predominately Th2-background suggesting that therapeutic AE (15–44 days post injury) attenuates the pro-inflammatory, Th2 immune response and fibrosis in the bleomycin model. PMID:27677175

  7. A designer bleomycin with significantly improved DNA cleavage activity.

    Science.gov (United States)

    Huang, Sheng-Xiong; Feng, Zhiyang; Wang, Liyan; Galm, Ute; Wendt-Pienkowski, Evelyn; Yang, Dong; Tao, Meifeng; Coughlin, Jane M; Duan, Yanwen; Shen, Ben

    2012-08-15

    The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.

  8. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice.

    Science.gov (United States)

    Choi, Sun Mi; Jang, An Hee; Kim, Hyojin; Lee, Kyu Hwa; Kim, Young Whan

    2016-09-01

    Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lungs. The remaining mice were sacrificed and analyzed on day 21. The right lungs were harvested for histological analyses. The messenger RNA (mRNA) levels of epithelial-mesenchymal transition markers were determined via analysis of the harvested lungs on day 21. The mice treated with BLM and metformin (50 mg/kg or 100 mg/kg) showed significantly lower levels of inflammatory cells in the BALF compared with the BLM-only mice on days 10 and 21. The histological examination revealed that the metformin treatment led to a greater reduction in inflammation than the treatment with BLM alone. The mRNA levels of collagen, collagen-1, procollagen, fibronectin, and transforming growth factor-β in the metformin-treated mice were lower than those in the BLM-only mice on day 21, although statistical significance was observed only in the case of procollagen due to the small number of live mice in the BLM-only group. Additionally, treatment with metformin reduced fibrosis to a greater extent than treatment with BLM alone. Metformin suppresses the inflammatory and fibrotic processes of BLM-induced pulmonary fibrosis in a murine model.

  9. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

    Science.gov (United States)

    Rey-Parra, G J; Vadivel, A; Coltan, L; Hall, A; Eaton, F; Schuster, M; Loibner, H; Penninger, J M; Kassiri, Z; Oudit, G Y; Thébaud, B

    2012-06-01

    Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury. ACE2, a recently discovered ACE homologue, acts as a negative regulator of the RAS and counterbalances the function of ACE. We hypothesized that ACE2 prevents Bleomycin (BLM)-induced lung injury. Fourteen to 16-week-old ACE2 knockout mice-male (ACE2(-/y)) and female (ACE2(-/-))-and age-matched wild-type (WT) male mice received intratracheal BLM (1.5U/kg). Male ACE2(-/y) BLM injured mice exhibited poorer exercise capacity, worse lung function and exacerbated lung fibrosis and collagen deposition compared with WT. These changes were associated with increased expression of the profibrotic genes α-smooth muscle actin (α-SMA) and Transforming Growth Factor ß1. Compared with ACE2(-/y) exposed to BLM, ACE2(-/-) exhibited better lung function and architecture and decreased collagen deposition. Treatment with intraperitoneal recombinant human (rh) ACE2 (2 mg/kg) for 21 days improved survival, exercise capacity, and lung function and decreased lung inflammation and fibrosis in male BLM-WT mice. Female BLM WT mice had mild fibrosis and displayed a possible compensatory upregulation of the AT2 receptor. We conclude that ACE2 gene deletion worsens BLM-induced lung injury and more so in males than females. Conversely, ACE2 protects against BLM-induced fibrosis. rhACE2 may have therapeutic potential to attenuate respiratory morbidity in ALI/ARDS.

  10. Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.

    Science.gov (United States)

    Mata, M; Ruíz, A; Cerdá, M; Martinez-Losa, M; Cortijo, J; Santangelo, F; Serrano-Mollar, A; Llombart-Bosch, A; Morcillo, E J

    2003-12-01

    Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.

  11. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-04-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.

  12. Efficient Nuclear DNA Cleavage in Human Cancer Cells by Synthetic Bleomycin Mimics

    NARCIS (Netherlands)

    Li, Qian; van der Wijst, Monique G. P.; Kazemier, Hinke G.; Rots, Marianne G.; Roelfes, Gerard

    2014-01-01

    Iron complexes of N,N-bis(2-Pyridylmethyl)-N-bis(2-pyridyl)-methylamine (N4Py) have proven to be excellent synthetic mimics of the Bleomycins (BLMs), which are a family of natural antibiotics used clinically in the treatment of certain cancers. However, most investigations of DNA cleavage activity o

  13. Evaluating the ameliorative potential of plant flavonoids and their nanocomposites in bleomycin induced idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Srabani Kar

    2016-07-01

    Full Text Available Introduction: Pulmonary Fibrosis can severely disrupt lung function. The cause of Idiopathic Pulmonary Fibrosis (IPF is still unclear. The treatment currently available for IPF provides minimal benefits. Bleomycin is used in research to induce experimental pulmonary fibrosis in animals. Plant flavonoids such as fisetin and curcumin are known for their anti-inflammatory properties. The aim was to demonstrate the path of physiological changes in bleomycin induced IPF and to further evaluate the reversal and ameliorative potentials of some plant flavonoids and their nanocomposites. Bleomycin administration is known to damage the lung epithelial cells resulting in lower cell numbers. Results: Our colony forming assay in BALF also demonstrated a reduction (1.65 fold in colony-forming unit after bleomycin administration. The number of colonies increased upon treatment with fisetin(1.20 fold and curcumin (1.13 fold respectively. MTT proliferation assay demonstrated a significant increase in the number of viable cells upon treatment with curcumin (1.42 fold and fisetin (1.74 fold respectively, in the lung. The NBT assay demonstrated a significant effect of curcumin in BALF, lung and peripheral blood. A significant effect of fisetin was observed in BALF and peripheral blood. Conclusion: These findings were also supported by the histological analyses of the lung samples. Curcumin showed highestpotential for the treatment of IPF and fisetin showed its ameliorative effect. [Biomed Res Ther 2016; 3(7.000: 707-722

  14. Studies on bleomycin-induced repair DNA synthesis in permeable mouse ascites sarcoma cells.

    Directory of Open Access Journals (Sweden)

    Mori,Shigeru

    1989-04-01

    Full Text Available To study the mechanism of DNA excision repair, a DNA repair system employing permeable mouse sarcoma (SR-C3H/He cells was established and characterized. SR-C3H/He cells were permeabilized with a 0.0175% Triton X-100 solution. The permeable cells were treated with 1 mM ATP and 0.11 mM bleomycin, and then washed thoroughly to remove ATP and bleomycin. Repair DNA synthesis occurred in the bleomycin-damaged, permeable SR-C3H/He cells when incubated with ATP and four deoxyribonucleoside triphosphates. The repair nature of the DNA synthesis was confirmed by the BrdUMP density shift technique, and by the reduced sensitivity of the newly synthesized DNA to Escherichia coli exonuclease III. The DNA synthesis was optimally enhanced by addition of 0.08 M NaCl. Studies using selective inhibitors of DNA synthesis showed that aphidicolin-sensitive DNA polymerase (DNA polymerase alpha and/or delta and DNA polymerase beta were involved in the repair process. The present DNA repair system is thought to be useful to study nuclear DNA damage by bleomycin, removal of the damaged ends by an exonuclease, repair DNA synthesis by DNA polymerases and repair patch ligation by DNA ligase(s.

  15. Effects of erdosteine on bleomycin-induced lung fibrosis in rats.

    Science.gov (United States)

    Boyaci, Haşim; Maral, Hale; Turan, Gupse; Başyiğit, Ilknur; Dillioğlugil, Meltem O; Yildiz, Füsun; Tugay, Melih; Pala, Ayşe; Erçin, Cengiz

    2006-01-01

    This study was designed to examine the effects of erdosteine on bleomycin (BLM)-induced lung fibrosis in rats. Thirty-three Sprague-Dawley rats were divided randomly into three groups, bleomycin alone (BLM), bleomycin + erdosteine (BLM + ERD), and saline alone (control). The BLM and BLM + ERD groups, were given 2.5 mg/kg BLM intratracheally. The first dose of oral erdosteine (10 mg/kg/day) in the BLM + ERD group was started 2 days before BLM administration and continued until animals were sacrificed. Animals were sacrificed 14 days after intratracheal instillation of BLM. The effect of erdosteine on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and biochemical measurements of lung tissue superoxide dismutase (SOD) and glutathione (GSH) as antioxidants, malondialdehyde (MDA) as an index for lipid peroxidation, and nitrite/nitrate levels. Bleomycin-induced lung fibrosis as determined by lung histology was prevented with erdosteine (grades of fibrosis were 4.9, 2.3, and 0.2 in BLM, BLM + ERD, and control groups, respectively). Erdosteine also prevented bleomycin-induced increase in MDA (MDA levels were 0.50 +/- 0.15, 0.11 +/- 0.02, and 0.087+/- 0.03 nmol/mg protein in BLM, BLM + ERD, and control groups, respectively) and nitrite/nitrate (nitrite/nitrate levels were 0.92 +/- 0.06, 0.60 +/- 0.09, and 0.56+/- 0.1 micromol/mg protein in BLM, BLM + ERD, and control groups respectively) levels. Bleomycin-induced decrease in GSH and SOD levels in the lung tissue also prevented by erdosteine [(GSH levels were 213.5 +/- 12.4, 253.2+/- 25.2, and 287.9+/- 34.4 nmol/mg protein) (SOD levels were 1.42+/- 0.12, 1.75+/- 0.17, and 1.89+/- 0.09 U/mg protein) in BLM, BLM + ERD, and control groups respectively]. Erdosteine prevented bleomycin-induced increases in total cell number and neutrophil content of the BAL fluid. In conclusion, oral erdosteine is effective in prevention of BLM-induced lung fibrosis in rats possibly via the

  16. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment.

    Science.gov (United States)

    Degryse, Amber L; Tanjore, Harikrishna; Xu, Xiaochuan C; Polosukhin, Vasiliy V; Jones, Brittany R; Boomershine, Chad S; Ortiz, Camila; Sherrill, Taylor P; McMahon, Frank B; Gleaves, Linda A; Blackwell, Timothy S; Lawson, William E

    2011-06-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

  17. Bleomycin-induced chromosome aberrations in head and neck cancer patients analyzed by classical cytogenetics and FISH.

    Science.gov (United States)

    Zych, M; Schlade-Bartusiak, K; Chorostkowska, A; Stembalska, A; Krêcicki, T; Sasiadek, M

    2000-05-01

    Individual sensitivity to mutagens has been considered to play an important role in head-and-neck squamous cells carcinoma (HNSCC) development. The bleomycin test was introduced for establishing constitutional susceptibility to mutagens (T.C. Hsu, D.A. Johnston, L.M. Cherry, D. Ramkisson, S.P. Schantz, J.M. Jessup, R.J. Winn, L. Shirley, C. Furlong, Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis, Int. J. Cancer 43 (1989) 403-409). Its criteria are based on scoring of chromosome aberrations (CAs, mainly breaks) in Giemsa-stained chromosomes. Fluorescence in situ hybridization (FISH) offers an easy method for analysis of translocations, acentric fragments and dicentrics. In the present study FISH was applied in the analysis of bleomycin-induced CAs of the HNSCC patients and controls. The results proved that FISH is a complementary method to the classical staining in monitoring of bleomycin-induced CAs.

  18. Angiotensin-converting enzyme: an indicator of bleomycin-induced pulmonary toxicity in humans?

    DEFF Research Database (Denmark)

    Sørensen, Peter G; Rømer, F K; Cortes, Dina

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical...... or radiological evidence of pulmonary damage. While the static and dynamic lung function parameters were unchanged, carbon monoxide diffusion capacity (DLCO) decreased significantly (P less than 0.01) during a total of 126 days of pulsed regimen, indicating damage to the alveolar-endothelial membrane. S...

  19. Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

    DEFF Research Database (Denmark)

    Lauritsen, Jakob; Kier, Maria Gry Gundgaard; Bandak, Mikkel

    2016-01-01

    PURPOSE: For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring...... of lung function before, during, and after treatment with BEP to disclose valid pulmonary toxicity risk factors. PATIENTS AND METHODS: All patients who were treated with BEP at Rigshospitalet, Copenhagen, Denmark, from 1984 to 2007, were included. Pulmonary function tests (PFTs) that measured...... the diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second, and forced vital capacity were performed systematically before, during, and after treatment with BEP for 5 years of follow-up. According to local protocol, bleomycin was discontinued if hemoglobin...

  20. Air leak: An unusual manifestation of organizing pneumonia secondary to bleomycin

    Science.gov (United States)

    Namitha, R; Nimisha, KP; Yusuf, Nasser; Rauf, CP

    2017-01-01

    Organizing pneumonia (OP) is a less common interstitial lung disease with varying clinical picture. The development of pulmonary air leak in a case of OP is an extremely rare complication. Here, we report the case of a 46-year-old female with carcinoma ovary, postchemotherapy who developed respiratory distress with pneumomediastinum, and subcutaneous emphysema. Lung biopsy showed evidence of OP. This turned out to be a rare case of OP, secondary to bleomycin chemotherapy, presenting with pulmonary air leak. PMID:28360468

  1. Indium 111-A-bleomycin--a new tracer for imaging orofacial neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Kment, G.; Matejka, M.; Porteder, H.; Sinzinger, H.

    1988-09-01

    Forty-six patients with maxillofacial squamous cell cancer of variable keratinization underwent radioisotope diagnosis using Indium 111-A-bleomycin. This new technique was applied to expand the battery of diagnostic tools available for detecting maxillofacial neoplasms. Its high specificity (100%) and sensitivity (96%) make it well suited for detection of both local and distant recurrences as well as tumor regrowth. Preliminary whole body retention measurements also indicate that this technique looks promising for potential therapeutic use.

  2. Radiation nephritis following combined abdominal radiation and chemotherapy (bleomycin-vinblastine)

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, D.N.; Hong, K.; Gault, M.H.

    1978-06-01

    A 29-year-old man presented with acute glomerulonephritis five weeks following completion of combined chemotherapy (bleomycin-vinblastine) and abdominal radiation for testicular carcinoma. There was no evidence for a post-infectious cause or a systemic collagen disorder. The renal biopsy showed changes consistent with radiation nephritis. The combined radiation and chemotherapy may have, by additive or synergistic action, caused the early appearance of radiation nephritis.

  3. Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice

    Science.gov (United States)

    Trivedi, Ruchit; Redente, Elizabeth F.; Thakur, Ashish; Riches, David W. H.; Kompella, Uday B.

    2012-12-01

    Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation. Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well. NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone. In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.

  4. CXC CHEMOKINE RECEPTOR 3 MODULATES BLEOMYCIN-INDUCED PULMONARY INJURY VIA INVOLVING INFLAMMATORY PROCESS

    Institute of Scientific and Technical Information of China (English)

    Jin-ming Gao; Bao Lu; Zi-jian Guo

    2006-01-01

    Objective To investigate the role of CXC chemokine receptor 3(CXCR3 ) in bleomycin-induced lung injury by using CXCR3 gene deficient mice.Methods Sex-, age-, and weight-matched C57BL/6 CXCR3 gene knockout mice and C57BL/6 wide type mice were challenged by injection of bleomycin via trachea. Lung tissue was stained with HE method. Airway resistance was measured. Bronchoalveolar lavage (BAL) was performed using phosphate buffered saline twice, cell number and differentials were counted by Diff-Qnick staining. Interleukin(IL)-4, IL-5, IL-12p40, and interfon-γ in BAL fluid and lung homogenate were measured by enzyme-linked immunosorbent assay. Unpaired t test was explored to compare the difference between two groups.Results On day 7 after bleomycin injection via trachea, CXCR3 knockout mice were protected from bleomycininduced lung injury as evidenced by fewer accumulation of inflammatory cells in the airway and lung interstitium compared with their wild type littermates ( P<0.05 ). Airway resistance was also lower in CXCR3 knockout mice compared with wild type mice (P<0.01 ). Significantly lower level of inflammatory cytokines release, including the altered production of IL-4 and IL-5 both in BAL fluid and lung tissue was seen in CXCR3 knockout mice than in wild type mice (both P<0.05).Conclusion CXCR3 signaling promotes inflammatory cells recruiting and initiates inflammatory cytokines cascade following endotracheal bleomycin administration, indicating that CXCR3 might be a therapeutic target for pulmonary injury.

  5. Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin.

    Science.gov (United States)

    Chyczewska, E; Chyczewski, L; Bańkowski, E; Sułkowski, S; Nikliński, J

    1993-01-01

    It was found that the BCG vaccine injected subcutaneously to the rats enhances the process of lung fibrosis induced by bleomycin. Pretreatment of rats with this vaccine results in accumulation of activated macrophages in lung interstitium and in the bronchoalveolar spaces. It may be suggested that the activated macrophages release various cytokines which may stimulate the proliferation of fibroblasts and biosynthesis of extracellular matrix components.

  6. TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment

    OpenAIRE

    Degryse, Amber L.; Tanjore, Harikrishna; Xu, Xiaochuan C.; Polosukhin, Vasiliy V.; Jones, Brittany R.; Chad S Boomershine; Ortiz, Camila; Sherrill, Taylor P.; McMahon, Frank B.; Gleaves, Linda A.; Blackwell, Timothy S.; Lawson, William E.

    2011-01-01

    The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice tha...

  7. B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

    Science.gov (United States)

    François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

  8. The Human Carnitine Transporter SLC22A16 Mediates High Affinity Uptake of the Anticancer Polyamine Analogue Bleomycin-A5*

    Science.gov (United States)

    Aouida, Mustapha; Poulin, Richard; Ramotar, Dindial

    2010-01-01

    Bleomycin is used in combination with other antineoplastic agents to effectively treat lymphomas, testicular carcinomas, and squamous cell carcinomas of the cervix, head, and neck. However, resistance to bleomycin remains a persistent limitation in exploiting the full therapeutic benefit of the drug with other types of cancers. Previously, we documented that the Saccharomyces cerevisiae l-carnitine transporter Agp2 is responsible for the high affinity uptake of polyamines and of the polyamine analogue bleomycin-A5. Herein, we document that the human l-carnitine transporter hCT2 encoded by the SLC22A16 gene is involved in bleomycin-A5 uptake, as well as polyamines. We show that NT2/D1 human testicular cancer cells, which highly express hCT2, are extremely sensitive to bleomycin-A5, whereas HCT116 human colon carcinoma cells devoid of detectable hCT2 expression or MCF-7 human breast cancer cells that only weakly express the permease showed striking resistance to the drug. NT2/D1 cells accumulated fluorescein-labeled bleomycin-A5 to substantially higher levels than HCT116 cells. Moreover, l-carnitine protected NT2/D1 cells from the lethal effects of bleomycin-A5 by preventing its influx, and siRNA targeted to hCT2 induced resistance to bleomycin-A5-dependent genotoxicity. Furthermore, hCT2 overexpression induced by transient transfection of a functional hCT2-GFP fusion protein sensitized HCT116 cells to bleomycin-A5. Collectively, our data strongly suggest that hCT2 can mediate bleomycin-A5 and polyamine uptake, and that the rate of bleomycin-A5 accumulation may account for the differential response to the drug in patients. PMID:20037140

  9. The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5.

    Science.gov (United States)

    Aouida, Mustapha; Poulin, Richard; Ramotar, Dindial

    2010-02-26

    Bleomycin is used in combination with other antineoplastic agents to effectively treat lymphomas, testicular carcinomas, and squamous cell carcinomas of the cervix, head, and neck. However, resistance to bleomycin remains a persistent limitation in exploiting the full therapeutic benefit of the drug with other types of cancers. Previously, we documented that the Saccharomyces cerevisiae L-carnitine transporter Agp2 is responsible for the high affinity uptake of polyamines and of the polyamine analogue bleomycin-A5. Herein, we document that the human L-carnitine transporter hCT2 encoded by the SLC22A16 gene is involved in bleomycin-A5 uptake, as well as polyamines. We show that NT2/D1 human testicular cancer cells, which highly express hCT2, are extremely sensitive to bleomycin-A5, whereas HCT116 human colon carcinoma cells devoid of detectable hCT2 expression or MCF-7 human breast cancer cells that only weakly express the permease showed striking resistance to the drug. NT2/D1 cells accumulated fluorescein-labeled bleomycin-A5 to substantially higher levels than HCT116 cells. Moreover, L-carnitine protected NT2/D1 cells from the lethal effects of bleomycin-A5 by preventing its influx, and siRNA targeted to hCT2 induced resistance to bleomycin-A5-dependent genotoxicity. Furthermore, hCT2 overexpression induced by transient transfection of a functional hCT2-GFP fusion protein sensitized HCT116 cells to bleomycin-A5. Collectively, our data strongly suggest that hCT2 can mediate bleomycin-A5 and polyamine uptake, and that the rate of bleomycin-A5 accumulation may account for the differential response to the drug in patients.

  10. A cell-free system for studying a priming factor involved in repair of bleomycin-damaged DNA.

    Directory of Open Access Journals (Sweden)

    Seki,Shuji

    1989-04-01

    Full Text Available A simple cell-free system for studying a priming factor involved in the repair of bleomycin-damaged DNA was established. The template-primer used for the repair DNA synthesis was prepared by treating the closed circular, superhelical form of pUC19 plasmid DNA with 2.2 microM bleomycin and 20 microM ferrous ions. Single-strand breaks were introduced into pUC19 DNA by the bleomycin treatment, and the DNA was consequently converted largely into the open circular form. A system for repair of this bleomycin-damaged DNA was constructed with a priming factor, DNA polymerase (DNA polymerase beta or Klenow fragment of DNA polymerase I, ATP, T4 DNA ligase and four deoxynucleoside triphosphates. After incubation, the conformation of the DNA was analyzed by agarose gel electrophoresis and electron microscopy. The open circular DNA was largely converted to the closed circular DNA, indicating that the single-strand breaks of DNA were repaired. When the priming factor was omitted, DNA repair did not occur. The present system seemed to be applicable to the study of priming factors involved in the repair of DNA with single-strand breaks caused not only by bleomycin but also by ionizing radiation or active oxygen.

  11. Administration of bleomycin via the oropharyngeal aspiration route leads to sustained lung fibrosis in mice and rats as quantified by UTE-MRI and histology.

    Directory of Open Access Journals (Sweden)

    Christine Egger

    Full Text Available Pulmonary fibrosis can be experimentally induced in small rodents by bleomycin. The antibiotic is usually administered via the intratracheal or intranasal routes. In the present study, we investigated the oropharyngeal aspiration of bleomycin as an alternative route for the induction of lung fibrosis in rats and mice. The development of lung injury was followed in vivo by ultrashort echo time magnetic resonance imaging (UTE-MRI and by post-mortem analyses (histology of collagen, hydroxyproline determination, and qRT-PCR. In C57BL/6 mice, oropharyngeal aspiration of bleomycin led to more prominent lung fibrosis as compared to intranasal administration. Consequently, the oropharyngeal aspiration route allowed a dose reduction of bleomycin and, therewith, a model refinement. Moreover, the distribution of collagen after oropharyngeal aspiration of bleomycin was more homogenous than after intranasal administration: for the oropharyngeal aspiration route, fibrotic areas appeared all over the lung lobes, while for the intranasal route fibrotic lesions appeared mainly around the largest superior airways. Thus, oropharyngeal aspiration of bleomycin induced morphological changes that were more comparable to the human disease than the intranasal administration route did. Oropharyngeal aspiration of bleomycin led to a homogeneous fibrotic injury also in rat lungs. The present data suggest oropharyngeal aspiration of bleomycin as a less invasive means to induce homogeneous and sustained fibrosis in the lungs of mice and rats.

  12. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report.

    Science.gov (United States)

    Calzas Rodríguez, Julia; Carmen Juarez Morales, María Del; Casero, Miguel Angel Racionero

    2016-01-01

    With cisplatin-based chemotherapy, most patients with ovarian dysgerminoma will survive long-term. Bleomycin is an important part of ovarian germ cell tumors (OGCT) treatment, and its dose-limiting toxicity is the development of pulmonary toxicity and it is increased in patients older than 40 years. We report the case of an elderly patient with an unresectable ovarian dysgerminoma who received neoadjuvant chemotherapy and who developed fatal bleomycin pulmonary toxicity (BPT) after surgery. A monitoring of pulmonary function is not routinely recommended for detecting BPT, although together with carefully assessment for symptoms or signs suggestive of pulmonary toxicity is the best way to reduce the risk of BPT. The frequency of pulmonary events in older patients makes us to think about the possibility of either reduce the dose of bleomycin or removing it from the BEP in ovarian GCT.

  13. Bleomycin-induced DNA synthesis in a cell-free system using a permeable mouse sarcoma cell Extract.

    Directory of Open Access Journals (Sweden)

    Seki,Shuji

    1987-10-01

    Full Text Available To investigate factors involved in excision repair DNA synthesis, a soluble extract was prepared from permeable mouse sarcoma (SR-C3H/He cells by homogenization and ultracentrifugation. DNA synthesis measured by using native calf thymus DNA as the template-primer and the extract as the polymerase source showed low activity. The DNA synthesis was enhanced more than ten-fold by the addition of an appropriate concentration of bleomycin, a radiomimetic DNA-damaging drug. Using selective inhibitors of DNA polymerases, it was shown that the DNA polymerase involved in the bleomycin-induced DNA synthesis was DNA polymerase beta. In addition to DNA polymerase beta, an exonuclease which converts bleomycin-damaged DNA into suitable template-primers for repair DNA synthesis appeared to be present in the permeable cell extract.

  14. Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice

    Science.gov (United States)

    Oh, Gi-Su; Lee, Su-Bin; Karna, Anjani; Kim, Hyung-Jin; Shen, AiHua; Pandit, Arpana; Lee, SeungHoon

    2016-01-01

    Background Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD+ levels. In this study, we examined the effect of increase in cellular NAD+ levels on bleomycin-induced lung fibrosis in mice. Methods C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1–induced ECM expression and EMT in A549 cells. Conclusion Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1–induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.

  15. Effects of 1,25( OH)2D3 on bleomycin-induced pulmonary fibrosis in mice

    Institute of Scientific and Technical Information of China (English)

    张宗梅

    2014-01-01

    Objective To observe the effects of 1,25(OH)2D3on bleomycin-induced pulmonary fibrosis in mice and to explore its mechanisms.Methods Ninety male C57BL/6mice,6 to 8 weeks old,were randomly divided into 3groups according to the table of random numbers:a control group,a model group and a treatment group(n=30each).Bleomycin was injected to the mice in the latter 2groups by single intratracheal injection to duplicate the pulmonary fibrosis model,while the control group was injected with

  16. Disruption of Calcium Signaling in Fibroblasts and Attenuation of Bleomycin-Induced Fibrosis by Nifedipine.

    Science.gov (United States)

    Mukherjee, Subhendu; Ayaub, Ehab A; Murphy, James; Lu, Chao; Kolb, Martin; Ask, Kjetil; Janssen, Luke J

    2015-10-01

    Fibrotic lung disease afflicts millions of people; the central problem is progressive lung destruction and remodeling. We have shown that external growth factors regulate fibroblast function not only through canonical signaling pathways but also through propagation of periodic oscillations in Ca(2+). In this study, we characterized the pharmacological sensitivity of the Ca(2+)oscillations and determined whether a blocker of those oscillations can prevent the progression of fibrosis in vivo. We found Ca(2+) oscillations evoked by exogenously applied transforming growth factor β in normal human fibroblasts were substantially reduced by 1 μM nifedipine or 1 μM verapamil (both L-type blockers), by 2.7 μM mibefradil (a mixed L-/T-type blocker), by 40 μM NiCl2 (selective at this concentration against T-type current), by 30 mM KCl (which partially depolarizes the membrane and thereby fully inactivates T-type current but leaves L-type current intact), or by 1 mM NiCl2 (blocks both L- and T-type currents). In our in vivo study in mice, nifedipine prevented bleomycin-induced fibrotic changes (increased lung stiffness, overexpression of smooth muscle actin, increased extracellular matrix deposition, and increased soluble collagen and hydroxyproline content). Nifedipine had little or no effect on lung inflammation, suggesting its protective effect on lung fibrosis was not due to an antiinflammatory effect but rather was due to altering the profibrotic response to bleomycin. Collectively, these data show that nifedipine disrupts Ca(2+) oscillations in fibroblasts and prevents the impairment of lung function in the bleomycin model of pulmonary fibrosis. Our results provide compelling proof-of-principle that interfering with Ca(2+) signaling may be beneficial against pulmonary fibrosis.

  17. Advanced and rapidly progressing head and neck cancer: good palliation following intralesional bleomycin.

    LENUS (Irish Health Repository)

    Quintyne, Keith Ian

    2011-09-01

    The authors herein report the case of a 61-year-old man undergoing adjuvant therapy for locally advanced laryngeal cancer, who developed parastomal recurrence in his radiation field around his tracheotomy site, while he was undergoing radiation therapy, and compromised the secure placement of his tracheotomy tube and maintenance of his upper airway. MRI restaging and biopsy confirmed recurrence and progressive disease in his mediastinum. He underwent local therapy with intralesional bleomycin with good palliation, and ability to maintain the patency of his upper airway.

  18. Prolonged Drainage and Intrapericardial Bleomycin Administration for Cardiac Tamponade Secondary to Cancer-Related Pericardial Effusion.

    Science.gov (United States)

    Numico, Gianmauro; Cristofano, Antonella; Occelli, Marcella; Sicuro, Marco; Mozzicafreddo, Alessandro; Fea, Elena; Colantonio, Ida; Merlano, Marco; Piovano, Pierluigi; Silvestris, Nicola

    2016-04-01

    Malignant pericardial effusion (MPE) is a serious complication of several cancers. The most commonly involved solid tumors are lung and breast cancer. MPE can give rise to the clinical picture of cardiac tamponade, a life threatening condition that needs immediate drainage. While simple pericardiocentesis allows resolution of the symptoms, MPE frequently relapses unless further procedures are performed. Prolonged drainage, talcage with antineoplastic agents, or surgical creation of a pleuro-pericardial window are the most commonly suggested ones. They all result in MPE resolution and high rates of long-term control. Patients suitable for further systemic treatments can have a good prognosis irrespective of the pericardial site of disease. We prospectively enrolled patients with cardiac tamponade treated with prolonged drainage associated with Bleomycin administration. Twenty-two consecutive patients with MPE and associated signs of hemodynamical compromise underwent prolonged drainage and subsequent Bleomycin administration. After injection of 100 mg lidocaine hydrochloride, 10 mg Bleomycin was injected into the pericardial space. The catheter was clumped for 48 h and then reopened. Removal was performed when the drainage volume was <25 mL daily. Twelve patients (54%) achieved complete response and 9 (41%) a partial response. Only 1 (5%) had a treatment failure and underwent a successful surgical procedure. Acute toxicity was of a low degree and occurred in 7 patients (32%). It consisted mainly in thoracic pain and supraventricular arrhythmia. The 1-year pericardial effusion progression-free survival rate was 74.0% (95% confidence interval [CI]: 51.0-97.3). At a median follow-up of 75 months, a pericardial progression was detected in 4 patients (18%). One- and two-year overall survival rates were 33.9% (95% CI: 13.6-54.2) and 14.5% (95% CI: 0.0-29.5), respectively, with lung cancer patients having a shorter survival than breast cancer patients. The worst

  19. Serum bleomycin-detectable iron in patients with thalassemia major with normal range of serum iron.

    Directory of Open Access Journals (Sweden)

    Han,Khin Ei

    1995-06-01

    Full Text Available "Free" iron, a potentially radical-generating low mass iron, and not found in normal human blood, was increased in the serum of blood-transfused thalassemia major patients seen in the Yangon General Hospital, Yangon, Myanmar (Burma. The low mass iron was detected by the bleomycin assay. Fifty-one blood samples were analyzed (from 28 males and 23 females. High "free" iron was detected in 47 sera samples from thalassemia patients. Serum ferritin, which reflects the body store iron, was higher than the normal range (10-200 ng/ml in 49 patients. On the other hand, serum iron of 39 sera samples fell within the normal range (50-150 micrograms/dl. Four were less than 50 micrograms/dl and eight were more than 150 micrograms/dl. Almost all the patients' sera of normal or higher serum iron level contained "free" iron. Thus, almost all the sera from thalassemic patients from Myanmar contain bleomycin-detectable iron, even when serum iron is within the normal range. In developing countries where undernutrition is prevalent (serum albumin in these patients was 3.6 +/- 0.4 g/dl, P < 0.0001 vs. control value of 4.0 - 4.8 g/dl, normal serum iron does not preclude the presence of free iron in the serum.

  20. An Escherichia coli mutant resistant to phleomycin, bleomycin, and heat inactivation is defective in ubiquinone synthesis.

    Science.gov (United States)

    Collis, C M; Grigg, G W

    1989-01-01

    A mutant of Escherichia coli, selected for resistance to the antibiotic and antitumor agent phleomycin, has been characterized, and the phleomycin resistance determinant has been identified. The mutant is equally resistant to bleomycins. The resistance to phleomycin is strongly dependent on the nature of the C-terminal amine of the drug, with the greatest resistance being shown to phleomycins and bleomycins with the most basic terminal amines. The mutation also confers resistance to the lethal effects of heating at 52 degrees C. Other characteristics of the phleomycin-resistant strain include a slow growth rate, an inability to grow on succinate as the sole carbon source (Suc- phenotype), cross resistance to aminoglycoside antibiotics, and a slight sensitivity to hydrogen peroxide, methyl methanesulfonate, and gamma-irradiation. Some of these characteristics, together with mapping data, suggested that the phleomycin resistance and Suc- determinant probably lies within the ubiF gene coding for an enzyme effecting a step in the biosynthesis of ubiquinone. The phenotypes of known mutants defective in this and other steps of the ubiquinone pathway were found to be closely similar to those of the original phleomycin-resistant strain. PMID:2475481

  1. Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Brewer, George J; Ullenbruch, Matthew R; Dick, Robert; Olivarez, Leovigildo; Phan, Sem H

    2003-03-01

    Tetrathiomolybdate (TM), a drug developed for the treatment of Wilson's disease, produces an antiangiogenic effect by reducing systemic copper levels. Several angiogenic cytokines appear to depend on normal levels of copper for activity. In both animal tumor models and in cancer patients, TM therapy has proved effective in inhibiting the growth of tumors. We have hypothesized that the activities of fibrotic and inflammatory cytokines are also subject to modulation by the availability of copper in a manner similar to angiogenic cytokines. As a first step in evaluating whether TM plays a therapeutic role in diseases of inflammation and fibrosis, we studied the effects of TM on a murine model of bleomycin-induced pulmonary fibrosis. Oral TM therapy resulted in dose-dependent reduction in serum ceruloplasmin, a surrogate marker of systemic copper levels. Significant decreases in systemic copper levels were associated with marked reduction in lung fibrosis as determined on the basis of histopathologic findings and a biochemical measure of fibrosis. The protection afforded by TM was also reflected in significantly reduced bleomycin-induced body-weight loss. In the next phase of this work, we will seek to determine the mechanisms by which TM brings about this therapeutic benefit.

  2. Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma

    Directory of Open Access Journals (Sweden)

    Citro Gennaro

    2008-11-01

    Full Text Available Abstract Sticker's sarcoma (also known as transmissible venereal tumor is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT, treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy. Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 μs each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations.

  3. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  4. Enhancement of antioxidant defense system by epigallocatechin-3-gallate during bleomycin induced experimental pulmonary fibrosis.

    Science.gov (United States)

    Sriram, Narayanan; Kalayarasan, Srinivasan; Sudhandiran, Ganapasam

    2008-07-01

    Oxidative stress resulting from an imbalance between radical-generating and radical scavenging systems plays an important role in the pathogenesis of pulmonary fibrosis. Epigallocatechin-3-gallate (EGCG), a polyphenol and a major component of green tea, possess a potent antioxidant property. This study was designed to evaluate the potential antioxidative activity of EGCG in the plasma and lungs during bleomycin induced experimental pulmonary fibrosis. Intratracheal administration of bleomycin (6.5 U/kg body weight) to rats resulted in significant reduction of body weight, enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) and non-enzymic antioxidants (reduced glutathione, vitamin C, vitamin E and vitamin A). Elevations in lung W/D (wet weight/dry weight) ratio, hydroxyproline content was observed with a synchronized increase in lipid peroxidation markers (thiobarbituric acid reactive substances and hydroperoxides). Intraperitoneal administration of EGCG at a dose of 20 mg/kg body weight significantly improved the body weight, enzymic and non enzymic antioxidants and considerably decreased the W/D ratio, hydroxyproline and lipid peroxidation marker levels. Histological observations also correlated with the biochemical parameters. Thus, this study confirms the beneficial use of EGCG in alleviating the oxidative stress induced during pulmonary fibrosis.

  5. Chemical activity of anticancer compounds : computational studies on the mechanism of bleomycin and the recognition of flavonoids

    NARCIS (Netherlands)

    Karawajczyk, Anna

    2007-01-01

    The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and testicular cancer. Although it has been in use for more than two decades, the mechanism of its action is not

  6. Interactions of radiation and adriamycin, bleomycin, mitomycin C or cis-diamminedichloroplatinum II in intestinal crypt cells

    DEFF Research Database (Denmark)

    von der Maase, H

    1984-01-01

    The interactions of radiation and adriamycin (ADM), bleomycin (BLM), mitomycin C (MM-C), or cis-diamminedichloroplatinum II (cis-DDP) in mouse jejunal crypt cells were studied using the microcolony survival assay. ADM administered from 24 h before to 48 h after irradiation resulted in an almost...

  7. A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair.

    Science.gov (United States)

    Karo-Atar, D; Bordowitz, A; Wand, O; Pasmanik-Chor, M; Fernandez, I E; Itan, M; Frenkel, R; Herbert, D R; Finkelman, F D; Eickelberg, O; Munitz, A

    2016-01-01

    Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.

  8. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage.

    Directory of Open Access Journals (Sweden)

    Orquidea Garcia

    Full Text Available The potential for amniotic fluid stem cell (AFSC treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF, is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0 or chronic (day 14 intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL, but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events.

  9. The anti-tumor drug bleomycin preferentially cleaves at the transcription start sites of actively transcribed genes in human cells.

    Science.gov (United States)

    Murray, Vincent; Chen, Jon K; Galea, Anne M

    2014-04-01

    The genome-wide pattern of DNA cleavage at transcription start sites (TSSs) for the anti-tumor drug bleomycin was examined in human HeLa cells using next-generation DNA sequencing. It was found that actively transcribed genes were preferentially cleaved compared with non-transcribed genes. The 143,600 identified human TSSs were split into non-transcribed genes (82,596) and transcribed genes (61,004) for HeLa cells. These transcribed genes were further split into quintiles of 12,201 genes comprising the top 20, 20-40, 40-60, 60-80, and 80-100 % of expressed genes. The bleomycin cleavage pattern at highly transcribed gene TSSs was greatly enhanced compared with purified DNA and non-transcribed gene TSSs. The top 20 and 20-40 % quintiles had a very similar enhanced cleavage pattern, the 40-60 % quintile was intermediate, while the 60-80 and 80-100 % quintiles were close to the non-transcribed and purified DNA profiles. The pattern of bleomycin enhanced cleavage had peaks that were approximately 200 bp apart, and this indicated that bleomycin was identifying the presence of phased nucleosomes at TSSs. Hence bleomycin can be utilized to detect chromatin structures that are present at actively transcribed genes. In this study, for the first time, the pattern of DNA damage by a clinically utilized cancer chemotherapeutic agent was performed on a human genome-wide scale at the nucleotide level.

  10. Heterologous Matrix Metalloproteinase Gene Promoter Activity Allows In Vivo Real-time Imaging of Bleomycin-Induced Lung Fibrosis in Transiently Transgenized Mice

    Science.gov (United States)

    Stellari, Fabio Franco; Ruscitti, Francesca; Pompilio, Daniela; Ravanetti, Francesca; Tebaldi, Giulia; Macchi, Francesca; Verna, Andrea Elizabeth; Villetti, Gino; Donofrio, Gaetano

    2017-01-01

    Idiopathic pulmonary fibrosis is a very common interstitial lung disease derived from chronic inflammatory insults, characterized by massive scar tissue deposition that causes the progressive loss of lung function and subsequent death for respiratory failure. Bleomycin is used as the standard agent to induce experimental pulmonary fibrosis in animal models for the study of its pathogenesis. However, to visualize the establishment of lung fibrosis after treatment, the animal sacrifice is necessary. Thus, the aim of this study was to avoid this limitation by using an innovative approach based on a double bleomycin treatment protocol, along with the in vivo images analysis of bleomycin-treated mice. A reporter gene construct, containing the luciferase open reading frame under the matrix metalloproteinase-1 promoter control region, was tested on double bleomycin-treated mice to investigate, in real time, the correlation between bleomycin treatment, inflammation, tissue remodeling and fibrosis. Bioluminescence emitted by the lungs of bleomycin-treated mice, corroborated by fluorescent molecular tomography, successfully allowed real time monitoring of fibrosis establishment. The reporter gene technology experienced in this work could represent an advanced functional approach for real time non-invasive assessment of disease evolution during therapy, in a reliable and translational living animal model. PMID:28298912

  11. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

  12. Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis.

    Science.gov (United States)

    Habgood, Anthony N; Tatler, Amanda L; Porte, Joanne; Wahl, Sharon M; Laurent, Geoffrey J; John, Alison E; Johnson, Simon R; Jenkins, Gisli

    2016-06-01

    Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-β (TGF-β) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype-specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-β activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-β activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF-β activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1α1), III, alpha 1(Col3α1), IV, alpha 1(Col4α1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-β activity following bleomycin, above their already elevated levels, although global TGF-β activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-β activation, and inhibits sustained Col1α1, Col3α1, and Col4α1 gene expression

  13. BlmB and TlmB provide resistance to the bleomycin family of antitumor antibiotics by N-acetylating metal-free bleomycin, tallysomycin, phleomycin, and zorbamycin.

    Science.gov (United States)

    Coughlin, Jane M; Rudolf, Jeffrey D; Wendt-Pienkowski, Evelyn; Wang, Liyan; Unsin, Claudia; Galm, Ute; Yang, Dong; Tao, Meifeng; Shen, Ben

    2014-11-11

    The bleomycin (BLM) family of glycopeptide-derived antitumor antibiotics consists of BLMs, tallysomycins (TLMs), phleomycins (PLMs), and zorbamycin (ZBM). The self-resistant elements BlmB and TlmB, discovered from the BLM- and TLM-producing organisms Streptomyces verticillus ATCC15003 and Streptoalloteichus hindustanus E465-94 ATCC31158, respectively, are N-acetyltransferases that provide resistance to the producers by disrupting the metal-binding domain of the antibiotics required for activity. Although each member of the BLM family of antibiotics possesses a conserved metal-binding domain, the structural differences between each member, namely, the bithiazole moiety and C-terminal amine of BLMs, have been suggested to instill substrate specificity within BlmB. Here we report that BlmB and TlmB readily accept and acetylate BLMs, TLMs, PLMs, and ZBM in vitro but only in the metal-free forms. Kinetic analysis of BlmB and TlmB reveals there is no strong preference or rate enhancement for specific substrates, indicating that the structural differences between each member of the BLM family play a negligible role in substrate recognition, binding, or catalysis. Intriguingly, the zbm gene cluster from Streptomyces flavoviridis ATCC21892 does not contain an N-acetyltransferase, yet ZBM is readily acetylated by BlmB and TlmB. We subsequently established that S. flavoviridis lacks the homologue of BlmB and TlmB, and ZbmA, the ZBM-binding protein, alone is sufficient to provide ZBM resistance. We further confirmed that BlmB can indeed confer resistance to ZBM in vivo in S. flavoviridis, introduction of which into wild-type S. flavoviridis further increases the level of resistance.

  14. Nucleobase-Based Barbiturates: Their Protective Effect against DNA Damage Induced by Bleomycin-Iron, Antioxidant, and Lymphocyte Transformation Assay

    Directory of Open Access Journals (Sweden)

    Bhaveshkumar D. Dhorajiya

    2014-01-01

    Full Text Available A number of nucleobase-based barbiturates have been synthesized by combination of nucleic acid bases and heterocyclic amines and barbituric acid derivatives through green and efficient multicomponent route and one pot reaction. This approach was accomplished efficiently using aqueous medium to give the corresponding products in high yield. The newly synthesized compounds were characterized by spectral analysis (FT-IR, 1H NMR, 13C NMR, HMBC, and UV spectroscopy and elemental analysis. Representative of all synthesized compounds was tested and evaluated for antioxidant, bleomycin-dependent DNA damage, and Lymphocyte Transformation studies. Compounds TBC > TBA > TBG showed highest lymphocyte transformation assay, TBC > TBA > BG showed inhibitory antioxidant activity using ABTS methods, and TBC > BPA > BAMT > TBA > 1, 3-TBA manifested the best protective effect against DNA damage induced by bleomycin.

  15. Therapeutic use of fisetin, curcumin, and mesoporous carbaon nanoparticle loaded fisetin in bleomycin-induced idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Srabani Kar

    2015-04-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. The conventional therapy has been steroids and immunosuppressive agents. But only a minority of patients responds to such a therapy. IPF is a progressive, ultimately fatal disorder for which substantive medical therapy is desperately needed. Fisetin is a flavonol which inhibits the activity of several pro-inflammatory cytokines. The polyphenol curcumin is used to treat inflammatory diseases, abdominal disorders, and a variety of other ailments. The aim of this study was to evaluate the beneficial effect of fistine, curcumin and mesoporous carbaon nanoparticle (MCN loaded fisetin as an anti-inflammatory agents against bleomycin-induced changes in mice with IPF. In our study, flavonoids showed their anti fibrotic action. The inflammatory cell count was greatly increased for bleo treated individuals and effectiveness of fisein was increased after addition of MCN particles with it, curcumin also showed anti- inflammatory effects. In another experiment, bleomycin effectively inhibits the cellular recruitment to the spleen and treatment with fisetin, and curcumin increases the cellular recruitment in spleen. Colony count was also increased in MCN+fisetin treated groups, and it was statistically significant. We also observed the increased level of cytokines with fisetin treatment, with curcumin treatment and with MCN +fisetin treatment as compared to the bleo treated sample. In conclusion, the present research suggests that fisetin and curcumin and MCN loaded fisetin may be a promising therapeutic agent for bleomycin-induced changes in mice with IPF. This will open up new perspectives for a potential role of these drugs as a molecular target in Idiopathic pulmonary fibrosis. [Biomed

  16. Calcium electroporation in three cell lines; a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gissel, Hanne; Hojman, Pernille;

    2013-01-01

    electroporation and electrochemotherapy. METHODS: The effects of calcium electroporation and bleomycin electroporation (alone or in combination) were compared in three different cell lines (DC-3F, transformed Chinese hamster lung fibroblast; K-562, human leukemia; and murine Lewis Lung Carcinoma). Furthermore...... survival at similar applied voltage parameters. The effect of calcium electroporation is independent of calcium compound. GENERAL SIGNIFICANCE: This study strongly supports the use of calcium electroporation as a potential cancer therapy and the results may aid in future clinical trials....

  17. Effects of Spaceflight on Molecular and Cellular Responses to Bleomycin-Induced DNA Damages in Confluent Human Fibroblasts

    Science.gov (United States)

    Lu, Tao; Zhang, Ye; Wong, Michael; Stodieck, Louis; Karouia, Fathi; Wu, Honglu

    2016-01-01

    Spaceflights expose human beings to various risk factors. Among them are microgravity related physiological stresses in immune, cytoskeletal, and cardiovascular systems, and space radiation related elevation of cancer risk. Cosmic radiation consists of energetic protons and other heavier charged particles that induce DNA damages. Effective DNA damage response and repair mechanism is important to maintain genomic integrity and reduce cancer risk. There were studies on effects of spaceflight and microgravity on DNA damage response in cell and animal models, but the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on molecular and cellular responses to DNA damages, bleomycin, an anti-cancer drug and radiomimetic reagent, was used to induce DNA damages in confluent human fibroblasts flown to the International Space Station (ISS) and on ground. After exposure to 1.0 µg/ml bleomycin for 3 hours, cells were fixed for immunofluorescence assays and for RNA preparation. Extents of DNA damages were quantified by foci and pattern counting of phosphorylated histone protein H2AX (?-H2AX). The cells on the ISS showed modestly increased average foci counts per nucleus while the distribution of patterns was similar to that on the ground. PCR array analysis showed that expressions of several genes, including CDKN1A and PCNA, were significantly changed in response to DNA damages induced by bleomycin in both flight and ground control cells. However, there were no significant differences in the overall expression profile of DNA damage response genes between the flight and ground samples. Analysis of cellular proliferation status with Ki-67 staining showed a slightly higher proliferating population in cells on the ISS than those on ground. Our results suggested that the difference in ?-H2AX focus counts between flight and ground was due to the higher percentage of proliferating cells in space, but spaceflight did not significantly affect

  18. Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments.

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    Wen-Jie Ji

    Full Text Available BACKGROUND: Recent experimental studies provide evidence indicating that manipulation of the mononuclear phagocyte phenotype could be a feasible approach to alter the severity and persistence of pulmonary injury and fibrosis. Mineralocorticoid receptor (MR has been reported as a target to regulate macrophage polarization. The present work was designed to investigate the therapeutic potential of MR antagonism in bleomycin-induced acute lung injury and fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: We first demonstrated the expression of MR in magnetic bead-purified Ly6G-/CD11b+ circulating monocytes and in alveolar macrophages harvested in bronchoalveolar lavage fluid (BALF from C57BL/6 mice. Then, a pharmacological intervention study using spironolactone (20 mg/kg/day by oral gavage revealed that MR antagonism led to decreased inflammatory cell infiltration, cytokine production (downregulated monocyte chemoattractant protein-1, transforming growth factor β1, and interleukin-1β at mRNA and protein levels and collagen deposition (decreased lung total hydroxyproline content and collagen positive area by Masson' trichrome staining in bleomycin treated (2.5 mg/kg, via oropharyngeal instillation male C57BL/6 mice. Moreover, serial flow cytometry analysis in blood, BALF and enzymatically digested lung tissue, revealed that spironolactone could partially inhibit bleomycin-induced circulating Ly6C(hi monocyte expansion, and reduce alternative activation (F4/80+CD11c+CD206+ of mononuclear phagocyte in alveoli, whereas the phenotype of interstitial macrophage (F4/80+CD11c- remained unaffected by spironolactone during investigation. CONCLUSIONS/SIGNIFICANCE: The present work provides the experimental evidence that spironolactone could attenuate bleomycin-induced acute pulmonary injury and fibrosis, partially via inhibition of MR-mediated circulating monocyte and alveolar macrophage phenotype switching.

  19. Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: Assessed by micro-computed tomography and pathologic scores

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    Jin, Gong Yong; Bok, Se Mi; Han, Young Min [Department of Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Chung, Myung Ja [Department of Pathology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Yoon, Kwon-Ha [Department of Radiology, Iksan Hospital, Iksan (Korea, Republic of); Kim, So Ri [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Yong Chul, E-mail: leeyc@jbnu.ac.kr [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2012-08-15

    Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists exhibit potent anti-fibrotic effects in the lung and other tissues. Recently, micro-computed tomography (CT) has been a useful tool for the investigation of lung diseases in small animals and is now increasingly applied to visualize and quantify the pulmonary structures. However, there is little information on the assessment for therapeutic effects of PPAR{gamma} agonists on the pulmonary fibrosis in mice using micro-CT. This study was aimed to determine the capability of micro-CT in examining the effects of rosiglitazone on pulmonary fibrosis. We used a murine model of bleomycin-induced lung fibrosis to evaluate the feasibility of micro-CT in evaluating the therapeutic potential of rosiglitazone on pulmonary fibrosis, comparing with pathologic scores. On micro-CT findings, ground glass opacity (80%) and consolidation (20%) were observed predominantly at 3 weeks after the instillation of bleomycin, and the radiologic features became more complex at 6 weeks. In bleomycin-instilled mice treated with rosiglitazone, the majority (80%) showed normal lung features on micro-CT. Radiological-pathologic correlation analyses revealed that ground glass opacity and consolidation were correlated closely with acute inflammation, while reticular opacity was well correlated with histological honeycomb appearance. These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis in mice and that the visualization of bleomycin-induced pulmonary fibrosis using micro-CT is satisfactory to assess the effects of rosiglitazone. It implies that micro-CT can be applied to evaluate therapeutic efficacies of a variety of candidate drugs for lung diseases.

  20. Resonance Rayleigh scattering study of the interaction of bleomycinA5 with nucleic acids and its analytical application

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    LIU; JiangTao; LIU; ZhongFang; LIU; ShaoPu

    2007-01-01

    The interaction of bleomycinA5 with nucleic acids has been investigated by using resonance Rayleigh scattering (RRS), molecular absorption and fluorescence spectra. The result shows that in near pH 2.2 buffer medium and absence of any metal ions, nucleic acids are capable of binding with bleomycinA5 (BLMA5) to form complexes which can remarkably enhance the RRS intensity and result in bathochromic and hyperchromic molecular absorption of nucleic acids and fluorescence quenching of bleomycinA5. The RRS spectral characteristics for the binding products of bleomycinA5 with various DNA and RNA are similar, and the maximum RRS peaks are at 301 nm for ctDNA and sDNA, 370 nm for hsDNA, 310 nm for RNAtypeVI and RNAtypeIII, respectively. The increments of RRS intensity are greatly different in which DNA enhances greatly and RNA enhances lightly. In this work, the optimum conditions of the interaction and some influencing factors have been investigated. The reaction mechanism and a binding model for the interaction of BLMA5 with the nucleic acids are discussed. In addition, a highly sensitive, simple and rapid new method for the determination of DNA has been developed. The detection limits (3σ) are 5.7 ng/mL for ctDNA, 7.4 ng/mL for sDNA and 9.2 ng/mL for hsDNA, respectively. The method can be applied to determination of trace amounts of DNA.

  1. Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro.

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    Sailaja Polavarapu

    Full Text Available In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs tested on human neuroblastoma IMR-32 (0.5 × 10(4 cells/100 µl of IMR cells (EPA > DHA > ALA = GLA = AA > DGLA = LA: ∼ 60, 40, 30, 10-20% respectively at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2α, and PGI2 and leukotrienes (LTD4 and LTE4 tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4, 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA and 10(S,17(S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S,17(SDiHDoHE, metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA at 60 and 20 µg/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions.

  2. Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10.

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    Emilio García-Prieto

    Full Text Available BACKGROUND: Matrix metalloproteinases (MMPs may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. METHODOLOGY AND PRINCIPAL FINDINGS: To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/- mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFβ and IL-10 were measured in lung tissue. Mmp8(-/- mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10 measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. CONCLUSIONS: According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo.

  3. Comparison of therapeutic response of keloids and hypertrophic scars to cryotherapy plus intralesional steroid and bleomycin tattoo

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    Farahnaz Fatemi

    2005-01-01

    Full Text Available Keloids and hypertrophic scars are abnormal responses of body to skin injuries. Overproduction of compacted fibrous tissue is the basic cause of these lesions. In this study the result of treatment of these skin conditions with bleomycin tattoo are compared with cryotherapy and triamcinolone injection. This study involved 45 patients with hypertrophic scar or keloid. Patients were divided into two groups consecutively. Group A (23 patients was treated with bleomycin tattoo and the group B with cryotherapy and triamcinolone injection. There were four therapeutic sessions one month apart. All patients were followedup for three month after the end of treatment .The therapeutic response was determined as reduction of lesion size or flattening relative to initial size. Therapeutic response was 88.3±14% in group A and 67.4 ±22.5% in group B (p<0.001. In group A 69%, but in group B only 49% of patients were asymptomatic after the end of treatment. In group A there was no relation between therapeutic response and lesion size (p=0.58 but in group B lesions those were smaller (<100mm2 had better therapeutic response than larger ones (p=0.007. It was concluded that bleomycin tattoo is more effective in treatment of hypertrophic scar and keloid than traditional treatment, cryotherapy plus triamcinolone injection especially in larger ones.

  4. Serial micro-CT assessment of the therapeutic effects of rosiglitazone in a bleomycin-induced lung fibrosis mouse model

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    Choi, Eun Jung; Jin, Gong Yong; Bok, Se Mi; Han, Young Min; Lee, Young Sun; Jung, Myung Ja; Kwon, Keun Sang [Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Institute for Medical Sciences, Jeonju (Korea, Republic of)

    2014-08-15

    The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.

  5. Bleomycin induced sensitivity to TRAIL/Apo-2L-mediated apoptosis in human seminomatous testicular cancer cells is correlated with upregulation of death receptors.

    Science.gov (United States)

    Timur, Mujgan; Cort, Aysegul; Ozdemir, Evrim; Sarikcioglu, Sureyya Bilmen; Sanlioglu, Salih; Sanlioglu, Ahter Dilsad; Ozben, Tomris

    2015-01-01

    The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL's apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated.

  6. The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis.

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    Ajit A Kulkarni

    Full Text Available Pulmonary Fibrosis (PF is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11dien-28-oate, Bardoxolone methyl is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01, inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001, and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05. On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation and by systemic autoimmune diseases.

  7. [Effects of erdosteine on inflammation and fibrosis in rats with pulmonary fibrosis induced by bleomycin].

    Science.gov (United States)

    Erden, Ersin Sükrü; Kirkil, Gamze; Deveci, Figen; Ilhan, Nevin; Cobanoğlu, Bengü; Turgut, Teyfik; Muz, Mehmet Hamdi

    2008-01-01

    We aimed to investigate the levels of some chemokines, inflammatory cell counts in bronchoalveolar lavage (BAL) fluid, histopathological changes in lung tissue, to determine the effect of erdosteine on acute inflammatory changes and fibrosis in a rat fibrosis model induced by bleomycine (BLM). Forty-five Wistar male rats were taken into the study. On day 0, intratracheal saline to control group (group 1, n= 15), intratracheal BLM 7.5 U/kg to BLM (group 2, n= 15) and erdosteine group (group 3, n= 15) was administered. In group 3, oral erdosteine (10 mg/kg/day) was applied two days before BLM. On day 0, 14, and 29th five rats in each groups were sacrificed, BAL fluid was performed. Malonyldialdehyde (MDA), macrophage inflammatory protein (MIP)-1alpha, MIP-2 levels in BAL fluid, hydroxyproline levels in lung tissue were measured. Histopathological examination was performed. When BLM group compared to erdosteine group, the levels of MDA, MIP-1alpha, MIP-2, and neutrophil counts, the hydroxyproline (OH-P) level of lung tissue were decreased in erdosteine group on acute inflammatory phase (day 14) (perdosteine group than BLM group on day 29 (p= 0.01). We conclude that erdosteine may prevent the acute lung inflammation and fibrosis by suppressing the accumulation of neutrophils, inhibition of lipid peroxydation, chemokine production, and release.

  8. Paracetamol Supplementation Does Not Alter The Antitumor Activity and Lung Toxicity of Bleomycin

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    Ghada M. Suddek

    2014-01-01

    Full Text Available Bleomycin (BLM is well known by its antitumor activity both in vitro and in vivo. However, pulmonary fibrosis has been considered the dose limiting toxicity of the drug. Hyperpyrexia following injection of BLM was reported thus, paracetamol is sometimes administered with BLM as antipyretic drug. Actually, paracetamol was found to interfere with cytotoxicity of some drugs. This study was conducted to investigate the effect of paracetamol administration on the antitumor and lung toxicity of BLM. The antitumor activity was evaluated both in vitro and in vivo using Ehrlich ascites carcinoma (EAC cells. Paracetamol did not alter the antitumor effect of BLM in vitro or in vivo. The lung toxicity of BLM was evidenced by decrease in the body weight, increase in the lung/body weight ratio, decrease in the response of pulmonary arterial rings to 5-hydroxytryptamine (5-HT and increase in the contractility of tracheal smooth muscles induced by acetylcholine (ACh. The toxicity was also confirmed biochemically by marked increases in hydroxyproline and lipid peroxidation in rat lung and the decrease in reduced glutathione (GSH level. Pretreatment with paracetamol did not significantly change lipid peroxidation, GSH level, percent survival of rats or the response of pulmonary arterial rings and tracheal smooth muscles to 5-HT and ACh respectively. The results of the present study indicated that paracetamol neither modified the antitumor effect of BLM nor changed drug-induced lung toxicity.

  9. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    Science.gov (United States)

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway.

  10. Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

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    Ramesh Verma

    2013-01-01

    Full Text Available The current study deals with the effect of a dietary flavanoid quercetin on fibrotic lung tissue in rats. Bleomycin was administered by single intratracheal instillation to Wistar rats to induce lung fibrosis. The pathologies associated with this included significantly reduced antioxidant capacity, ultimately leading to protracted inflammation of the lung tissue. The hallmark of this induced fibrosis condition was an excessive collagen deposition in peribronchial and perialveolar regions of the lung. Oral quercetin treatment over a period of twenty days resulted in significant reversal of the pathologies. The antioxidant defense in lung tissue was revived. Moreover, activity of the collagenase MMP-7, which was high in fibrotic tissue, was seen restored after quercetin administration. Trichome staining of lung tissue sections showed high collagen deposition in fibrotic rats, which may be a direct result of increased mobilization of collagen by MMP-7. This was appreciably reduced in quercetin treated animals. These results point towards an important protective role of quercetin against idiopathic lung fibrosis, which remains a widely prevalent yet incurable condition in the present times.

  11. Protective Effect of Onion Extract on Bleomycin-Induced Cytotoxicity and Genotoxicity in Human Lymphocytes

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    Yoon Hee Cho

    2016-02-01

    Full Text Available Following one of the world’s largest nuclear accidents, occured at Fukushima, Japan in 2011, a significant scientific effort has focused on minimizing the potential adverse health effects due to radiation exposure. The use of natural dietary antioxidants to reduce the risk of radiation-induced oxidative DNA damage is a simple strategy for minimizing radiation-related cancer rates and improving overall health. The onion is among the richest sources of dietary flavonoids and is an important food for increasing their overall intake. Therefore, we examined the effect of an onion extract on cyto- and geno-toxicity in human lymphocytes treated with bleomycin (BLM, a radiomimetic agent. In addition, we measured the frequency of micronuclei (MN and DNA damage following treatment with BLM using a cytokinesis-blocked micronucleus assay and a single cell gel electrophoresis assay. We observed a significant increase in cell viability in lymphocytes treated with onion extract then exposed to BLM compared to cells treated with BLM alone. The frequency of BLM induced MN and DNA damage increased in a dose-dependent manner; however, when lymphocytes were pretreated with onion extract (10 and 20 μL/mL, the frequency of BLM-induced MN was decreased at all doses of BLM and DNA damage was decreased at 3 μg/mL of BLM. These results suggest that onion extract may have protective effects against BLM-induced cyto- and genotoxicity in human lymphocytes.

  12. Bleomycin/interleukin-12 electrochemogenetherapy for treating naturally occurring spontaneous neoplasms in dogs.

    Science.gov (United States)

    Reed, S D; Fulmer, A; Buckholz, J; Zhang, B; Cutrera, J; Shiomitsu, K; Li, S

    2010-08-01

    On the basis of superior outcomes from electrochemogenetherapy (ECGT) compared with electrochemotherapy in mice, we determined the efficacy of ECGT applied to spontaneous canine neoplasms. Intralesional bleomycin (BLM) and feline interleukin-12 DNA injection combined with translesional electroporation resulted in complete cure of two recurrent World Health Organization stage T(2b)N(0)M(0) oral squamous cell carcinomas (SCCs) and one T(2)N(0)M(0) acanthomatous ameloblastoma. Three remaining dogs, which had no other treatment options, had partial responses to ECGT; one had mandibular T(3b)N(2b)M(1) melanoma with pulmonary and lymph node metastases; one had cubital T(3)N(0)M(1) histiocytic sarcoma with spleen metastases; and one had soft palate T(3)N(0)M(0) fibrosarcoma. The melanoma dog had decrease in the size of the primary tumor before recrudescence and euthanasia. The histiocytic sarcoma dog had resolution of the primary tumor, but was euthanized because of metastases 4 months after the only treatment. The dog with T(3)N(0)M(0) fibrosarcoma had tumor regression with recrudescence. Treatment was associated with minimal side effects and was easy to perform, was associated with repair of bone lysis in cured dogs, improved quality of life for dogs with partial responses and extended overall survival time. ECGT seems to be a safe and resulted in complete responses in SCC and acanthomatous ameloblastoma.

  13. Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes

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    Benkhaled, L.; Xuncla, M.; Caballin, M.R. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain); Barrios, L. [Universitat Autonoma de Barcelona, Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular, Fisiologia i Immunologia (Spain); Barquinero, J.F. [Universitat Autonoma de Barcelona, Unitat d' Antropologia Biologica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, E-08193 Bellaterra (Spain)], E-mail: Francesc.Barquinero@uab.es

    2008-01-01

    Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation ({approx}0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM.

  14. Role of thioredoxin nitration in bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Wang, Lei; Song, Yimin; Li, Xiankui; Guo, Haizhou; Zhang, Guojun

    2016-01-01

    Oxidant stimulation has been suggested to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate the role and mechanisms of thioredoxin (Trx) nitration during the development of IPF. A rat model of IPF was established by intratracheal instillation of bleomycin (BLM). Male Wistar rats were randomly distributed among the control group and BLM-treated group, in which rats were intratracheally instilled with a single dose of BLM (5.0 mg/kg body mass in 1.0 mL phosphate-buffered saline). At 7 or 28 days after instillation the rats were euthanized. Histopathological and biochemical examinations were performed. The activity and protein level of thioredoxin were assessed. The thioredoxin nitration level was determined using immunoprecipitation and immunoblotting techniques. Our results demonstrated that protein tyrosine nitration increased in the BLM-treated group compared with the control group. Trx activity decreased in the BLM group compared with control group, whereas Trx expression and nitration level increased dramatically in the BLM group compared with the control group. Our results indicated that Trx nitration might be involved in the pathogenesis of IPF.

  15. Bleomycin Loaded Magnetite Nanoparticles Functionalized by Polyacrylic Acid as a New Antitumoral Drug Delivery System

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    Yue Xu

    2013-01-01

    Full Text Available Objective. To prepare, characterize, and analyze the release behavior of bleomycin-loaded magnetite nanoparticles (BLM-MNPs coated with polyacrylic acid (PAA as a new drug delivery system that can be specifically distributed in the tumor site. Methods. BLM-MNPs coated with PAA were prepared using a solvothermal approach. The particles were characterized using scanning electron microscope (SEM, vibrating sample magnetometer (VSM, and Fourier transform infrared spectroscopy (FTIR. The loading and release behaviors of BLM-MNPs were examined by a mathematical formula and in vitro release profile at pH 7.5. Results. The sphere Fe3O4 nanoparticles with the size of approximately 30 nm exhibit a saturation magnetization of 87 emu/g. The noncoordinated carboxylate groups of PAA confer on the good dispersibility in the aqueous solution and lead to a good loading efficiency of BLM reaching 50% or higher. Approximately 98% of immobilized BLM could be released within 24 h, of which 22.4% was released in the first hour and then the remaining was released slowly and quantitatively in the next 23 hours. Conclusion. BLM-MNPs were prepared and characterized successfully. The particles show high saturation magnetization, high drug loading capacity, and favorable release property, which could contribute to the specific delivery and controllable release of BLM, and the BLM-MNPs could be a potential candidate for the development of treating solid tumors.

  16. Expression of PEPT2 mRNA in the lung of rat with bleomycin-induced pulmonary fibrosis

    Institute of Scientific and Technical Information of China (English)

    Li Li; Dianhua Wang; Xuan Zhang; Xing Song

    2013-01-01

    Objective:Pulmonary fibrosis is a common pathological phenomena in lung cancer patients after chemotherapy or radiotherapy, which is a key factor hindering to transport ion of high concentrated drug to the lung tissue, peptide trans-porter has become targets of the rational design of peptides and peptide drug. The purpose of the study is to investigate the expression of PEPT2 mRNA in the lung of rats with bleomycin (BLM)-induced pulmonary fibrosis. Methods:Fifty healthy adult Spragne-Dawley rats were randomized into five groups, the rats in BLM 7d, 14d and 28d groups were treated with a single instil ation of 5 mg/kg of BLM, to induced pulmonary fibrosis models. On days 7, 14 and 28, the animals were kil ed by exsan-guination respectively. Normal saline (NS) group were treated by NS, on days 14, the animals were kil ed by exsanguinations. Control group were untreated. The lung samples were processed for light microscopy and determined the hydroxyproline (HYP) concentration. The expression of PEPT2 mRNA were measured by RT-PCR. PEPT2 cDNA fragments were tested by dideoxy chain termination. Results:Compared with control and NS group, HYP levels increased on day 7 of BLM group, but there was no statistical significant dif erence (P>0.05). HYP levels markedly increased on days 14 and 28 of BLM group, there was statistical significant dif erence (P0.05). Conclusion:The pulmonary fibrosis models of SD rats can be induced by a single instil ation of 5 mg/kg of bleomycin on 28d. There were no significant changes of PEPT2 mRNA expression in the lung of rats with bleomycin-induced pulmonary fibrosis.

  17. Effects of Spaceflight on Molecular and Cellular Responses to Bleomycin-induced DNA Damages in Confluent Human Fibroblasts

    Science.gov (United States)

    Lu, Tao; Wu, Honglu; Karouia, Fathi; Stodieck, Louis; Zhang, Ye; Wong, Michael

    2016-07-01

    Spaceflights expose human beings to various risk factors. Among them are microgravity related physiological stresses in immune, cytoskeletal, and cardiovascular systems, and space radiation related elevation of cancer risk. Cosmic radiation consists of energetic protons and other heavier charged particles that induce DNA damages. Effective DNA damage response and repair mechanism is important to maintain genomic integrity and reduce cancer risk. There were studies on effects of spaceflight and microgravity on DNA damage response in cell and animal models, but the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on molecular and cellular responses to DNA damages, bleomycin, an anti-cancer drug and radiomimetic reagent, was used to induce DNA damages in confluent human fibroblasts flown to the International Space Station (ISS) and on ground. After exposure to 1.0 mg/ml bleomycin for 3 hours, cells were fixed for immunofluorescence assays and for RNA preparation. Extents of DNA damages were quantified by focus pattern and focus number counting of phosphorylated histone protein H2AX (γg-H2AX). The cells on the ISS showed modestly increased average focus counts per nucleus while the distribution of patterns was similar to that on the ground. PCR array analysis showed that expressions of several genes, including CDKN1A and PCNA, were significantly changed in response to DNA damages induced by bleomycin in both flight and ground control cells. However, there were no significant differences in the overall expression profiles of DNA damage response genes between the flight and ground samples. Analysis of cellular proliferation status with Ki-67 staining showed a slightly higher proliferating population in cells on the ISS than those on ground. Our results suggested that the difference in γg-H2AX focus counts between flight and ground was due to the higher percentage of proliferating cells in space, but spaceflight did not

  18. Effect of intramuscular injection of hepatocyte growth factor plasmid DNA with electroporation on bleomycin-induced lung fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    LONG Xiang; XIONG Sheng-dao; XIONG Wei-ning; XU Yong-jian

    2007-01-01

    Background So far, there is no efficient treatment for pulmonary fibrosis. The objective of this study was to determine whether intramuscular injection of the hepatocyte growth factor (HGF) plasmid DNA by in vivo electroporation could prevent bleomycin-induced pulmonary fibrosis in rats, and to investigate the possible mechanisms.Methods Twenty male Wistar rats were randomly divided into four groups: control group(group C), model group (group M), early intervention group (group Ⅰ ) and late intervention group (groupⅡ). Groups M, Ⅰ and Ⅱ were intratracheally infused with bleomycin, then injected the plasmid pcDNA3.1-hHGF to group Ⅰ on day 7, 14 and 21. Group Ⅱ received the same treatment like Group Ⅰ on day 14 and 21. All the rats were killed on day 28 after bleomycin injection. We detected Homo HGF expression in the rats with ELISA method and estimated the pathological fibrosis score of lung tissue using hematoxylin eosin (HE) and Massion staining. The mRNA expression of transforming growth factor-β1 (TGF-β1),cycloxygenase-2 (COX-2), and rat HGF in rat pulmonary parenchyma were evaluated by RT-PCR.Immunohistochemistry and Western blotting were performed to determine the protein expression of transforming TGF-β1 and COX-2 in lung parenchyma.Results The plasmid pcDNA3.1-hHGF could express hHGF in NIH3T3 cells and the hHGF protein is secreted into the culture medium. The expression of hHGF protein could be monitored in quadriceps muscle, plasma and lung in Groups Ⅰ and Ⅱ. Pulmonary fibrosis levels of Groups Ⅰ and Ⅱ were obviously lower than that of group M (P<0.05).Expression of TGF-β1 protein and mRNA in lung tissue was markedly decreased in Groups Ⅰ and Ⅱ compared with Group M (P<0.05). The level of expression of HGF and COX-2 mRNA was higher in Groups Ⅰ and Ⅱ than in Group M (P<0.05).Conclusions Injection of the plasmid pcDNA3.1-hHGF into skeletal muscle with electroporation has a potential role in the treatment of bleomycin

  19. Effect of early treatment with transcutaneous electrical diaphragmatic stimulation (TEDS on pulmonary inflammation induced by bleomycin

    Directory of Open Access Journals (Sweden)

    Laisa A. Santos

    2013-12-01

    Full Text Available BACKGROUND : Bleomycin (B is an antineoplastic drug that has pulmonary fibrosis as a side effect. There are few experimental studies about the effects of physical therapy treatment in this case. OBJECTIVE: The objective was to study rat lungs treated with B and precocious intervention by transcutaneous electrical diaphragmatic stimulation (TEDS. METHOD : Wistar rats were divided into 4 groups (n=5: a control group (C; a stimulated group (TEDS; a group treated with a single dose of B (intratracheally, 2.5 mg/kg (B; and a group treated with B and electric stimulation (B + TEDS. After the B instillation, the electrical stimulation was applied for 7 days, for a duration of 20 minutes. Lung fragments were histologically processed with hematoxylin and eosin (HE and 8-isoprostane-PGF2α (8-iso-PGF2α. The density of the alveolar area was determined by planimetry, the inflammatory profile was defined by the number of cells, and the level of oxidative stress in the pulmonary tissue was evaluated by 8-iso-PGF2α. For statistical analysis of the data, the Shapiro-Wilk test was used, followed by a one-way ANOVA with the post-hoc Bonferroni test (p≤0.05. RESULTS : The B group exhibited a significant reduction in the area density, and the acute treatment with B + TEDS prevented this reduction. There were increased numbers of fibroblasts, leukocytes, and macrophages in the B group, as well as increased lipid peroxidation, which was observed only in this group. CONCLUSION : B promoted a reduction in the alveolar density area, thereby inducing the inflammatory process and increasing the production of free radicals. These effects were minimized by the application of TEDS at the initial treatment stage.

  20. Histopathologic observation of anti-tumor effect of bleomycin and irradiation on cancers of tongue

    Energy Technology Data Exchange (ETDEWEB)

    Kohmura, Yuji (Aichi-Gakuin Univ., Nagoya (Japan). School of Dentistry); Hosoda, Syun; Kawabe, Yoshitaka; Isojima, Genzo

    1983-05-01

    Nine cases of squamous cell carcinoma of the tongue were treated by either intramuscular or local injections of total 60 to 200 mg of Bleomycin (BLM), and 7 cases by total doses of 1,200 to 5,320 rads of irradiation, followed by surgical removal of primary neoplasm. The histologic examination was done focussing on the antitumor effect of both treatments. In the cases with keratinizing component more than 25 % in the biopsy specimens, the earliest change due to BLM was vacuolar degeneration of proliferating cells either at the base of superficial cancer epithelia or at the periphery of invading cancer foci. When the proliferating cancer cells disappeared, an appearance of invading cancer foci resembled that of ectopic islands of normal squamous epithelium. These foci of differentiated squamous cell carcinoma gradually underwent morphological change into the so-called cancer pearls. Finally, the cancer pearls degenerated, leaving foreign bodies consisting of concreted keratin. The stromal reaction was characterized by the formation of granulation tissues accompanying significant numbers of foreign body giant cells. In the cases of lingual carcinoma with poor squamous differentiation, these processes were indistinct. Instead, the proliferating anaplastic cancer cells were markedly reduced and the remaining cancer cells transformed into large bizarre cells, probably at degenerative stage. On the histologic level, irradiation showed essentially similar antitumor effect to BLM, except for the rapid formation of concreted keratin bodies accompanying more abundant foreign body giant cells and the presence of irregular granulation tissues at different stages. We concluded that both BLM and irradiation had a powerful antitumor action on squamous cell carcinoma of the tongue.

  1. Rikkunshito ameliorates cachexia associated with bleomycin-induced lung fibrosis in mice by stimulating ghrelin secretion.

    Science.gov (United States)

    Tsubouchi, Hironobu; Yanagi, Shigehisa; Miura, Ayako; Mogami, Sachiko; Yamada, Chihiro; Iizuka, Seiichi; Hattori, Tomohisa; Nakazato, Masamitsu

    2014-10-01

    Cachexia is a frequent complication in patients with respiratory failure, such as lung fibrosis, and it is a determining factor for functional capacity, health status, and mortality. Reductions in body weight and skeletal muscle mass are key features of cachexia that are resistant to current therapies. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment for patients with gastrointestinal symptoms and known to stimulate ghrelin secretion. By using bleomycin (BLM)-induced lung fibrosis mice in this study, we tested our hypothesis that RKT administration could ameliorate pulmonary cachexia. After BLM administration, mice were provided with either RKT or distilled water on a daily basis. Compared with the BLM-injected mice, the RKT-treated mice had smaller reductions of food intake and body weight. Skeletal muscle weights were retained in the RKT-treated mice, in conjunction with reduced expressions of MuRF-1 and atrogin-1 in the lysates of skeletal muscle found in lung fibrosis. Rikkunshito administration restored the plasma concentrations of ghrelin in BLM-injected mice. The anticachectic efficacies of RKT administration in BLM-injected mice were canceled by the concurrent treatment of a ghrelin receptor antagonist. Rikkunshito administration did not decrease the degree of loss of body weight or food intake reduction in either ghrelin-deficient mice or growth hormone secretagogue receptor-deficient mice. Our results indicate that RKT administration exerts protective effects on pulmonary cachexia by ameliorating skeletal muscle wasting and food intake reduction as mediated by the ghrelin system and, thus, highlight RKT as a potential therapeutic agent for the management of lung fibrosis.

  2. Neotuberostemonine attenuates bleomycin-induced pulmonary fibrosis by suppressing the recruitment and activation of macrophages.

    Science.gov (United States)

    Xiang, Juan; Cheng, Si; Feng, Tianlong; Wu, Yan; Xie, Weina; Zhang, Mian; Xu, Xianghong; Zhang, Chaofeng

    2016-07-01

    Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages.

  3. Influence of pH and length of post-treatment incubation on bleomycin-induced DNA damage

    Energy Technology Data Exchange (ETDEWEB)

    Moore, C.W.; Vossler, D.A.

    1980-01-01

    The dependence of the extent of DNA damage by anticancer bleomycin on pH and length of post-treatment incubation was studied in yeast. Bleomycin was always removed from cells after 20-min exposures, and cells were washed prior to incubation in non-nutrient buffer. Following exposures of late stationary-phase cells to the very low dose of only 3 ..mu..g/ml, 1.5 h incubation in non-nutrient buffer, pH 5, had hardly any effect on profiles derived from alkaline sucrose gradient sedimentation of nucleic acids released from spheroplasts. In contrast, after incubation of cells for 1.5 h in buffer, pH 7, DNA was all low molecular weight. Thus, even after extensive washing of cells, pH strongly influences the drug's action on DNA. At pH 5, washed cells were increasingly susceptible to DNA damage up to 26 h in non-nutrient buffer.

  4. The resonance Rayleigh scattering of the interaction of copper(Ⅱ)-bleomycinA2 with DNA and its analytical application

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The forming of bleomycinA2-Cu(Ⅱ) cationic chelate and the interaction of the chelate with DNA have been investigated by using resonance Rayleigh scattering(RRS),molecular absorption and fluorescence spectra.The result shows that in aqueous solution,bleomycinA2(BLMA2) can react with Cu(Ⅱ) to form 1:1 cationic chelate which contributes to the changes of the absorption spectra and the quenched fluorescence of BLMA2.When the cationic chelate further bound with DNA to form ternary ion-association complexes,the remarkable enhancement of the RRS intensity was observed.In this work,the optimum conditions for the coordination reaction of BLMA2 with Cu(Ⅱ) and some influencing factors have been investigated.The reaction mechanism of BLMA2-Cu(Ⅱ) binding with DNA was suggested and a binding model was proposed.In addition,the fluorescence quenching type of BLMA2 was investigated.A highly sensitive,simple and rapid new method for the determination of DNA by using BLMA2-Cu(Ⅱ) as RRS probe has been developed.The detection limits(3σ) are 7.2 ng/mL for ctDNA,7.1 ng/mL for sDNA and 18 ng/mL for hsDNA.The method can be applied to the determination of trace amounts of DNA.

  5. Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

    Science.gov (United States)

    Liu, Lei V.; Bell, Caleb B.; Wong, Shaun D.; Wilson, Samuel A.; Kwak, Yeonju; Chow, Marina S.; Zhao, Jiyong; Hodgson, Keith O.; Hedman, Britt; Solomon, Edward I.

    2010-01-01

    Bleomycin (BLM) is a glycopeptide anticancer drug capable of effecting single- and double-strand DNA cleavage. The last detectable intermediate prior to DNA cleavage is a low spin FeIII peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4′ hydrogen atom of the deoxyribose sugar unit. Nuclear resonance vibrational spectroscopy (NRVS) aided by extended X-ray absorption fine structure spectroscopy and density functional theory (DFT) calculations are applied to define the natures of FeIIIBLM and ABLM as (BLM)FeIII─OH and (BLM)FeIII(η1─OOH) species, respectively. The NRVS spectra of FeIIIBLM and ABLM are strikingly different because in ABLM the δFe─O─O bending mode mixes with, and energetically splits, the doubly degenerate, intense O─Fe─Nax transaxial bends. DFT calculations of the reaction of ABLM with DNA, based on the species defined by the NRVS data, show that the direct H-atom abstraction by ABLM is thermodynamically favored over other proposed reaction pathways. PMID:21149675

  6. Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice.

    Science.gov (United States)

    Bai, Feng; Nakanishi, Yoichi; Takayama, Koichi; Pei, Xin-Hai; Inoue, Koji; Harada, Taishi; Izumi, Miiru; Hara, Nobuyuki

    2003-01-01

    Bleomycin is a radiomimetic antitumor agent with unique genotoxic properties. 1-nitropyrene is an environmental mutagen and carcinogen that undergoes both oxidative and reductive metabolism. In the present study, hepatocellular carcinomas were induced in male A/J mice by the intraperitoneal injection of bleomycin (120 mg/kg) followed by the intraperitoneal administration of 1-nitropyrene (total dose: 1,575 mg/kg). In order to understand the mechanism by which these two compounds induce hepatocellular carcinomas, the incidence and spectrum of mutations in the K-ras proto-oncogene in these hepatocellular carcinomas were analyzed. The hepatocellular carcinomas were induced by the administration of bleomycin and 1-nitropyrene were evaluated for point mutations in exon 1 and exon 2 of the K-ras gene by the polymerase chain reaction and a sequencing analysis. No mutation was found in the hotspots regions of the K-ras gene codon 12, 13, or 61. However, the codon 64 of the K-ras gene mutation was identified in 10 of 10 (100%) hepatocellular carcinomas. All mutations showed the same pattern, which was TAC-CAC transition. Codon 64 of the K-ras gene mutation may thus play an important role in the induction of hepatocellular carcinomas by bleomycin in the existence of 1-nitropyrene. As far as we know, this is the first report of a codon 64 mutation in the K-ras gene in a chemically induced tumor.

  7. Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2015-08-01

    To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

  8. The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin

    NARCIS (Netherlands)

    Korteland, J.; Dekker, B.G.; Ligny, C.L. de

    1980-01-01

    The valence state of technetium-99 in its complexes with bleomycin, 1-hydroxy-ethylidene-1,1-diphosphonate and human serum albumin was determined by titration of 99TcO4− with Sn(II) in the presence of these complexing agents. Both direct titration, and addition of an excess of Sn(II) and back-titrat

  9. Atorvastatin Attenuates Bleomycin-Induced Pulmonary Fibrosis via Suppressing iNOS Expression and the CTGF (CCN2/ERK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Bo Zhu

    2013-12-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disorder with high mortality rate. To date, despite the fact that extensive research trials are ongoing, pulmonary fibrosis continues to have a poor response to available medical therapy. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known for its broad pharmacological activities, remains a remedy against multiple diseases. The present study investigated the antifibrotic potential of atorvastatin against bleomycin-induced lung fibrosis and to further explore the possible underlying mechanisms. Our results showed that atorvastatin administration significantly ameliorated the bleomycin mediated histological alterations and blocked collagen deposition with parallel reduction in the hydroxyproline level. Atorvastatin reduced malondialdehyde (MDA level and lung indices. Atorvastatin also markedly decreased the expression of inducible nitric oxide synthase (iNOS in lung tissues and, thus, prevented nitric oxide (NO release in response to bleomycin challenge. Furthermore, atorvastatin exhibited target down-regulation of connective tissue growth factor (CTGF (CCN2 and phosphorylation extracellular regulated protein kinases (p-ERK expression. Taken together, atorvastatin significantly ameliorated bleomycin-induced pulmonary fibrosis in rats, via the inhibition of iNOS expression and the CTGF (CCN2/ERK signaling pathway. The present study provides evidence that atorvastatin may be a potential therapeutic reagent for the treatment of lung fibrosis.

  10. The response of normal and ataxia-telangiectasia cells to bleomycin: relationships between chromosome damage, cell cycle delay and cell killing.

    Science.gov (United States)

    Zampetti-Bosseler, F; Scott, D

    1985-08-01

    In agreement with our earlier observation (Scott and Zampetti-Bosseler, 1982) on X-irradiated normal and ataxia-telangiectasia (A-T) fibroblasts, we now report that after bleomycin or neocarzinostatin treatment also, A-T cells exhibit less G2 delay than normal cells. We confirm that A-T cells sustain more chromosome damage and lethality than normal cells after bleomycin. These observations support the hypothesis (Painter and Young, 1980) that A-T cells are defective in the recognition of certain lesions which normally lead to delays in progression through the cell cycle, during which they are repaired, and which, if unrepaired, lead to cell-lethal chromosome damage. However, we find that after bleomycin, as opposed to X-rays, the contribution of this type of lesion to cell death is minimal. The predominant lesions leading to cell death after bleomycin are not manifested at chromosome aberrations and do not lead to G2 delay or DNA-synthesis inhibition. A-T cells are defective in the recognition and/or repair of both types of lesion.

  11. Adenosine A2A receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis.

    Science.gov (United States)

    Katebi, Majid; Fernandez, Patricia; Chan, Edwin S L; Cronstein, Bruce N

    2008-10-01

    Peripheral blood fibrocytes are a newly identified circulating leukocyte subpopulation that migrates into injured tissue where it may display fibroblast-like properties and participate in wound healing and fibrosis of skin and other organs. Previous studies in our lab demonstrated that A(2A) receptor-deficient and A(2A) antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis, thus the aim of this study was to determine whether the adenosine A(2A) receptor regulates recruitment of fibrocytes to the dermis in this bleomycin-induced model of dermal fibrosis. Sections of skin from normal mice and bleomycin-treated wild type, A(2A) knockout and A(2A) antagonist-treated mice were stained for Procollagen alpha2 Type I and CD34 and the double stained cells, fibrocytes, were counted in the tissue sections. There were more fibrocytes in the dermis of bleomycin-treated mice than normal mice and the increase was abrogated by deletion or blockade of adenosine A(2A) receptors. Because fibrocytes play a central role in tissue fibrosis these results suggest that diminished adenosine A(2A) receptor-mediated recruitment of fibrocytes into tissue may play a role in the pathogenesis of fibrosing diseases of the skin. Moreover, these results provide further evidence that adenosine A(2A) receptors may represent a new target for the treatment of such fibrosing diseases as scleroderma or nephrogenic fibrosing dermopathy.

  12. LOW DOSE PIRFENIDONE SUPPRESSES TRANSFORMING GROWTH FACTOR BETA-1 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1,AND PROTECTS RATS FROM LUNG FIBROSIS INDUCED BY BLEOMYCIN

    Institute of Scientific and Technical Information of China (English)

    Xin-lun Tian; Wei Yao; Zi-jian Guo; Li Gu; Yuan-jue Zhu

    2006-01-01

    Objective To investigate the optimal dosage of pirfenidone for the treatment of pulmonary fibrosis induced by bleomycin in Wistar rats, and the alteration of expressions of transforming growth factor beta-1 (TGF-β1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and matrix metalloproteinase-13 (MMP-13) in lung tissue.Methods Male Wistar rats were endotracheally instilled with bleomycin or normal saline. Pirfenidone (25-800 mg·kg-1·d-1), dexamethasone (3 mg/kg), or 1% carboxymethylcellulose sodium were given daily by feed 2 days before instillation of bleomycin. Groups T7 and T14 were fed pirfenidone 50 mg·kg -1·d-1 at 7 days or 14 days after bleomycin instillation. Lungs were harvested at 28 days after bleomycin instillation. Patholological changes in lung tissues were evaluated with HE staining. Lung collagen was stained by sirius red and measured by content of hydroxyproline. Expression of proteins of TGF-β, TIMP-1, and MMP-13 were detected by Western blotting.Results At doses of 25, 50, and 100 mg·kg-1·d-1, pirfenidone had significant anti-fibrofic effects for bleomycin-induced rat pulmonary fibrosis, and these effects were most significantly attenuated at the dosage of 50mg·kg-1 1d-1 (HE: P<0.01, P<0.01, and P =0.064; sirius red: P<0.05, P<0.01, and P<0. 05; hydroxyproline: P=0.595, P<0.01, and P=0.976). Pirfenidone at a dosage of 50 mg·kg -1·d-1 inhibited protein expression of TGF-β1 and TIMP-1 in lung tissue in the early phase (0.79 and 0.75 times of control group), but had no effect on expression of MMP-13.Conclusion Low dose pirfenidone, especially at dosage of 50 mg·kg-1·d-1, has significant anti-fibrotic effects on bleomycin-induced rat pulmonary fibrosis. Pirfenidone partially inhibits the enhancement of the expression of TGF-β1 and TIMP-1 in lung tissue.

  13. Dysregulated macrophages are present in bleomycin-induced murine laryngotracheal stenosis

    Science.gov (United States)

    Hillel, Alexander T.; Samad, Idris; Ma, Garret; Ding, Dacheng; Sadler, Kaitlyn; Powell, Jonathan D.; Lane, Andrew P.; Horton, Maureen R.

    2015-01-01

    Objective To define the inflammatory cell infiltrate preceding fibrosis in a laryngotracheal stenosis (LTS) murine model. Study Design Prospective controlled murine study. Setting Tertiary care hospital in a research university. Subjects and Methods Chemomechanical injury mice (n=44) sustained bleomycin-coated wire-brush injury to the laryngotracheal complex while mechanical injury controls (n=42) underwent PBS-coated wire-brush injury. Mock surgery controls (n=34) underwent anterior transcervical tracheal exposure only. Inflammatory and fibrosis protein and gene expression was assessed in each condition. Immunohistochemistry served as a secondary outcome. Results In chemomechanical injury mice, there was an up-regulation of: Collagen I (p<0.0001, p<0.0001), Tgf-β (p=0.0023, p=0.0008), and elastin (p<0.0001, p<0.0001) on Day 7, acute inflammatory gene: Il1β (p=0.0027, p=0.0008) on Day 1, and macrophage gene: CD11b (p=0.0026, p=0.0033) on Day 1 versus mechanical and mock controls respectively. M1 marker iNOS expression decreased (p=0.0014) while M2 marker arg1 (p=0.0002) increased on Day 7 compared to mechanical controls. Flow cytometry demonstrated increased macrophages (p=0.0058, day 4) and M1 macrophages (p=0.0148, day 4, p=0.0343, day 7, p=0.0229, day 10) compared to mock controls. There were similarities between chemomechanical and mechanical injury mice with an increase in M2 macrophages at day 10 (p=0.0196). Conclusions The mouse model demonstrated increased macrophages involved with the development of LTS. Macrophage immunophenotype suggested that dysregulated M2 macrophages have a role in abnormal laryngotracheal wound healing in both species. These results support this animal model as a representation for human disease. Furthermore, this data delineates inflammatory cells and signaling pathways in LTS that may potentially be modulated to lessen fibroblast proliferation and collagen deposition. PMID:26084828

  14. Preventive Effects of Rhodiola rosea L. on Bleomycin-Induced Pulmonary Fibrosis in Rats

    Directory of Open Access Journals (Sweden)

    Ke Zhang

    2016-06-01

    Full Text Available Rhodiola rosea L. (RRL possesses a wide range of pharmacological properties, including lung-protective activity, and has been utilized in folk medicine for several 100 years. However, the lung-protective mechanism remains unclear. This study investigated the possible lung-protective activity mechanism of RRL in a pulmonary fibrosis (PF rat model. Lung fibrotic injury was induced in Sprague–Dawley rats by single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg. The rats were administered 125, 250, or 500 mg/kg of a 95% ethanol extract of RRL for 28 days. The animals were killed to detect changes in body weight, serum levels of glutathione (GSH and total superoxide dismutase (T-SOD, as well as lung tissue hydroxyproline (HYP content. Tumor necrosis factor-α (TNF-α, transforming growth factor-β1 (TGF-β1, and interleukin 6 (IL-6 levels were measured in bronchoalveolar lavage fluid (BALF by enzyme-linked immunosorbent assay. Hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining were performed to observe the histopathological changes in lung tissues. Additionally, target-related proteins were measured by Western blotting. RRL alleviated the loss of body weight induced by instilling BLM in PF rats, particularly at the 500 mg/kg per day dose. RRL reduced HYP (p < 0.01 and increased GSH and T-SOD contents. BALF levels of TNF-α, TGF-β1, and IL-6 decreased significantly in the RRL-treated groups. Expression levels of matrix metalloproteinase-9 (MMP-9 and α-smooth muscle actin decreased significantly in a dose-dependent manner in response to RRL. Moreover, the levels of TGF-β1 and tissue inhibitor of metalloproteinase-1 in lung tissues also decreased in the RRL-treated groups. RRL alleviated BLM-induced PF in rats. Our results reveal that the protective effects of RRL against fibrotic lung injury in rats are correlated with its anti-inflammatory, antioxidative, and anti-fibrotic properties. MMP-9 may

  15. Gene Expression Profile Changes and Cellular Responses to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

    Science.gov (United States)

    Lu, Tao; Zhang, Ye; Kidane, Yared; Feiveson, Alan; Stodieck, Louis; Karouia, Fathi; Rohde, Larry; Wu, Honglu

    2016-01-01

    Living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. In addition, DNA in space can be damaged by toxic chemicals or reactive oxygen species generated due to increased levels of environmental and psychological stresses. Understanding the impact of spaceflight factors, microgravity in particular, on cellular responses to DNA damage affects the accuracy of the radiation risk assessment for astronauts and the mutation rate in microorganisms. Although possible synergistic effects of space radiation and microgravity have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate the effects of spaceflight on cellular responses to DNA damage, confluent human fibroblast cells (AG1522) flown on the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induced DNA damages including double-strand breaks (DSB). Damages in the DNA were quantified by immunofluorescence staining for ?-H2AX, which showed similar percentages of different types of stained cells between flight and ground. However, there was a slight shift in the distribution of the ?-H2AX foci number in the flown cells with countable foci. Comparison of the cells in confluent and in exponential growth conditions indicated that the proliferation rate between flight and the ground may be responsible for such a shift. A microarray analysis of gene expressions in response to bleomycin treatment was also performed. Comparison of the responsive pathways between the flown and ground cells showed similar responses with the p53 network being the top upstream regulator. Similar responses at the RNA level between different gravity conditions were also observed with a PCR array analysis containing a set of genes involved in DNA damage signaling; with BBC3, CDKN1A, PCNA and PPM1D being significantly

  16. Pneumomediastinum, subcutaneous emphysema, and pneumothorax after a pulmonary function testing in a patient with bleomycin-induced interstitial pneumonitis

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    Mariana Sponholz Araujo

    2013-09-01

    Full Text Available Spontaneous pneumomediastinum is an uncommon event, the clinical picture of which includes retrosternal chest pain, subcutaneous emphysema, dyspnea, and dysphonia. The pathophysiological mechanism involved is the emergence of a pressure gradient between the alveoli and surrounding structures, causing alveolar rupture with subsequent dissection of the peribronchovascular sheath and infiltration of the mediastinum and subcutaneous tissue with air. Known triggers include acute exacerbations of asthma and situations that require the Valsalva maneuver. We described and documented with HRCT scans the occurrence of pneumomediastinum after a patient with bleomycin-induced interstitial lung disease underwent pulmonary function testing. Although uncommon, the association between pulmonary function testing and air leak syndromes has been increasingly reported in the literature, and lung diseases, such as interstitial lung diseases, include structural changes that facilitate the occurrence of this complication.

  17. Effects and possible anti-tumor immunity of electrochemotherapy with bleomycin on human colon cancer xenografts in nude mice

    Institute of Scientific and Technical Information of China (English)

    Min-Hua Zheng; Bao-Ming Yu; Bo Feng; Jian-Wen Li; Ai-Guo Lu; Ming-Liang Wang; Wei-Guo Hu; Ji-Yuan Sun; Yan-Yan Hu; Jun-Jun Ma

    2005-01-01

    AIM: To evaluate the anti-tumor effects and possible involvement of anti-tumor immunity of electrochemotherapy (ECT) employing electroporation and bleomycin in human colon cancer xenografts in nude mice, and to establish the experimental basis for clinical application of ECT.METHODS: Forty nude mice, inoculated subcutaneously human colon cancer cell line LoVo for 3 wk, were allocated randomly into four groups: B+E+ (ECT), B+E- (administration of bleomycin alone), B-E+ (administration of electric pulses alone), and B-E- (no treatment). Tumor volumes were measured daily. The animals were killed on the 7th d, the weights of xenografts were measured, and histologies of tumors were evaluated. Cytotoxicity of spleen natural killer (NK) and lymphokine-activated killer (LAK) cells was then assessed by lactic dehydrogenase release assay.RESULTS: The mean tumor volume of group B+E+ was statistically different from the other three groups after the treatment (F= 36.80, P<0.01). There was one case of complete response, seven cases of partial response (PR) in group B+E+, one case of PR in group B+E- and group B-E+ respectively, and no response was observed in group B-E-. The difference of response between group B+E+ and the other three groups was statistically significant (χ2 = 25.67, P<0.01). Histologically, extensive necrosis of tumor cells with considerable vascular damage and inflammatory cells infiltration were observed in group B+E+. There was no statistical difference between the cytotoxicity of NK and LAK cells in the four treatment groups.CONCLUSION: ECT significantly enhances the chemosensitivity and effects of chemotherapy in human colon cancer xenografts in nude mice, and could be a kind of novel treatment modality for human colon cancer.The generation of T-cell-dependent, tumor-specific immunity might be involved in the process of ECT.

  18. Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Li, Min; Krishnaveni, Manda Sai; Li, Changgong; Zhou, Beiyun; Xing, Yiming; Banfalvi, Agnes; Li, Aimin; Lombardi, Vincent; Akbari, Omid; Borok, Zea; Minoo, Parviz

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

  19. Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis.

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    Susana Aguilar

    Full Text Available Many common diseases of the gas exchange surface of the lung have no specific treatment but cause serious morbidity and mortality. Idiopathic Pulmonary Fibrosis (IPF is characterized by alveolar epithelial cell injury, interstitial inflammation, fibroblast proliferation and collagen accumulation within the lung parenchyma. Keratinocyte Growth Factor (KGF, also known as FGF-7 is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. During repair, the lung not only uses resident cells after injury but also recruits circulating bone marrow-derived cells (BMDC. Several groups have used Mesenchymal Stromal Cells (MSCs as therapeutic vectors, but little is known about the potential of Hematopoietic Stem cells (HSCs. Using an inducible lentiviral vector (Tet-On expressing KGF, we were able to efficiently transduce both MSCs and HSCs, and demonstrated that KGF expression is induced in a regulated manner both in vitro and in vivo. We used the in vivo bleomycin-induced lung fibrosis model to assess the potential therapeutic effect of MSCs and HSCs. While both populations reduced the collagen accumulation associated with bleomycin-induced lung fibrosis, only transplantation of transduced HSCs greatly attenuated the histological damage. Using double immunohistochemistry, we show that the reduced lung damage likely occurs through endogenous type II pneumocyte proliferation induced by KGF. Taken together, our data indicates that bone marrow transplantation of lentivirus-transduced HSCs can attenuate lung damage, and shows for the first time the potential of using an inducible Tet-On system for cell based gene therapy in the lung.

  20. EM703 improves bleomycin-induced pulmonary fibrosis in mice by the inhibition of TGF-β signaling in lung fibroblasts

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    Inagaki Hirofumi

    2006-01-01

    Full Text Available Abstract Background Fourteen-membered ring macrolides have been effective in reducing chronic airway inflammation and also preventing lung injury and fibrosis in bleomycin-challenged mice via anti-inflammatory effects. EM703 is a new derivative of erythromycin (EM without the bactericidal effects. We investigated the anti-inflammatory and antifibrotic effects of EM703 in an experimental model of bleomycin-induced lung injury and subsequent fibrosis in mice. Methods Seven-week-old male ICR mice were used. All experiments used eight mice/group, unless otherwise noted in the figure legends. Bleomycin was administered intravenously to the mice on day 0. EM703 was orally administered daily to mice. All groups were examined for cell populations in the bronchoalveolar lavage (BAL fluid and for induction of messenger RNA (mRNA of Smad3 and Smad4 in the lung tissues by reverse transcriptase (RT-polymerase chainreaction (PCR on day 7. Fibroblastic foci were assessed histologically, and the hydroxyproline content was chemically determined in the lung tissues on day 28. We performed assay of proliferation and soluble collagen production, and examined the induction of mRNA of Smad3 and Smad4 by RT-PCR in murine lung fibroblast cell line MLg2908. We also examined Smad3, Smad4 and phosphorylated Smad2/3 (p-Smad2/3 protein assay by western blotting in MLg2908. Results Bleomycin-induced lung fibrosis, and the infiltration of macrophages and neutrophils into the airspace were inhibited by EM703. The expression of Smad3 and Smad4 mRNA was clearly attenuated by bleomycin, but was recovered by EM703. EM703 also inhibited fibroblast proliferation and the collagen production in lung fibroblasts induced by Transforming growth factor-beta (TGF-β. The expression of Smad3 and Smad4 mRNA in murine lung fibroblasts disappeared due to TGF-β, but was recovered by EM703. EM703 inhibited the expression of p-Smad2/3 and Smad4 protein in murine lung fibroblasts induced by TGF

  1. Resistance to Bleomycin in Cancer Cell Lines Is Characterized by Prolonged Doubling Time, Reduced DNA Damage and Evasion of G2/M Arrest and Apoptosis

    OpenAIRE

    Qi Wang; Kangping Cui; Osvaldo Espin-Garcia; Dangxiao Cheng; Xiaoping Qiu; Zhuo Chen; Malcolm Moore; Bristow, Robert G.; Wei Xu; Der, Sandy; Geoffrey Liu

    2013-01-01

    BACKGROUND: To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM) resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell ...

  2. Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

    Energy Technology Data Exchange (ETDEWEB)

    Kalayarasan, Srinivasan, E-mail: kalaivasanbio@gmail.com; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam, E-mail: sudhandiran@yahoo.com

    2013-09-01

    Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.

  3. Resistance to bleomycin in cancer cell lines is characterized by prolonged doubling time, reduced DNA damage and evasion of G2/M arrest and apoptosis.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available BACKGROUND: To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines. RESULTS: Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352% in BLM-resistant sub-clones (p<0.05 for both. Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05. Significantly reduced DNA damage (COMET and γ-H2AX assays, G2/M arrest, and apoptosis (p<0.05 for each set of comparison following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05. CONCLUSION: Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis.

  4. Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response

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    Pazit Y. Cohen

    2015-01-01

    Full Text Available Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1− myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days, as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+ lymphocytes and Thy1− myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.

  5. Fibroblast-specific expression of AC6 enhances beta-adrenergic and prostacyclin signaling and blunts bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Liu, Xiaoqiu; Li, Fengying; Sun, Shu Qiang; Thangavel, Muthusamy; Kaminsky, Joseph; Balazs, Louisa; Ostrom, Rennolds S

    2010-06-01

    Pulmonary fibroblasts regulate extracellular matrix production and degradation and are critical in maintenance of lung structure, function, and repair, but they also play a central role in lung fibrosis. cAMP-elevating agents inhibit cytokine- and growth factor-stimulated myofibroblast differentiation and collagen synthesis in pulmonary fibroblasts. In the present study, we overexpressed adenylyl cyclase 6 (AC6) in pulmonary fibroblasts and measured cAMP production and collagen synthesis. AC6 overexpression enhanced cAMP production and the inhibition of collagen synthesis mediated by isoproterenol and beraprost, but not the responses to butaprost or PGE(2). To examine if increased AC6 expression would impact the development of fibrosis in an animal model, we generated transgenic mice that overexpress AC6 under a fibroblast-specific promoter, FTS1. Lung fibrosis was induced in FTS1-AC6(+/-) mice and littermate controls by intratracheal instillation of saline or bleomycin. Wild-type mice treated with bleomycin showed extensive peribronchial and interstitial fibrosis and collagen deposition. By contrast, FTS1-AC6(+/-) mice displayed decreased fibrotic development, lymphocyte infiltration (as determined by pathological scoring), and lung collagen content. Thus, AC6 overexpression inhibits fibrogenesis in the lung by reducing pulmonary fibroblast-mediated collagen synthesis and myofibroblast differentiation. Because AC6 overexpression does not lead to enhanced basal or PGE(2)-stimulated levels of cAMP, we conclude that endogenous catecholamines or prostacyclin is produced during bleomycin-induced lung fibrosis and that these signals have antifibrotic potential.

  6. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue

    Institute of Scientific and Technical Information of China (English)

    Jin Xiaoguang; Dai Huaping; Ding Ke; Xu Xuefeng; Pang Baosen; Wang Chen

    2014-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic.There is no effective therapy except for lung transplantation.Rapamycin is an immunosuppressive drug with potent antifibrotic activity.The purpose of this study was to examine the effects of rapamycin on bleomycininduced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1).Methods Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model.Rapamycin was given at a dose of 0.5 mg/kg per gavage,beginning one day before bleomycin instillation and once daily until animal sacrifice.Ten rats in each group were sacrificed at 3,7,14,28 and 56 days after bleomycin administration.Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System.Type Ⅰ and Ⅲ collagen fibers were identified by Picro-sirius-polarization.Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay,MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR).Results Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin.Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days.The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P <0.05).It was also demonstrated that rapamycin treatment reduced the expression of MMP-9 and TIMP-1 in lung tissue that was increased by bleomycin.Conclusion These results highlight the significance of rapamycin in alleviating

  7. STAT1 Antisense Oligonucleotides Attenuate the Proinflammatory Cytokine Release of Alveolar Macrophages in Bleomycin-Induced Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Xianming Fan; Zengli Wang

    2005-01-01

    To investigate the effect of signal transducers and activators of transcription 1 (STAT1) antisense oligonucleotides (ASON) on concentrations of TNF-α, IL-8, NO secreted by alveolar macrophages (AMs) in bleomycin-induced rat pulmonary fibrosis, five adult female Wistar rats were intratracheally instilled with bleomycin. After 7 days, the rats were killed by right ventricle of heart exsanguinations under ketamine anaesthesia and bronchoalveolar lavage (BAL) was performed to obtain AMs. AMs were divided into four groups, treated with STAT1 ASON, STAT1 sense oligonucleotides (SON), dexamethasone (DEX) and medium alone (control), respectively. AMs and media were collected after culture for 36 h. The mRNA and protein expressions of STAT1 and ICAM-1 in AMs were detected by RT-PCR and ELISA, respectively. The concentrations of TNF-α, IL-8, NO in cultured medium were detected.The STAT1 mRNA expression by AMs in the STAT1 ASON group was lower than those of AMs in the STAT1 SON group, the DEX group and the control group (p < 0.05). Moreover, the STAT1 mRNA expression by AMs in the DEX group was also lower than those of AMs in the STAT1 SON group and the control group (p < 0.05), but the STAT1 mRNA expression by AMs in the STAT1 SON group was not different from that of the control group (p >0.05). The protein expressions of STAT1 and ICAM-1 and the mRNA expression of ICAM-1 showed similar changes to the STAT1 mRNA expression by AMs. The concentrations of TNF-α, IL-8, NO in cultured medium from STAT1 ASON group were lower than those from STAT1 SON, DEX and the control groups (p < 0.05). Moreover,the concentrations of TNF-α, IL-8, NO in cultured medium from DEX group were also lower than those from the control and STAT1 SON group (p < 0.05), but no difference between STAT1 SON group and the control (p > 0.05).The results suggest that STAT1 ASON could inhibit the secretion of TNF-α, IL-8, NO in AMs, and STAT1 could become a target of treating pulmonary fibrosis.

  8. Antifibrotic effects of curcumin are associated with overexpression of cathepsins K and L in bleomycin treated mice and human fibroblasts

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    Zhang Dongwei

    2011-11-01

    Full Text Available Abstract Background Lung fibrosis is characterized by fibroblast proliferation and the deposition of collagens. Curcumin, a polyphenol antioxidant from the spice tumeric, has been shown to effectively counteract fibroblast proliferation and reducing inflammation and fibrotic progression in animal models of bleomycin-induced lung injury. However, there is little mechanistic insight in the biological activity of curcumin. Here, we study the effects of curcumin on the expression and activity of cathepsins which have been implicated in the development of fibrotic lung diseases. Methods We investigated the effects of curcumin administration to bleomycin stimulated C57BL/6 mice and human fetal lung fibroblasts (HFL-1 on the expression of cathepsins K and L which have been implicated in matrix degradation, TGF-β1 modulation, and apoptosis. Lung tissues were evaluated for their contents of cathepsins K and L, collagen, and TGF-β1. HFL-1 cells were used to investigate the effects of curcumin and cathepsin inhibition on cell proliferation, migration, apoptosis, and the expression of cathepsins K and L and TGF-β1. Results Collagen deposition in lungs was decreased by 17-28% after curcumin treatment which was accompanied by increased expression levels of cathepsins L (25%-39% and K (41%-76% and a 30% decrease in TGF-β1 expression. Moreover, Tunel staining of lung tissue revealed a 33-41% increase in apoptotic cells after curcumin treatment. These in vivo data correlated well with data obtained from the human fibroblast line, HFL-1. Here, cathepsin K and L expression increased 190% and 240%, respectively, in the presence of curcumin and the expression of TGF-β1 decreased by 34%. Furthermore, curcumin significantly decreased cell proliferation and migration and increased the expression of surrogate markers of apoptosis. In contrast, these curcumin effects were partly reversed by a potent cathepsin inhibitor. Conclusion This study demonstrates that

  9. Biochemical evaluation of a 108-member deglycobleomycin library: viability of a selection strategy for identifying bleomycin analogues with altered properties.

    Science.gov (United States)

    Ma, Qian; Xu, Zhidong; Schroeder, Benjamin R; Sun, Wenyue; Wei, Fang; Hashimoto, Shigeki; Konishi, Kazuhide; Leitheiser, Christopher J; Hecht, Sidney M

    2007-10-17

    The bleomycins (BLMs) are clinically used glycopeptide antitumor antibiotics that have been shown to mediate the sequence-selective oxidative damage of both DNA and RNA. Previously, we described the solid-phase synthesis of a library of 108 unique analogues of deglycoBLM A6, a congener that cleaves DNA analogously to BLM itself. Each member of the library was assayed for its ability to effect single- and double-strand nicking of duplex DNA, sequence-selective DNA cleavage, and RNA cleavage in the presence and absence of a metal ion cofactor. All of the analogues tested were found to mediate concentration-dependent plasmid DNA relaxation to some extent, and a number exhibited double-strand cleavage with an efficiency comparable to or greater than deglycoBLM A6. Further, some analogues having altered linker and metal-binding domains mediated altered sequence-selective cleavage, and a few were found to cleave a tRNA3Lys transcript both in the presence and in the absence of a metal cofactor. The results provide insights into structural elements within BLM that control DNA and RNA cleavage. The present study also permits inferences to be drawn regarding the practicality of a selection strategy for the solid-phase construction and evaluation of large libraries of BLM analogues having altered properties.

  10. Gamma rays and bleomycin nick DNA and reverse the DNase I sensitivity of beta-globin gene chromatin in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Villeponteau, B.; Martinson, H.G.

    1987-05-01

    The active beta-globin genes in chicken erythrocytes, like all active genes, reside in large chromatin domains which are preferentially sensitive to digestion by DNase I. We have recently proposed that the special structure of chromatin in active domains is maintained by torsional stress in the DNA. This hypothesis predicts that nicking of the DNA within any such chromosomal domain in vivo will relax the DNA and lead to loss of the special DNase I-sensitive state. Here we have tested this prediction by using gamma irradiation and bleomycin treatment to cleave DNA within intact chicken embryo erythrocytes. Both treatments cause reversal of DNase I sensitivity. Moreover, reversal occurs at approximately one nick per 150 kilobase pairs for both agents despite their entirely unrelated modes of cell penetration and DNA attack. These results suggest that the domain of DNase I sensitivity surrounding the beta-globin genes comprises 150 kilobase pairs of chromatin under torsional stress and that a single DNA nick in this region is sufficient to reverse the DNase I sensitivity throughout the entire domain.

  11. Intratracheal Bleomycin Aerosolization: The Best Route of Administration for a Scalable and Homogeneous Pulmonary Fibrosis Rat Model?

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    Alexandre Robbe

    2015-01-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time.

  12. Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury.

    Science.gov (United States)

    Liebler, Janice M; Lutzko, Carolyn; Banfalvi, Agnes; Senadheera, Dinithi; Aghamohammadi, Neema; Crandall, Edward D; Borok, Zea

    2008-08-01

    We studied the capacity of adult human bone marrow-derived cells (BMDC) to incorporate into distal lung of immunodeficient mice following lung injury. Immunodeficient NOD/SCID and NOD/SCID/beta(2) microglobulin (beta(2)M)(null) mice were administered bleomycin (bleo) or saline intranasally. One, 2, 3 and 4 days after bleo or saline, human BMDC labeled with CellTracker Green CMFDA (5-chloromethylfluorescein diacetate) were infused intravenously. Retention of CMFDA(+) cells was maximal when delivered 4 days after bleo treatment. Seven days after bleo, cells from NOD/SCID mice were CMFDA(+), which increased 10- to 100-fold in NOD/SCID/beta(2)M(null) mice. Preincubation of BMDC with Diprotin A, a reversible inhibitor of CD26 peptidase activity that enhances the stromal-derived factor-1 (SDF-1/CXCL12)/CXCR4 axis, resulted in a 30% increase in the percentage of CMFDA(+) cells retained in the lung. These data indicate that human BMDC can be identified in lungs of mice following injury, albeit at low levels, and this may be modestly enhanced by manipulation of the SDF-1/CXCR4 axis. Given the overall low number of human cells detected, methods to increase homing and retention of adult BMDC, and consideration of other stem cell populations, will likely be required to facilitate engraftment in the treatment of lung injury.

  13. Preventive and therapeutic effects of thymosin β4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis.

    Science.gov (United States)

    Conte, Enrico; Fagone, Evelina; Gili, Elisa; Fruciano, Mary; Iemmolo, Maria; Pistorio, Maria Provvidenza; Impellizzeri, Daniela; Cordaro, Marika; Cuzzocrea, Salvatore; Vancheri, Carlo

    2016-06-01

    In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo. Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses). To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7). Animals were sacrificed at one, two, or three weeks later. Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed. Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days. Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-β expression in lung tissue. Importantly, α-SMA expression, the hallmark of myofibroblast differentiation, was also decreased. This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.

  14. Absence of O sup 6 -alkylguanine-DNA alkyltransferase induction in chick embryo liver and brain following X-irradiation or treatment with bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Stammberger, I.; Tempel, K. (Munich Univ. (Germany). Faculty of Veterinary Medicine)

    1991-01-01

    The presence of O{sup 6}-alkylguanine-DNA alkyltransferase (AT) in liver and brain of chick embryos, chicks and hens was demonstrated. An induction of AT activity has only been found in the liver of chicks and hens 48 h after X-irradiation. The administration of methylmethanesulphonate to the chick embryo resulted 3-24 hr later in strong inhibition of AT activity accompanied by DNA alkylation. Under the same conditions, X-irradiation, dimethylnitrosamine and bleomycin exhibited no effect. The results are compared with those obtained in mouse, rat and human foetal tissues. (author).

  15. Modulation of the genotoxicity of bleomycin by amines through noncovalent DNA interactions and alteration of physiological conditions in yeast

    Energy Technology Data Exchange (ETDEWEB)

    Hoffmann, George R. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)], E-mail: ghoffmann@holycross.edu; Gessner, Gabrielle S.; Hughes, Jennifer F.; Ronan, Matthew V.; Sylvia, Katelyn E.; Willett, Christine J. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)

    2007-10-01

    The effects of amines on the induction of mitotic gene conversion by bleomycin (BLM) were studied at the trp5 locus in Saccharomyces cerevisiae strain D7. BLM induces double-strand breaks in DNA and is a potent recombinagen in this assay. The polyamine spermidine causes concentration-dependent protection against the genotoxicity of BLM, reducing the convertant frequency by over 90% under the most protective conditions. Spermine, diethylenetriamine, ethylenediamine, putrescine, and ethylamine were also antigenotoxic in combined treatments with BLM. There was a general correspondence between the protective effect and the number of amino groups, suggesting that more strongly cationic amines tend to be stronger antirecombinagens. Electrostatic association of the amines with DNA probably hinders BLM access to the 4' position of deoxyribose where it generates a free radical. Other amines interact with BLM differently from these unbranched aliphatic amines. The aminothiol cysteamine inhibits the genotoxicity of BLM under hypoxic conditions but increases it under euoxic conditions. In contrast, pargyline potentiates the genotoxicity of BLM under hypoxic conditions but not under euoxic conditions. The antirecombinagenic effect of cysteamine apparently involves DNA binding and depletion of oxygen needed for BLM activity, whereas its potentiation of BLM entails its serving as an electron source for the activation of BLM. Pargyline may enhance BLM indirectly by preventing the depletion of oxygen by monoamine and polyamine oxidase. The planar 9-aminoacridine weakly induces gene conversion in strain D7, but it is strongly synergistic with BLM. Enhancement of BLM activity by this compound and by the related nitroacridine Entozon is apparently mediated by intercalation of the acridine ring system into DNA. Thus, the influence of amines on the genotoxicity of BLM in yeast encompasses antigenotoxic, potentiating, and synergistic interactions. The underlying mechanisms involve

  16. Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina.

    Science.gov (United States)

    Bolzán, Alejandro D; Bianchi, Martha S; Giménez, Esteban M; Flaqué, María C Díaz; Ciancio, Vicente R

    2008-03-01

    Spontaneous and bleomycin (BLM)-induced chromosomal aberrations in G0 and G2 stages of the cell cycle have been analyzed in peripheral lymphocytes of 21 long-haul aircrew members from Argentina in order to assess BLM-induced clastogenesis as a first approach to determine the DNA repair capacity and thereby the susceptibility to environmental cancers in aircrew. The possibility that occupational exposure of flight personnel to cosmic radiation can induce an adaptive response in their peripheral lymphocytes that can be detected by a subsequent in vitro treatment with BLM was also investigated. For comparison, aberrations were also scored in the lymphocytes of 15 healthy volunteers matched by age, health, sex, drinking and smoking habits to the flight personnel group. Aircrew exhibited a higher frequency of spontaneous dicentrics and ring chromosomes than the control population (paircrew and controls are equally sensitive to BLM G2 clastogenic effects, since both groups exhibited a similar frequency of chromatid breaks per cell (p>0.05). However, the aircrew sampled population was almost two times more sensitive to BLM G0 clastogenic effects than controls (paircrew to cosmic radiation increases the in vitro chromosomal sensitivity of their peripheral lymphocytes to BLM (at least in the G0 stage of the cell cycle), and that occupational exposure of flight personnel to cosmic radiation does not induce an adaptive response to this radiomimetic compound. Our results justify further studies aimed at determine if those aircrew members hypersensitive to BLM are more prone to develop environmental cancer than BLM-insensitive individuals.

  17. Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina

    Energy Technology Data Exchange (ETDEWEB)

    Bolzan, Alejandro D. [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Miembro de la Carrera del Investigador Cientifico del CONICET (Argentina)], E-mail: abolzan@imbice.org.ar; Bianchi, Martha S. [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Miembro de la Carrera del Investigador Cientifico del CONICET (Argentina); Gimenez, Esteban M.; Flaque, Maria C. Diaz [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Ciancio, Vicente R. [Universidad Nacional de La Plata, Facultad de Ciencias Medicas, 120 y 60, 1900 La Plata (Argentina)

    2008-03-01

    Spontaneous and bleomycin (BLM)-induced chromosomal aberrations in G0 and G2 stages of the cell cycle have been analyzed in peripheral lymphocytes of 21 long-haul aircrew members from Argentina in order to assess BLM-induced clastogenesis as a first approach to determine the DNA repair capacity and thereby the susceptibility to environmental cancers in aircrew. The possibility that occupational exposure of flight personnel to cosmic radiation can induce an adaptive response in their peripheral lymphocytes that can be detected by a subsequent in vitro treatment with BLM was also investigated. For comparison, aberrations were also scored in the lymphocytes of 15 healthy volunteers matched by age, health, sex, drinking and smoking habits to the flight personnel group. Aircrew exhibited a higher frequency of spontaneous dicentrics and ring chromosomes than the control population (p < 0.05). BLM sensitivity test showed that aircrew and controls are equally sensitive to BLM G2 clastogenic effects, since both groups exhibited a similar frequency of chromatid breaks per cell (p > 0.05). However, the aircrew sampled population was almost two times more sensitive to BLM G0 clastogenic effects than controls (p < 0.05). Therefore, our data suggest that chronic exposure of aircrew to cosmic radiation increases the in vitro chromosomal sensitivity of their peripheral lymphocytes to BLM (at least in the G0 stage of the cell cycle), and that occupational exposure of flight personnel to cosmic radiation does not induce an adaptive response to this radiomimetic compound. Our results justify further studies aimed at determine if those aircrew members hypersensitive to BLM are more prone to develop environmental cancer than BLM-insensitive individuals.

  18. Lung inflammation and thymic atrophy after bleomycin are controlled by the prostaglandin D2 receptor DP1.

    Science.gov (United States)

    van den Brule, Sybille; Huaux, François; Uwambayinema, Francine; Ibouraadaten, Saloua; Yakoub, Yousof; Palmai-Pallag, Mihaly; Trottein, François; Renauld, Jean-Christophe; Lison, Dominique

    2014-01-01

    Acute lung injury (ALI) can be accompanied by secondary systemic manifestations. In a model of ALI induced by bleomycin (bleo), we examined the response of D prostanoid receptor 1 (DP1)-deficient mice (DP1(-/-)) to better understand these processes. DP1 deficiency aggravated the toxicity of bleo as indicated by enhanced body weight loss, mortality, and lung inflammation including bronchoalveolar permeability and neutrophilia. Thymic atrophy was also observed after bleo and was strongly exacerbated in DP1(-/-) mice. This resulted from the enhanced depletion of immature T lymphocytes in the thymus of DP1(-/-) mice, a phenomenon usually related to increased glucocorticoid release in blood. Serum corticosterone was more elevated in DP1(-/-) mice after bleo than in wild-type (wt) mice. Thymocytes of DP1(-/-) mice were not more sensitive to dexamethasone in vitro, and systemic delivery of dexamethasone or peritoneal inflammation after LPS induced a similar thymic atrophy in wt and DP1(-/-) mice, indicating that pulmonary DP1 was critical to the control of thymic atrophy after bleo. DP1(-/-) mice showed increased lung and/or blood mediators involved in neutrophil recruitment and/or glucocorticoid production/thymic atrophy (osteopontin, leukemia inhibitory factor, and keratinocyte-derived chemokine) after bleo. Finally, local pulmonary DP1 activation or inhibition in wt mice abrogated or amplified thymic atrophy after bleo, respectively. Altogether, our data reveal that ALI can perturb the systemic T-cell pool by inducing thymic atrophy and that both pathological processes are controlled by the pulmonary DP1 receptor. This new pathway represents a potential therapeutic target in ALI.

  19. VEGFmRNA and eNOSmRNA expression in immature rabbits with bleomycin-induced pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    龚方戚; 林幼敏; 汤宏峰; 顾伟忠; 汪伟; 康曼丽

    2004-01-01

    Objective: To investigate the evolution of pulmonary hypertension, the pathological changes of pulmonary arteries, and the expression of VEGFmRNA and eNOSmRNA of pulmonary arterial endothelial cells in immature rabbits treated with intratracheal bleomycin (BLM). Methods: Immature rabbits were divided into control and BLM group. Two and four weeks after intratracheal normal saline or BLM injection, the systolic, diastolic and mean pulmonary artery pressure (PASP, PADP, MPAP) were measured by micro-catheter; the pathological changes and the expression of VEGFmRNA and eNOSmRNA of endothelial cells in pulmonary arteries were evaluated by HE and in situ hybridization.Results: Two and four weeks after intratracheal injection of BLM, the PASP, PADP and MPAP increased 53%, 49%, 52%in 2 weeks, and 43%, 89%, 56% in 4 weeks; the wall thickness increased and the cavity in middle and small pulmonary arteries became narrow; the Thickness Index (TI) and Area Index (AI) increased 25%, 14% in 2 weeks, and 22%, 24% in 4 weeks; the level of VEGFmRNA and eNOSmRNA expression decreased 46%, 43% in 2 weeks, and 43%, 51% in 4 weeks.There was no significant difference between 2 weeks and 4 weeks BLM groups. Conclusion: The pulmonary artery pressure was elevated, the thickness of wall increased and the cavity became narrow in middle and small pulmonary arteries, and the level of VEGFmRNA and eNOSmRNA expression in pulmonary arterial endothelial cells decreased in immature rabbits after 2 weeks and 4 weeks of intratracheal 4 U/kg BLM injection.

  20. Heat Shock Protein 27 Plays a Pivotal Role in Myofibroblast Differentiation and in the Development of Bleomycin-Induced Pulmonary Fibrosis.

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    Ah-Mee Park

    Full Text Available Heat shock protein 27 (HSP27 is a member of the small molecular weight HSP family. Upon treatment with transforming growth factor β1 (TGF-β1, we observed upregulation of HSP27 along with that of α-smooth muscle actin (α-SMA, a marker of myofibroblast differentiation, in cultured human and mouse lung fibroblasts. Furthermore, by using siRNA knockdown, we demonstrated that HSP27 was involved in cell survival and upregulation of fibronectin, osteopontin (OPN and type 1 collagen, all functional markers of myofibroblast differentiation, in TGF-β1-treated MRC-5 cells. In lung tissues of bleomycin-treated mice, HSP27 was strongly upregulated and substantially co-localized with α-SMA, OPN and type I collagen but not with proSP-C (a marker of type II alveolar epithelial cells, E-cadherin (a marker of epithelial cells or F4/80 (a marker of macrophages. A similar co-localization of HSP27 and α-SMA was observed in lung tissues of patients with idiopathic pulmonary fibrosis. Furthermore, airway delivery of HSP27 siRNA effectively suppressed bleomycin-induced pulmonary fibrosis in mice. Collectively, our findings indicate that HSP27 is critically involved in myofibroblast differentiation of lung fibroblasts and may be a promising therapeutic target for lung fibrotic diseases.

  1. Bach1 siRNA attenuates bleomycin-induced pulmonary fibrosis by modulating oxidative stress in mice

    Science.gov (United States)

    Liu, Yuan; Zheng, Yi

    2017-01-01

    Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is an important transcriptional repressor that acts by modulating oxidative stress and represents a potential target in the treatment of pulmonary fibrosis (PF). In this study, we knocked down Bach1 using adenovirus-mediated small interfering RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective therapeutic strategy in mice with bleomycin (BLM)-induced PF. Mouse lung fibroblasts (MLFs) were incubated with transforming growth factor (TGF)-β1 (5 ng/ml) and subsequently infected with recombined adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector was used as the negative control. The selected Bach1 siRNA with higher interference efficiency was used for the animal experiments. A mouse model of BLM-induced PF was established, and Bach1 siRNA (1×109 PFU) was administered to the mice via the tail vein. The results revealed that the Bach1 mRNA and protein levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs infected with Bach1 siRNA exhibited increased mRNA and protein expression levels of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-β1 and interleukin-6 in the cell supernatants compared with the cells exposed to TGF-β1 alone. Bach1 knockdown by siRNA also enhanced the expression of antioxidant factors, but suppressed that of fibrosis-related cytokines in mice compared with the BLM group. Finally, the inflammatory infiltration of alveolar and interstitial cells and the destruction of lung structure were significantly attenuated in the mide administered Bach1 siRNA compared with those in the BLM group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective effects against BLM-induced PF in mice. Our data may provide the basis for the development of novel targeted therapeutic strategies for PF. PMID:27959382

  2. Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats.

    Science.gov (United States)

    Altintas, Nejat; Erboga, Mustafa; Aktas, Cevat; Bilir, Bulent; Aydin, Murat; Sengul, Aysun; Ates, Zehra; Topcu, Birol; Gurel, Ahmet

    2016-02-01

    We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate

  3. Boswellic acids extract attenuates pulmonary fibrosis induced by bleomycin and oxidative stress from gamma irradiation in rats

    Directory of Open Access Journals (Sweden)

    Mansour Somaya

    2011-09-01

    Full Text Available Abstract Background Interstitial pulmonary fibrosis is characterized by an altered cellular composition of the alveolar region with excessive deposition of collagen. Lung inflammation is also common in pulmonary fibrosis. This study aims to test the inhibition of 5-lipooxygenase (5-LOX by boswellic acid (BA extract in an experimental model of pulmonary fibrosis using bleomycin (BL. Methods Boswellic acid extract (1 g/kg was force-fed to rats seven days prior to administration of BL or gamma irradiation or both. BL (0.15 U/rat in 25 μl of 0.9% normal saline (NS or 0.9% NS alone was administered intratracheally. Rats were exposed to two fractionated doses of gamma irradiation (0.5 Gy/dose/week with a gamma cell-40 (Cesium-137 irradiation units, Canada during the last two weeks of the experiment. BA was administered during BL or irradiation treatment or both. After the animals were sacrificed, bronchoalveolar lavage was performed; lungs were weighed and processed separately for biochemical and histological studies. Results In rats treated with BL, levels of transforming growth factor-β1 (TGF-β1 and tumor necrosis factor-α (TNF-α were significantly elevated (P = 0.05 and P = 0.005. Hydroxyproline was highly and extensively expressed. Immunoreactive compounds were abundantly expressed, represented in the levels of macrophages infiltrate, accumulation of eosinophils and neutrophils in the lung as well as the aggregation of fibroblasts in the fibrotic area. The levels of lipoxygenase enzyme activity were significantly increased (P = 0.005. Antioxidant activities measured in BL-treated rats deteriorated, coupled with the elevation of both levels of plasma lipid peroxide (LP content and bronchoalveolar lavage lactate dehydrogenase activity. BA-treated rats had reduced number of macrophages, (P = 0.01, neutrophils in bronchoalveolar lavage (P = 0.01 and protein (P = 0.0001. Moreover, the hydroxyproline content was significantly lowered in BA

  4. Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: Possible role of oxidative stress in the pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Cheng-Fan, E-mail: zhouchengfan@sohu.com [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Zhou, Deng-Chuan [Department of Emergency Medicine and Critical Care Medicine, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Zhang, Jia-Xiang; Wang, Feng; Cha, Wan-Sheng [Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Wu, Chang-Hao [Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey (United Kingdom); Zhu, Qi-Xing, E-mail: zqxing@yeah.net [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China)

    2014-06-15

    Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4 weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100 mg/kg body weight/day) injected daily for 3 weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice. - Highlights: • We provided the first evidence that EMT occurred in BLM-induced skin fibrosis. • Epithelial cells superficial to the BMZ underwent

  5. Meiotic and Mitotic Phenotypes Conferred by the blm1-1 Mutation in Saccharomyces cerevisiae and MSH4 Suppression of the Bleomycin Hypersusceptibility

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    Carol Wood Moore

    2003-01-01

    Full Text Available Abstract: Oxidative damage can lead to a number of diseases, and can be fatal. The blm1-1 mutation of Saccharomyces cerevisiae confers hypersusceptibility to lethal effects of the oxidative, anticancer and antifungal agent, bleomycin. For the current report, additional defects conferred by the mutation in meiosis and mitosis were investigated. The viability of spores produced during meiosis by homozygous normal BLM1/BLM1, heterozygous BLM1/blm1-1, and homozygous mutant blm1-1/blm1-1 diploid strains was studied and compared. Approximately 88% of the tetrads derived from homozygous blm1-1/blm1-1 mutant diploid cells only produced one or two viable spores. In contrast, just one tetrad among all BLM1/BLM1 and BLM1/blm1-1 tetrads only produced one or two viable spores. Rather, 94% of BLM1/BLM1 tetrads and 100% of BLM1/blm1-1 tetrads produced asci with four or three viable spores. Thus, at least one copy of the BLM1 gene is essential for the production of four viable spores after meiosis. During mitotic growth, mutant blm1-1 strains grew at reduced rates and produced cells with high frequencies of unusual morphologies compared to wild-type strains. These results indicated BLM1 is also essential for normal mitotic growth. We also investigated the suppression by the MSH4 gene, a meiosis-specific MutS homolog, of the bleomycin hypersusceptibility of blm1-1 mutant cells, and the relationship of MSH4 to BLM1. We screened a genomic library, and isolated the MSH4 gene on the basis of its ability to suppress lethal effects of bleomycin in blm1-1 cells. However, genetic mapping studies indicated that BLM1 and MSH4 are not the same gene. The possibility that chromosomal nondisjunction could be the basis for the inability of blm1-1/blm1-1 mutant cells to produce four viable spores after meiosis is discussed.

  6. Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with Gorlin-Goltz syndrome.

    Science.gov (United States)

    Kis, Erika; Baltás, Eszter; Kinyó, Agnes; Varga, Erika; Nagy, Nikoletta; Gyulai, Rolland; Kemény, Lajos; Oláh, Judit

    2012-11-01

    Gorlin-Goltz syndrome is a rare multisystemic disease, characterized by numerous basal cell carcinomas. The ideal approach for patients with the syndrome would be a treatment with a high cure rate, minimal scarring, short healing time and mild side-effects. Electrochemo-therapy is a novel therapeutic option that ablates tumours with electrical current and simultaneously administered anticancer drugs. Three patients with Gorlin-Goltz syndrome were treated with electrochemotherapy using intravenous bleomycin. Clinical response was obtained in 98 (99%) of the lesions, 86 (87%) of them showed complete response. In 2 tumours, regression was confirmed with histological examination. Long-term cosmetic results were excellent. We consider electrochemotherapy to be an additional tool in the therapeutic armamentarium for Gorlin-Goltz syndrome, and suggest using it as early as possible in selected patients to avoid disfiguring scarring.

  7. Extensive deep vein thrombosis as a complication of testicular cancer treated with the BEP protocol (bleomycin, etoposide and cisplatin: case report

    Directory of Open Access Journals (Sweden)

    Max Senna Mano

    Full Text Available CONTEXT: There are no reports in the literature of massive deep venous thrombosis (DVT associated with cisplatin, bleomycin and etoposide (BEP cancer treatment. CASE REPORT: The patient was a 18-year-old adolescent with a nonseminomatous germ cell tumor of the right testicle, with the presence of pulmonary, liver, and massive retroperitoneal metastases. Following radical orchiectomy, the patient started chemotherapy according to the BEP protocol (without routine prophylaxis for DVT. On day 4 of the first cycle, massive DVT was diagnosed, extending from both popliteal veins up to the thoracic segment of the inferior vena cava. Thrombolytic therapy with streptokinase was immediately started. On day 2 of thrombolytic therapy, the patient developed acute renal failure, due to extension of the thrombosis to the renal veins. Streptokinase was continued for six days and the outcome was remarkably favorable.

  8. Treatment of bleomycin-induced pulmonary fibrosis by inhaled tacrolimus-loaded chitosan-coated poly(lactic-co-glycolic acid) nanoparticles.

    Science.gov (United States)

    Lee, Changkyu; Seo, Jisoo; Hwang, Ha Shin; Thao, Le Quang; Lee, Seunghyun; Lee, Eun Seong; Lee, Eun Hee; Choi, Han-Gon; Youn, Yu Seok

    2016-03-01

    Pulmonary fibrosis is a chronic lung disease characterized by inflammation and collagen deposition, with an estimated mortality rate exceeding 70%. Here, we evaluated the therapeutic effectiveness of inhaled tacrolimus-loaded chitosan-coated poly(lactic-co-glycolic acid) nanoparticles (chitosan TAC PLGA-NPs) in a bleomycin-induced pulmonary fibrosis mouse model. Chitosan TAC PLGA-NPs were fabricated using an o/w emulsification diffusion method, and uncoated TAC PLGA-NPs and chitosan TAC PLGA-NPs were spherical with approximate diameters of 320 and 441 nm, respectively. The zeta potential of chitosan TAC PLGA-NPs (+13.6 mV) was increased significantly by chitosan-coating versus uncoated TAC PLGA-NPs (-28.3 mV). The incorporation efficiency of tacrolimus was 37.7%, and the tacrolimus was gradually released until about 5 day. Direct inhalation of chitosan TAC PLGA-NPs (TAC 180 μg/mouse) twice a week produced marked anti-fibrotic efficacy in mice with bleomycin-induced pulmonary fibrosis, which was much better than the efficacy resulting from daily oral administration (TAC 300 μg/mouse) on the basis of hematoxylin/eosin and Masson's trichrome staining assessments. Imaging of lung deposition showed that chitosan TAC PLGA-NPs were located well in the lungs and gradually faded over 96 h. The pulmonary delivery of tacrolimus could be therapeutically efficacious for treating pulmonary fibrosis. TAC-loaded PLGA nanoparticles should be considered to be an efficient sustained-release type inhalation system that reduces administration frequency and relevant side effects.

  9. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

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    Ken Murakami

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

  10. MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Stefen A Boehme

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

  11. 应用博莱霉素治疗儿童颜面部海绵状血管瘤%Treatment of orofacial cavernous haemangioma in children by bleomycin

    Institute of Scientific and Technical Information of China (English)

    陆东辉; M.Jiddawei

    2003-01-01

    目的应用博莱霉素(Bleomycin)治疗儿童颜面部海绵状血管瘤并观察其疗效.方法对58例儿童颜面部血管瘤病灶采用瘤体直接注射Bleomycin.结果对临床范围小于2cm×2cm血管瘤,Bleomycin治愈率可达85%,对大于4×4cm血管瘤,经多次注射瘤体缩小,亦有显著疗效.结论单一使用Bleomycin治疗儿童颜面部海绵状血管瘤,具有疗效显著,副作用小,安全可靠等特点.

  12. Persistent improved results after adding vincristine and bleomycin to a cyclophosphamide/hydroxorubicin/Vm-26/prednisone combination (CHVmP) in stage III-IV intermediate- and high-grade non-Hodgkin's lymphoma. The EORTC Lymphoma Cooperative Group.

    Science.gov (United States)

    Meerwaldt, J H; Carde, P; Somers, R; Thomas, J; Kluin-Nelemans, J C; Bron, D; Noordijk, E M; Cosset, J M; Bijnens, L; Teodorovic, I; Hagenbeek, A

    1997-01-01

    CHOP has been and still is regarded by many as the 'standard' treatment of advanced non-Hodgkin's lymphoma. In 1980 the EORTC Lymphoma Cooperative Group started a study to evaluate the addition of vincristine and bleomycin to its standard four-drug combination chemotherapy, CHVmP (cyclophosphamide, hydroxorubicin, Vm-26, prednisone). Eligible patients were stage III or IV, intermediate- to high-grade non-Hodgkin's lymphoma (Working Formulation E-I). One-hundred-eighty-nine patients were entered, of whom 140 were eligible and evaluable. A previous report showed an improved response rate and failure-free survival (FFS) and overall survival for the combination CHVmP-VB. At ten years, the outcome still favors the addition of vincristine and bleomycin. The FFS was 34% vs. 23% and the overall survival 34% vs 22%. This difference was mainly due to a difference in CR rate (74% vs. 49%), Relapse-free survival for patients reaching a CR was the same in both arms. When the patients were grouped according to the International Prognostic Factor Index, no statistically significant difference could be observed in favor of one treatment within either group. This trial clearly demonstrates the benefit gained by the addition of vincristine and bleomycin to 'standard' chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma.

  13. A genome-wide screen in Saccharomyces cerevisiae reveals altered transport as a mechanism of resistance to the anticancer drug bleomycin.

    Science.gov (United States)

    Aouida, Mustapha; Pagé, Nicolas; Leduc, Anick; Peter, Matthias; Ramotar, Dindial

    2004-02-01

    The potent DNA damaging agent bleomycin (BLM) is highly effective for treating various cancers, although, in certain individuals, the development of cellular resistance to the drug can severely diminish its antineoplastic properties. We performed two independent genome-wide screens using a Saccharomyces cerevisiae mutant collection to isolate variants exhibiting either sensitivity or resistance to BLM. This procedure reproducibly identified a relatively large collection of 231 BLM-hypersensitive mutants, representing genes belonging to diverse functional groups. In contrast, only five BLM-resistant mutants could be recovered by our screens. Among these latter mutants, three were deleted for genes involved in plasma membrane transport, including the L-carnitine transporter Agp2, as well as the kinases Ptk2 and Sky1, which are involved in regulating polyamine transport. We further showed that Agp2 acts as a transporter of BLM and that overexpression of this transporter significantly enhances BLM-induced cell killing. Our data strongly implicate membrane transport as a key determinant in BLM resistance in yeast. This finding is critical, given that very little is known about BLM transport in human cells. Indeed, characterization of analogous mechanisms in humans may ultimately lead to enhancement of the antitumor properties of BLM.

  14. Aerosolized STAT1 Antisense Oligodeoxynucleotides Decrease the Concentrations of Inflammatory Mediators in Bronchoalveolar Lavage Fluid in Bleomycin-Induced Rat Pulmonary Fibrosis

    Institute of Scientific and Technical Information of China (English)

    Ming Zeng; Bin Liao; Chen Zhu; Wenjun Wang; Xiaoqin Zhan; Xianming Fan

    2008-01-01

    It has been demonstrated that alveolar macrophages (AMs) play a key role in the pathogenesis of pulmonary fibrosis by releasing a variety of cytokines and inflammatory mediators. In addition, abnormal signal transducer and activator of transcription-1 (STAT1) activation in AMs may play a pivotal role in the process of alveolitis and pulmonary fibrosis. In this study, we transfected STAT1 antisense oligodeoxynucleotide (ASON) into rats by aerosolization, and then investigated the effect of STAT1 ASON on inflammatory mediators such as TGF-β, PDGF and TNF-α in bronchoalveolar lavage fluid (BALF) from rats with bleomycin (BLM)-induced rat pulmonary fibrosis. Our results showed that STAT1 ASON by aerosolization could enter into lung tissues and AMs. STAT1 ASON could inhibit mRNA and protein expressions of STATI and ICAM-1 in AMs of rat with pulmonary fibrosis, and had no toxic side effect on liver and kidney. Aerosolized STAT1 ASON could ameliorate the alveolitis through inhibiting the secretion of inflammatory mediators in BLM-induced rat pulmonary fibrosis. These results suggest that aerosolized STAT1 ASON might be considered as a promising new strategy in the treatment of pulmonary fibrosis. Cellular & Molecular Immunology. 2008;5(3):219-224.

  15. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats.

    Science.gov (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi

    2016-03-01

    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  16. Dose evaluation of therapeutic radiolabeled bleomycin complexes based on biodistribution data in wild-type rats:Effect of radionuclides in absorbed dose of different organs

    Institute of Scientific and Technical Information of China (English)

    Hassan Yousefnia; Samaneh Zolghadri; Amir Reza Jalilian; Mohammad Ghannadi-Maragheh

    2015-01-01

    Bleomycins (BLMs), as tumor-seeking antibiotics, have been used for over 20 years in treatment of several types of cancers. Several radioisotopes are used in radiolabeling of BLMs for therapeutic and diagnostic purpos-es. An important points in developing new radiopharmaceuticals, especially therapeutic agents, is the absorbed dose delivered in critical organs. In this work, absorbed dose to organs after injection of 153Sm-, 177Lu-and 166Ho-labeled BLM was investigated by radiation dose assessment resource (RADAR) method based on biodis-tribution data in wild-type rats. The absorbed dose effect of the radionuclides was evaluated. The maximum absorbed dose for the complexes was observed in the kidneys, liver and lungs. For all the radiolabeled BLMs, bone and red marrow received considerable absorbed dose. Due to the high energy beta particles emitted by 166Ho, higher absorbed dose is observed for 166Ho-BLM in the most organs. The reported data can be useful for the determination of the maximum permissible injected activity of the radiolabeled BLMs in the treatment planning programs.

  17. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice

    Science.gov (United States)

    Chow, Leola N.; Schreiner, Petra; Ng, Betina Y. Y.; Lo, Bernard; Hughes, Michael R.; Scott, R. Wilder; Gusti, Vionarica; Lecour, Samantha; Simonson, Eric; Manisali, Irina; Barta, Ingrid; McNagny, Kelly M.; Crawford, Jason; Webb, Murray; Underhill, T. Michael

    2016-01-01

    Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis. PMID:26998906

  18. Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltration.

    Science.gov (United States)

    Ishida, Yuko; Kimura, Akihiko; Kondo, Toshikazu; Hayashi, Takahito; Ueno, Masaya; Takakura, Nobuyuki; Matsushima, Kouji; Mukaida, Naofumi

    2007-03-01

    We investigated the pathogenic roles of CC chemokine ligand (CCL)3 and its receptors, CC chemokine receptor (CCR)1 and CCR5, in bleomycin (BLM)-induced pulmonary fibrosis (PF). An intratracheal injection of BLM into wild-type (WT) mice caused a massive infiltration of granulocytes and macrophages, followed by the development of diffuse PF with fibrocyte accumulation. Intrapulmonary CCL3 expression was enhanced rapidly and remained at elevated levels until PF developed. Moreover, CCL3 protein was detected mainly in infiltrating granulocytes and macrophages, whereas transforming growth factor-beta1 protein was detected in macrophages and myofibroblasts. Compared with WT mice, collagen accumulation was reduced in CCL3(-/-) and CCR5(-/-) but not CCR1(-/-) mice. Moreover, the BLM-induced increases in intrapulmonary macrophage and fibrocyte numbers were attenuated in CCL3(-/-) and CCR5(-/-) but not CCR1(-/-) mice, although BLM increased bone marrow (BM) fibrocyte number to a similar extent in these strains. BM transplantation from CCR5(-/-) to WT, but not that from WT to CCR5(-/-) mice, recapitulated the phenotypes in CCR5(-/-) mice. Furthermore, CCR5(+/-) mice exhibited a significant reduction in BLM-induced fibrotic changes. These results demonstrated that locally produced CCL3 was involved in BLM-induced recruitment of BM-derived macrophages and fibrocytes, main producers of transforming growth factor-beta1, and subsequent development of PF by interacting mainly with CCR5.

  19. High-dose-rate brachytherapy with local injection of bleomycin for N0 oral tongue cancer. Possibilities of the control of tumor implant by inserting applicators and the decrease in tumor dose

    Energy Technology Data Exchange (ETDEWEB)

    Ohga, Saiji; Uehara, Satoru [National Kyushu Medical Center Hospital, Fukuoka (Japan); Miyoshi, Makoto [Kitakyushu Municipal Medical Center Hospital, Fukuoka (Japan); Jingu, Kenichi [Fukuoka Univ. (Japan). School of Medicine

    2003-01-01

    Twenty-eight patients with N0 oral tongue cancer were treated with high-dose-rate (HDR) interstitial brachytherapy combined with local injection of bleomycin between December 1997 and June 2001 at the Department of Radiology, National Kyushu Medical Center Hospital. A median dose of 5 mg of bleomycin was injected locally, and 16-20 Gy was delivered to the area surrounding applicators for control of the tumor implant during the initial two days. The two-year local recurrence-free survival rate was 96% [T1, 2: 100% (8/8, 15/15), T3: 80% (4/5)]. The two-year secondary neck node metastasis rate was 7.1% [T1: 12.5% (1/8), T2: 6.7% (1/15), T3: 0% (0/5)]. There were no tumor implants in any patients. We tried to decrease the minimal tumor dose step by step. The groups with median minimal tumor doses of 60 Gy, 50 Gy, and 40 Gy had local recurrence rates of 12.5% (1/8), 0% (0/14), and 0% (0/6), respectively. Local recurrence rates were not increased by decreasing the minimal tumor dose. Two patients (7%) had secondary neck node metastasis. Late adverse effects were tongue ulcer: 11% (3/28), oral floor ulcer: 4% (1/28), and osteonecrosis: 4% (1/28). These results suggest that control of the tumor implant and the decrease in minimal tumor dose below 60 Gy may be possible with the local injection of bleomycin and delivery of doses to the area surrounding the applicators when N0 tongue cancer is treated using {sup 192}Ir-HDR brachytherapy. (author)

  20. Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

    Directory of Open Access Journals (Sweden)

    Hong-Mei Yang

    2017-02-01

    Full Text Available Bleomycin (BLM, a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22 tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

  1. Distribution of cells labelled by a novel somatic stem cell-recognizing antibody (A3) in pulmonary genesis and bleomycin induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Hori, M; Juniantito, V; Izawa, T; Ichikawa, C; Tanaka, M; Tanaka, K; Takenaka, S; Kuwamura, M; Yamate, J

    2013-05-01

    Stem cells play important roles in organogenesis and remodelling after tissue injury. A monoclonal antibody (A3) has been produced against rat somatic stem cells. The present study investigated the distribution of cells labelled by A3 in the lung of fetal, neonatal and adult rats, as well as in the lung of rats with bleomycin (BLM) induced pulmonary fibrosis. In developing fetal lungs, A3(+) interstitial cells were present around the bronchi/bronchioles and arterioles, while in neonatal and adult lungs, the A3 reactivity of the interstitial cells gradually disappeared and instead, vascular endothelial cells in alveolar capillaries and arterioles expressed A3. By double immunofluorescence labelling, the A3(+) interstitial cells also expressed vimentin (a mesenchymal marker) and CD34 (a marker of immature mesenchymal cells), indicating that the interstitial cells were immature mesenchymal cells concentrated in organs as precursors to cells of connective tissues. A3(+)endothelial cells were co-expressed RECA-1 (a marker of rat endothelial cells) and A3 was localized to the cell membrane and cytoplasm of these cells by immunoelectron microscopy. In BLM induced fibrotic lesions, there were many A3(+) cells, which also expressed vimentin or RECA-1 by dual immunofluorescence labelling. There were few CD34(+)/A3(+) double positive cells. No cells co-expressed A3 and α-smooth muscle actin (a marker of well-differentiated myofibroblastic cells). Although the detailed properties of cells labelled by A3 remain to be discovered, A3 would appear to be a useful marker of immature mesenchymal cells and vascular endothelial cells in developing lungs and in pulmonary fibrosis.

  2. Effect of antisense TIMP-1 cDNA on the expression of TIMP-1 and MMP-2 in lung tissue with pulmonary fibrosis induced by bleomycin.

    Science.gov (United States)

    Tang, Haiying; Mao, Jingwei; Gao, Lili; Liu, Jia; Wu, Taihua

    2013-01-01

    The aim of this study was to observe the effect of antisense tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) cDNA on the concentration of hydroxyproline (HYP) and the expression of TIMP-1 and matrix metalloproteinase-2 (MMP-2) in the lung tissue of rats with bleomycin (BLM)‑induced pulmonary fibrosis. Sprague-Dawley rats were randomly divided into 5 groups: the control, pulmonary fibrosis model, sense TIMP-1 transfection, antisense TIMP-1 transfection and empty vector transfection groups. For the transfection groups, following the intratracheal injection of BLM on days 1, 3, 7, 14, 28 and 60, the rats were treated with retroviral vectors and sacrificed on day 28. The control and pulmonary fibrosis groups were treated with normal saline at the same time‑points. The concentration of HYP and the expression levels of TIMP-1 and MMP-2 in the lung tissue were detected. The HYP concentration and lung tissue TIMP-1 expression levels of the antisense TIMP-1 group decreased significantly on days 1 and 3 compared with those of the empty vector and pulmonary fibrosis groups at the same time-points (Ppulmonary fibrosis groups on days 7, 14, 28 and 60. The lung expression levels of MMP-2 in all groups, with the exception of the control group, had no significant differences at all time-points (P>0.05). Antisense TIMP-1 cDNA retroviral vectors are able to suppress the development of pulmonary fibrosis in the early stages.

  3. Atomic resolution structure of EhpR: phenazine resistance in Enterobacter agglomerans Eh1087 follows principles of bleomycin/mitomycin C resistance in other bacteria

    Directory of Open Access Journals (Sweden)

    Itzen Aymelt

    2011-08-01

    Full Text Available Abstract Background The phenazines are redox-active secondary metabolites that a large number of bacterial strains produce and excrete into the environment. They possess antibiotic activity owing to the fact that they can reduce molecular oxygen to toxic reactive oxygen species. In order to take advantage of this activity, phenazine producers need to protect themselves against phenazine toxicity. Whereas it is believed that phenazine-producing pseudomonads possess highly active superoxide dismutases and catalases, it has recently been found that the plant-colonizing bacterium Enterobacter agglomerans expresses a small gene ehpR to render itself resistant towards D-alanyl-griseoluteic acid, the phenazine antibiotic produced by this strain. Results To understand the resistance mechanism installed by EhpR we have determined its crystal structure in the apo form at 2.15 Å resolution and in complex with griseoluteic acid at 1.01 Å, respectively. While EhpR shares a common fold with glyoxalase-I/bleomycin resistance proteins, the ligand binding site does not contain residues that some related proteins employ to chemically alter their substrates. Binding of the antibiotic is mediated by π-stacking interactions of the aromatic moiety with the side chains of aromatic amino acids and by a few polar interactions. The dissociation constant KD between EhpR and griseoluteic acid was quantified as 244 ± 45 μM by microscale thermophoresis measurements. Conclusions The data accumulated here suggest that EhpR confers resistance by binding D-alanyl-griseoluteic acid and acting as a chaperone involved in exporting the antibiotic rather than by altering it chemically. It is tempting to speculate that EhpR acts in concert with EhpJ, a transport protein of the major facilitator superfamily that is also encoded in the phenazine biosynthesis operon of E. agglomerans. The low affinity of EhpR for griseoluteic acid may be required for its physiological function.

  4. IL-21 induction of CD4+ T cell differentiation into Th17 cells contributes to bleomycin-induced fibrosis in mice.

    Science.gov (United States)

    Lei, Ling; Zhong, Xiao-Ning; He, Zhi-Yi; Zhao, Cheng; Sun, Xue-Jiao

    2015-04-01

    Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Th17 cells and interleukin-17 (also called IL-17A) have been found to be increased in peripheral blood and skin in patients with SSc. IL-21 is a potent inducer of Th17 differentiation that is produced by activated T cells, and whose relationship with Th17 cells in SSc is unclear. Here, using a bleomycin (BLM)-induced mouse model of skin fibrosis, we detected the frequency of CD4+/IL-17+ (Th17) cells, CD4+/IL-21+ T cells and IL-21+ Th17 cells in peripheral blood, skin and lungs, as well as the serum content of IL-17A and IL-21. In addition, we assessed the differentiation of CD4+ T cells cultured from these mice into Th17 cells in response to treatment with IL-21. Compared with the control mice, Th17 cell counts and IL-17A levels were significantly increased and correlated with inflammatory and fibrotic indices in the skin and lungs of the BLM-induced fibrosis mice. Moreover, serum levels of CD4+/IL-21+ T cells, IL-21+ Th17 cells, and IL-21 were significantly increased in these mice, and correlated positively with serum levels of Th17 cells. In vitro experiments showed that IL-21 treated CD4+ T cells derived from BLM-induced mice differentiated into Th17 cells. Our results indicate that Th17 cells and IL-17A contributes to inflammatory and fibrotic processes in the skin and lungs in a BLM-induced mouse model of SSc. Moreover, the expansion of the Th17 cell population may be subsequent to IL-21 promotion of the differentiation of CD4+ T cells in these mice.

  5. Second-line chemotherapy with bleomycin, methotrexate, and vinorelbine (BMV) for patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) pretreated with a cisplatin-containing regimen: a phase II study.

    Science.gov (United States)

    Moroni, M; Giannetta, L; Gelosa, G; Secondino, S; Chillura, G; Colombo, E; Siena, S

    2003-08-01

    We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m2, and vinorelbine 30 mg/m2) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) 127%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.

  6. Induced pluripotent stem cells inhibit bleomycin-induced pulmonary fibrosis in mice through suppressing TGF-β1/Smad-mediated epithelial to mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Yan Zhou

    2016-11-01

    Full Text Available Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS cells have been considered as an ideal resource for stem cell-based therapy. Although an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF-β1 signaling pathway, and epithelial to mesenchymal transition (EMT during bleomycin (BLM-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2 to its tissue inhibitor -2 (TIMP-2 and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3 and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse

  7. 博莱霉素联合局部热疗治疗恶性胸腔积液的临床观察%Clinical observation of bleomycin combined with local thermotherapy in the treatment of malignant pleural effusion

    Institute of Scientific and Technical Information of China (English)

    周洋; 黄河; 张家洪; 龚建化

    2014-01-01

    Objective To observe the clinical effect of bleomycin combined with local thermotherapy in the treatment of NSCLC patients with malignant pleural effusion. Methods 50 NSCLC patients with malignant pleural effusion were randomly divided into two groups. All patients were treated with thoracentesis and inserted central ve-nous catheter to drainage pleural effusion. After exhaustion of pleural effusion, the control group was treated with ble-omycin by pleural perfusion, and the experiment group was treated with local thermotherapy on the base of the control group. The treatment, side effect and quality of life were compared. Results After the treatment, the KPS scores of living quality and the total effective rate of controlling pleural effusion were better in the experiment group than in the control group (P<0. 05), and the side effect was significant lower in the experiment group than in the control group (P<0. 05). Conclusion Bleomycin combined with local thermotherapy has a synergistic effect in the treatment of NSCLC with malignant pleural effusion.%目的:观察博莱霉素联合局部热疗治疗非小细胞肺癌( NSCLC)恶性胸腔积液的临床疗效。方法将50例NSCLC恶性胸腔积液的患者随机分为两组,采用胸腔穿刺术置入中心静脉导管引流胸腔积液,待排尽胸腔积液后,对照组给予胸腔灌注博莱霉素,实验组在对照组的基础上给予患者局部热疗,比较两组治疗情况、毒副反应及生活质量改善情况。结果两组患者治疗后,实验组患者的生活质量KPS评分及控制胸水的总有效率均明显高于对照组(P<0.05),且不良反应明显少于对照组(P<0.05)。结论博莱霉素联合局部热疗治疗NSCLC恶性胸腔积液具有协同作用,值得临床推广。

  8. Experimental Study on Effect of Compound Biejia Ruangan Prescription(复方鳖甲软肝方) on High-Resolution Computerized Tomographic Images in Bleomycin Induced Pulmonary Fibrosis Rats

    Institute of Scientific and Technical Information of China (English)

    张东伟; 王继峰; 牛建昭; 高宝华; 李贡宇

    2003-01-01

    Objective: To study the therapeutic effect of Compound Biejia Ruangan prescription (CBRP) on rat model with pulmonary fibrosis induced by bleomycin. Methods: Fifty-four male Sprague-Dawley rats were randomly divided into 6 groups (9 rats in each group). From the first day to the 28th day of the experiment, except to those in the sham-model control group that were treated with normal saline, the same amount of bleomycin injection as the normal saline given to the control group was given through endotracheal instillation to all the rats in all the other groups. From the 29th day of the modeling, CBRP solution of different dosages was respectively injected into the rats in the high, moderate and low CBRP dose group, while equal volume of normal saline was given to those in the sham-model control group and the model control group, and an equal volume of prednisone solution was given to rats in the prednisone group. On the 80th day, the high-resolution computerized tomographic (HRCT) images were observed on an equal footing, and HRCT-pathology was correlatively studied. Results: Different HRCT pathological changes were shown in the rats with pulmonary fibrosis, such as lung consolidation, thickening of interlobular septum and interlobular mesenchyma as well as lobular deformation, nodule shadow, abnormal brochiovascular tract, thickened pleura with irregular junction and polished glass-like dense shadows. Honeycomb lung was observed in some cases. Pathological sections showed fibrotic proliferation of lung tissues and noticeable pulmonary interstitial fibrosis. CBRP could improve HRCT images of rats with pulmonary fibrosis, and lower fibrotic proliferation of the lung tissue.Conclusion: CBRP plays its therapeutic role possibly through its effect on the structure of the lung in rats with pulmonary fibrosis.

  9. Antagonistic effect of vitamin E and taurine on mutagenesis of bleomycin%维生素E、牛黄酸等抗氧化剂对博莱霉素致突变性的拮抗作用

    Institute of Scientific and Technical Information of China (English)

    宗传龙; 周白云; 郭淼; 刘景升; 李效良

    2004-01-01

    目的观察抗氧化剂(维生素E、牛黄酸、二甲亚砜和维生素C)针对博莱霉素(Bleomycin,BLM)的拮抗作用.方法在人外周血淋巴细胞培养物中注入一定剂量的BLM并一定剂量的抗氧化剂,然后观察淋巴细胞的姐妹染色单体交换率(sister chromatid exchanges,SCE rate)的变化.结果维生素E浓度为5μl/ml时,可显著地拮抗BLM(28.6 nmol/ml)的致突变作用(P<0.05);而维生素E浓度为10μl/ml时,可极显著地拮抗BLM的作用(P<0.01);当加入牛黄酸的终浓度为100和200μg/rl时,均可显著地拮抗BLM(28.6nmol/m1)的致突变作用(P<0.05).结论一定剂量的维生素E和牛黄酸对BLM的致突变性存在着拮抗作用.%Objective: To observe antagonistic effect of vitamin E, taurine and some other antioxidants on mutagenesis of bleomycin. Methods: The changes of SCE (sister chromatid exchanges) rates of human blood lymphocytes were observed when vitamin E and taurine had been added into the culture medium for human blood lymphocytes. Results: Vitamin E(5μl/ml)or taurine(100 or 200μg/ml) had a significant effect on lowering SCE of lymphocytes treated by BLM(28.6 nmol/rml) (P <0.05); While vitamin E( 10μl/ml) has a very significant effect on lowering SCE of lymphocytes treated by BLM(28.6 nmol/ml) (P <0.01). Conclusion: A certain dosage of either vitamin E or taurine has a significant effect on antagonizing mutagenesis of BLM by lowering SCE of human blood lymphocytes.

  10. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

    Science.gov (United States)

    del Río, Carmen; Navarrete, Carmen; Collado, Juan A; Bellido, M Luz; Gómez-Cañas, María; Pazos, M Ruth; Fernández-Ruiz, Javier; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Cantarero, Irene; Muñoz, Eduardo

    2016-02-18

    Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.

  11. Non-apoptotic programmed cell death with paraptotic-like features in bleomycin-treated plant cells is suppressed by inhibition of ATM/ATR pathways or NtE2F overexpression.

    Science.gov (United States)

    Smetana, Ondřej; Široký, Jiří; Houlné, Guy; Opatrný, Zdeněk; Chabouté, Marie-Edith

    2012-04-01

    In plants, different forms of programmed cell death (PCD) have been identified, but they only partially correspond to those described for animals, which is most probably due to structural differences between animal and plant cells. Here, the results show that in tobacco BY-2 cells, bleomycin (BLM), an inducer of double-strand breaks (DSBs), triggers a novel type of non-apoptotic PCD with paraptotic-like features. Analysis of numerous PCD markers revealed an extensive vacuolization, vacuolar rupture, and chromatin condensation, but no apoptotic DNA fragmentation, fragmentation of the nuclei, or sensitivity to caspase inhibitors. BLM-induced PCD was cell cycle regulated, occurring predominantly upon G(2)/M cell cycle checkpoint activation. In addition, this paraptotic-like PCD was at least partially inhibited by caffeine, a known inhibitor of DNA damage sensor kinases ATM and ATR. Interestingly, overexpression of one NtE2F transcriptional factor, whose homologues play a dual role in animal apoptosis and DNA repair, reduced PCD induction and modulated G(2)/M checkpoint activation in BY-2 cells. These observations provide a solid ground for further investigations into the paraptotic-like PCD in plants, which might represent an ancestral non-apoptotic form of PCD conserved among animals, protists, and plants.

  12. Redox activation of Fe(III)-thiosemicarbazones and Fe(III)-bleomycin by thioredoxin reductase: specificity of enzymatic redox centers and analysis of reactive species formation by ESR spin trapping.

    Science.gov (United States)

    Myers, Judith M; Cheng, Qing; Antholine, William E; Kalyanaraman, Balaraman; Filipovska, Aleksandra; Arnér, Elias S J; Myers, Charles R

    2013-07-01

    Thiosemicarbazones such as Triapine (Tp) and Dp44mT are tridentate iron (Fe) chelators that have well-documented antineoplastic activity. Although Fe-thiosemicarbazones can undergo redox cycling to generate reactive species that may have important roles in their cytotoxicity, there is only limited insight into specific cellular agents that can rapidly reduce Fe(III)-thiosemicarbazones and thereby promote their redox activity. Here we report that thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR) have this activity and that there is considerable specificity to the interactions between specific redox centers in these enzymes and various Fe(III) complexes. Site-directed variants of TrxR1 demonstrate that the selenocysteine (Sec) of the enzyme is not required, whereas the C59 residue and the flavin have important roles. Although TrxR1 and GR have analogous C59/flavin motifs, TrxR is considerably faster than GR. For both enzymes, Fe(III)(Tp)2 is reduced faster than Fe(III)(Dp44mT)2. This reduction promotes redox cycling and the generation of hydroxyl radical (HO) in a peroxide-dependent manner, even with low-micromolar levels of Fe(Tp)2. TrxR also reduces Fe(III)-bleomycin and this activity is Sec-dependent. TrxR cannot reduce Fe(III)-EDTA at significant rates. Our findings are the first to demonstrate pro-oxidant reductive activation of Fe(III)-based antitumor thiosemicarbazones by interactions with specific enzyme species. The marked elevation of TrxR1 in many tumors could contribute to the selective tumor toxicity of these drugs by enhancing the redox activation of Fe(III)-thiosemicarbazones and the generation of reactive oxygen species such as HO.

  13. 香菇多糖对平阳霉素抑制血管内皮瘤细胞的增殖的影响%Effects of lentinan on bleomycin A5’s inhibition effects in hemangioma- derivedendothelial cell

    Institute of Scientific and Technical Information of China (English)

    付桂莉; 郑源泉; 卢静静; 黄美莲; 李延

    2014-01-01

    Objective To study the effects of Lentinan on bleomycin A5’s inhibition effects in hemangioma-derived endothelial cell. Methods Hemangioma-derived endothelial cell line EOMA were divided into LTN group (only lentinan treatment), BLE group (only bleomycin A 5 treatment), L+B group (Lentinan and bleomycin A5 treatment) and CON group (no lentinan and bleomycin A5 treatment). Cell proliferation, cell cycle, PI and apoptosis were detected and compared among four groups. Results The differences of absorbance in LBE group was significantly higher than that in L+B group after treatment for d 1-d 7 (P<0.05), but both of them were significantly lower than in CON group and LTN group (P<0.05). The G 0/G 1 stage and apoptosis rate in L+B group was significantly higher than in BLE group(P<0.05), while it was significantly lower in S stage, G 2/M stage and PI(P<0.05). Conclusion Lentinan could significantly promote bleomycin A5’s inhibition effects on hemangioma-derived endothelial cell.%目的:研究香菇多糖对平阳霉素抑制血管内皮瘤细胞的增殖的影响。方法将EOMA小鼠血管内皮瘤细胞分别单用香菇多糖处理(LTN组)、单用平阳霉素处理(BLE组)、香菇多糖联合平阳霉素处理(L+B组)和未做任何处理(CON组),比较4组细胞处理前后细胞增殖和凋亡的差异。结果 CON组和LTN组作用后d 1-d 7的吸光度无显著差异,但均显著高于BLE组和L+B组(P<0.05);L+B组作用后d 1-d7的吸光度显著低于BLE组(P<0.05)。BLE组和L+B组G 0/G1期和凋亡率显著高于CON组和LTN组(P<0.05),S期、G 2/M期和PI显著低于CON组和LTN组(P<0.05);L+B组G 0/G1期和凋亡率显著高于BLE组(P<0.05),S期、G 2/M期和PI显著低于BLE组(P<0.05)。结论香菇多糖可显著增强平阳霉素对小鼠血管内皮瘤细胞抑制增殖及促进凋亡的作用。

  14. 3种材质输液容器对盐酸博来霉素A2和B2的吸附性考察%Study on Adsorbability of Bleomycin Hydrochloride A2 and B2 in 3 Different Kinds of Intravenous Solution Containers

    Institute of Scientific and Technical Information of China (English)

    潘文; 黄天文; 雷宇; 梁宁生; 涂文升

    2012-01-01

    目的:考察非聚氯乙烯(PVC)多层共挤膜输液袋、聚丙烯(PP)输液瓶和玻璃瓶3种材质输液容器对盐酸博来霉素的吸附性.方法:取相同量的盐酸博来霉素加入3种包装材质的2种输液(5%葡萄糖注射液和5%葡萄糖氯化钠注射液)中,混合均匀后分别于0、6、24、48 h时取样,采用高效液相色谱法测定药物浓度,与0h时浓度相比计算相对百分含量.结果:48h时,溶媒分别为5%葡萄糖注射液和5%葡萄糖氯化钠注射液时,在PP输液瓶中,盐酸博来霉素A2、B2相对百分含量分别为90.81%、89.56%和55.65%、82.4%;而在另2种材质包装的2种溶媒中,盐酸博来霉素A2、B2相对百分含量均大于95%.结论:3种材质中,以PP输液瓶对盐酸博来霉素吸附性最强,尤其是在以5%葡萄糖氯化钠注射液为溶媒时;临床使用该药时应避免选用该材质输液瓶.%OBJECTIVE: To investigate the adsorbability of non-polyvinly chloride (NPVC) infusion bags, polypropylene (PP) infusion bags and glass bottles to bleomycin hydrochloride, respectively. METHODS: Bleomycin hydrochloride was separately added into above infusion bags or bottles containing 5% Glucose injection (GS) or 5% Glucose sodium chloride injection (GNS). Samples of drug solutions were collected at 0, 6, 24, 48 hours and analyzed by HPLC methods. Relevant percentage content was calculated, compared with concentration at 0 h. RESULTS: At 48 h, solvent were 5% GS and 5% GNS, and relevant percentage contents of bleomycin hydrochloride A2 and B2 in PP bottles were 90.81% , 89.56% and 55.65% , 82.4%. Relevant percentage contents of bleomycin hydrochloride A2 and B2 in other 2 kinds of container were all more than 95%. CONCLUSION: Among 3 kinds of materials, PP infusion bottle shows the strongest adsorbability, especially for 5% GNS as solvent. PP should not be used for bleomycin hydrochloride.

  15. Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

    Science.gov (United States)

    El-Mallawany, Nader Kim; Kamiyango, William; Slone, Jeremy S; Villiera, Jimmy; Kovarik, Carrie L; Cox, Carrie M; Dittmer, Dirk P; Ahmed, Saeed; Schutze, Gordon E; Scheurer, Michael E; Kazembe, Peter N; Mehta, Parth S

    2016-01-01

    Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7-17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15-50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22-163.90 and 1.60-83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01-90.99 and 1.00-524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84-33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08-0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk

  16. Respuesta de ratones Balb/c frente a ciclofosfamida y bleomicina en el ensayo de la morfología de la cabeza del espermatozoide - Balb/c mice’s response against bleomycin and cyclophosphamide in the head sperm morphology assay

    Directory of Open Access Journals (Sweden)

    Rosario Fernández Luis Alfredo

    2011-02-01

    Full Text Available ResumenEl ensayo de la morfología de la cabeza del espermatozoide permite el estudio del potencial genotóxico de muestras problemas a nivel celular. En este artículo se decidió evaluar y comparar en 16 ratones Balb/c machos por grupo, el efecto de dos sustancias mutagénicas en este ensayo.SummaryThe head sperm morphology assay, allows the study of the genotoxic potencial of samples at the cellular level problems. In this article we decide to evaluate and to compare in 16 Balb/c males mice per group, the effect of two mutagenic substances in these assay, the Cyclophosphamide (CF in dose of 50 mg/kg and the Bleomycin (BL in dose of 20 mg/kg, administered by intraperitoneal route during 5 consecutive days, being sacrificed the animals 35 days after the last administration of the mutagens.

  17. The effect of autologous bone marrow-derived cells mobilized by granulocyte colony stimulating factor on bleomycin-induced lung injury in mice%粒细胞集落刺激因子动员自体骨髓源性细胞对博来霉素致小鼠肺损伤的治疗作用

    Institute of Scientific and Technical Information of China (English)

    姜寒水; 李惠萍; 胡洋; 褚建新; 陈岗; 张容轩; 郑卉

    2009-01-01

    显低于未重建对照组[33.9、(56±13)×10~3、(0.49±0.08)μg/mg、(53.6±8.7)×10~(-3)、(320±98)×10~3、(409±61)×10~3和(288±75)×10~3].重建动员组在第7大肺内BMDC表达的绿色荧光蛋白阳性细胞比例(0.65±0.13)明显高于重建对照组(0.46±0.11).结论 G-CSF动员BMDC对博来霉素所敛肺损伤有一定的保护作用,本实验方法尚不能明显延长小鼠的存活时间.%Objective To investigate the contribution of mobilized autologous bone marrow-derived cells ( BMDC) to lung repair after lung injury induced by bleomycin, and the mechanisms of any protective effects conferred by BMDC. Methods Sixty marrow-reconstructed mice were randomly divided into 2 groups: group A [bleomycin + granulocyte colony stimulating factor( G-CSF) ] and group B (bleomycin +saline). Seventy-five normal mice were randomly divided into 3 groups: group C (bleomycin + G-CSF) :group D (bleomycin + saline) and group N (saline only). Each group was further divided into 3 subgroups,which were sacrificed respectively on days 3, 7 and 14. Therapeutic evaluations were made by means of HE stain, Masson' s trichrome stain, hydroxyproline concentration and pulmonary permeability index. The expressions of TGF-β_1, IFN-γ, MMP-9 and TIMP-1 in the lung tissue were detected by immunohistochemistry. Intrapulmonary BMDC was evaluated by flow cytometry and laser scanning confocal microscope. Another 20 mice were randomly divided into 2 groups including group E ( bleomycin + G-CSF) and group F (bleomycin + saline). The survival time of each mouse was observed without end point Results The alveolitis score ( mean rank 15.3 ) , the pulmonary fibrosis score (46 ±8 ) , the hydroxyproline concentrations (0.44 ±0.09) μg/mg, the TGF-β_1, level (111 ±23), the IFN-γ level (250 ±72) and the MMP-9 level (59±19) were significantly decreased in reconstructed treatment group on day 7 as compared to reconstructed control group, which was respectively (mean rank 28.0) , (73 ± 10) , (0. 52 ±0. 07)

  18. Preventive effects of Citrus reticulata essential oil on bleomycin-induced pulmonary fibrosis in rats and the mechanism%陈皮挥发油对大鼠肺纤维化的干预作用

    Institute of Scientific and Technical Information of China (English)

    周贤梅; 赵阳; 何翠翠; 李建新

    2012-01-01

    化具有干预作用,其作用机制可能是通过调节氧化和抗氧化失衡,降低CTGF蛋白及其mRNA表达,减少胶原沉积以减轻纤维化程度.%OBJECTIVE: To investigate the effects of essential oil of Citrus reticulata (EOCR) on proliferation of human embryonic lung fibroblasts (HELFs),and to explore its protective effects on bleomycin (BLM)-induced lung fibrosis in rats.METHODS: Routinely cultured HELFs during the logarithmic phase of growth were divided into control and treated groups,and applied for evaluation of inhibitory activity using methylthiazol tetrazolium (MTT) assay.A rat model of BLM-induced pulmonary fibrosis was used for the evaluation of antifibrotic effect of EOCR.Forty-two Sprague-Dawley rats were randomly divided into normal group,model group,prednisone group and different doses of EOCR groups.BLM was intratracheally instilled into all the rats except those in the normal group,and EOCR was orally given to BLM-treated rats at doses of 25,50,100 and 200 mg/kg once per day for four weeks.The rats in the normal group were intratracheally administered the same volume of saline.On the 28th day,rats were sacrificed under anesthesia,and the serum and lung tissues were collected.Superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents in serum and lung tissues were analyzed with corresponding kits; type Ⅰ collagen (Col Ⅰ ) content in lung tissues was evaluated with enzyme-linked immunosorbent assay; pulmonary fibrosis was assessed by lung histology; protein and mRNA expressions of connective tissue growth factor (CTGF) in lung tissues were measured with immunohistochemical and in situ hybridization semiquantitative image analyses,respectively.RESULTS: The EOCR at different concentrations displayed inhibitory activity on proliferation of HELFs.In in vivo experiment,the weight gain of the rats in groups treated with EOCR at doses of 50,100 and 200 mg/kg per day was significantly higher than those in the model group at

  19. Long term outcome of localized aggressive non-Hodgkin lymphoma treated with a short weekly chemotherapy regimen (doxorubicin, cyclophosphamide, bleomycin, vincristine, and prednisone) and involved field radiotherapy: result of a Gruppo Italiano Multiregionale per lo Studio dei Linfomi e Leucenie (GIMURELL) study.

    Science.gov (United States)

    Cabras, Maria Giuseppina; Mamusa, Angela Maria; Vitolo, Umberto; Freilone R, Roberto; Dessalvi, Paolo; Orsucci, Lorella; Tonso, Anna; Levis, Alessandro; Liberati, Marina; Lay, Giancarlo; Angelucci, Emanuele

    2009-09-01

    Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

  20. 平阳霉素联合32P不同治疗方式对儿童血管瘤的疗效对照%Comparative effect on different treatment methods of Bleomycin and 32P in children with hemangiomas

    Institute of Scientific and Technical Information of China (English)

    杨蕾华

    2012-01-01

    Objective To explore the clinical effect of Bleomycin combined with 32P in the treatment of children with he-mangiomas, and to provide the effective reference for the clinical treatment of hemangiomas. Methods From May 2008 to May 2010 in our hospital, 82 cases of children with hemangiomas were selected as the object of clinical observation. The children were divided into two groups, with 42 cases of the observation group and 40 cases of the control group. The observation group was treated by Bleomycin combined with 32P Injection, the control group was treated by 32P for local injection and external application. The different ages, different types of hemangioma, gender and number of lesions and the incidence of adverse reactions of two groups were compared. Results The observation group had a significant curative effect on cavernous hemangioma and mixed hemangioma, the control group had a significant curative effect on capillary hemangioma and port wine stains; the age factor had significant influence for treatment approaches of children with hemangioma in two groups, the younger, the better application therapy's effect of 32P local injection and external application, Bleomycin combined with 32P has a better effect on children over the age of 2; the gender and number of lesions had no significant effect on the efficacy of two treatment methods; there was no significant difference in the incidence of adverse reactions of two groups, but there was a significant difference in the kinds of adverse reactions of two groups. Conclusion Bleomycin combined with 32P is a good way of treating elder children with hemangioma, which is worthy of promotion.%目的 探讨联用平阳霉素和32P治疗儿童血管瘤的临床效果,为临床血管瘤的治疗提供有效的借鉴.方法 选择2008年5月~2010年5月到我院接受治疗的82例血管瘤患儿作为临床观察对象.将患儿分为观察组和对照组,其中观察组42例,对照组40例.

  1. Modulation of the mutagenic effect of benzo[a]pyrene and bleomycin by isoflavone extracts in a rat hepatoma cell line Modulação do efeito mutagênico do benzo[a]pireno e bleomicina por extratos de isoflavonas em células de hepatoma de roedor

    Directory of Open Access Journals (Sweden)

    Mário Sérgio Mantovani

    2012-06-01

    Full Text Available Epidemiologic studies show that the intake of foods rich in isoflavones (phytoestrogens, such as soybeans, confers protection against various types of cancer, what increases the scientific and popular interest on these compounds. In the present study, phytoestrogens extracts from soybeans were tested for genotoxic potential and modulatory effects on benzo[a]pyrene and bleomycin. Two phytoestrogens were evaluated in vitro, phytoestrogen “A” was supplied by EMBRAPA-Soja, Londrina – PR, and phytoestrogen “B” was purchased in a local drug store. The methods used were the comet assay (genotoxicity and antigenotoxicity and micronucleus test with cytokinesis block (mutagenicity in rat hepatoma cells (HTC cell. The isoflavones were tested at three concentrations pre-established by the MTT cytotoxicity assay. Both isoflavone extracts showed no genotoxic effects in the comet assay, but showed induction of micronucleus. In the evaluation of the phytoestrogens for a modulatory effect, both phytoestrogens extracts showed antigenotoxicity in the comet assay.Estudos epidemiológicos mostram que a ingestão de alimentos ricos em isoflavonas (fitoestrógenos, como a soja, confere proteção contra vários tipos de câncer, o que aumenta o interesse científico e popular sobre esses compostos. No presente estudo, os fitoestrógenos de extrato de soja foram testados quanto aos efeitos genotóxicos e modulador de benzo [a] pireno e bleomicina. Dois fitoestrogênios foram avaliados in vitro, o fitoestrógenos “A” foi fornecido pela Embrapa-Soja, Londrina - PR, e o fitoestrógenos “B” foi comprado em uma farmácia de manipulação local. Os métodos utilizados foram o teste do Cometa (genotoxicidade e antigenotoxicidade e teste do Micronúcleo com Bloqueio Citocinese (mutagenicidade em células de hepatoma de rato (HTC celulares. As isoflavonas foram testadas em três concentrações pré-estabelecidas pelo ensaio de citotoxidade MTT. Ambos os

  2. Modulatory action of endogenous and exogenous nitric oxide on survival of alveolar macrophages from normal and bleomycin-treated rats%内源性和外源性一氧化氮对正常和滴注博莱霉素大鼠肺泡巨噬细胞生存的调节

    Institute of Scientific and Technical Information of China (English)

    陈晓玲; 黄善生; 刘昆; 艾洁

    2005-01-01

    To investigate the modulatory action of endogenous and exogenous nitric oxide (NO) on survival of alveolar macrophages (AMs) in different cellular states, AMs from normal rats (normal AMs) and from bleomycin (BLM)-treated rats (BLM AMs) were incubated by sodium nitroprusside (SNP, NO donor) and L-arginin (L-Arg, NO precursor), respectively. The survival of AMs was evaluated by apoptosis and cell cycles. The molecular mechanisms were investigated by the contents of Bcl-2, Bax proteins in AMs.The results are as follows: (1) The degree of BLM AMs apoptosis was higher than that of normal AMs; the number of BLM AMs in G0/G1 phases was less than that of normal AMs; there was no significant difference in S+G2M phases between the number of BLM AMs and that of normal AMs. (2) Down-regulation of Bcl-2 and up-regulation of Bax occurred in BLM AMs, compared to those in normal AMs. (3) Apoptosis of AMs, either normal AMs or BLM AMs, was induced by both SNP and L-Arg, when compared to their respective control; only the number of BLM AMs in S+G2M phases was increased by L-Arg. (4) SNP and L-Arg induced a downregulation of Bcl-2 and an up-regulation of Bax proteins in normal AMs, but did not induce the same change pattern in BLM AMs. (5)The Bax in BLM AMs was down-regulated by L-Arg. It is concluded that NO can induce the apoptosis of BLM AMs and normal AMs; that Bcl-2 and Bax are implicated in NO-induced apoptosis of normal AMs, whereas they are not involved in that of BLM AMs,suggesting the differential molecular mechanisms underlying the NO-induced apoptosis of normal AMs and BLM AMs; and that endogenous NO promotes proliferation of BLM AMs, which might be associated with down-regulation of Bax.%分别用一氧化氮(nitric oxide,NO)供体硝普钠(sodium nitroprusside,SNP)和前体L-精氨酸(L-arginin,L-Arg)孵育来自正常大鼠(alveolar macrophages from normal rats,normal AMs)和滴注博莱霉素大鼠的肺泡巨噬细胞(alveolar macrophages fromBLM-treated rats

  3. 抗纤维化治疗对大鼠支气管肺泡灌洗液中头孢噻肟浓度的影响%Effect of Anti-fibrosis treatment on the Concentration of Cefotaxim in Bronchioalveolar Lavage Fluid in Rats with Bleomycin-Induced Pulmonary Fibrosis

    Institute of Scientific and Technical Information of China (English)

    陈峰

    2011-01-01

    Objective To observe the effect of anti-fibrosis drug on the concentration of cefotaxim in bronchioalveolar lavage fluid.Methods 90 Wister male rats were randomly divided into five groups, including normal control( Group A) 、model( Group B) 、interferon-γ-troated( Group C) 、ambroxol-treated ( Group D) 、Dexamethason-treated( Group E) group.On experimengtal day( day 0), the rats in B,C,D and E were intratracheally instilled with bleomycin(5 mg/Kg body weght) or sterile saline, and then the rats in C, D and E were treated with the interferon-γ(30000 IU/per mouse), ambroxol(75 mg/per mouse), Dexamethason(0.1 mg/per mouse) or sterile saline intraperitoneally respectively.On day 7,14,28 after instillation, six rats form each group were then given a tail vein injection of cefotaxime (600 mg/kg) and bronchoalveolar lavage.The concentration of cefotaxim in the the bronchial alveolar fluids was assayed by liquid chromatography-massspectrometry method.Results On day 7 the concentration of cefotaxim in the the bronchial alveolar fluids of Group D,Group E was lower than Group B and those of Group C higher than group B.The difference between Group E and Group B was significant statistically(P =0.012.On day 14 the concentration of cefotaxim in the the bronchial alveolar fluids of Group D, Group E increased,while Group C decreased.The three groups were all higher than Group B.The diferonce between Group D and Group B was significant statistically( P = 0.000.On day 28 the concentration of cefotaxim in the the bronchial alveolar fluids of Group E increased continuously,which was significanfiy higher than other groups.Group C and Group D decreased continuously, and the concentration of cefotaxim of both groups was lower than Group B.Conclusion Dexamethason could increase the concentration of cefotaxim in the the bronchial alveolar fluids of the fibrosis stage.%目的 观察抗肺纤维化药物对支气管肺泡灌洗液(BALF)中头孢噻肟浓度的影响.方法 将90只

  4. Central venous catheter insertion drainage and intrapleural administration staphylococcal enterotoxin C injection plus low dose cisplatin for treatment of malignant pleural effusion compared with bleomycin:a clinical control study%中心静脉导管置入引流并胸腔内灌注金葡素注射液联合小剂量顺铂治疗恶性胸腔积液与博莱霉素临床对照研究

    Institute of Scientific and Technical Information of China (English)

    闫培清; 于晓红; 张华; 卜宪聪; 葛长胜

    2008-01-01

    目的 评价中心静脉导管置入引流并胸腔内灌注金葡素注射液联合小剂量顺铂治疗恶性胸腔积液的疗效及不良反应.方法 64例恶性胸腔积液随机分成两组:治疗组32例,胸腔内灌注金葡素注射液20 ml+顺铂20 mg;对照组32例,胸腔内灌注博莱霉素60 mg.结果 治疗组和对照组胸水控制、生活质量Karnofsky评分有效率差异无统计学意义(P>0.05);治疗组不良反应程度明显低于对照组(P<0.05).结论 中心静脉导管置入引流并胸腔内灌注金葡素注射液联合小剂量顺铂治疗恶性胸腔积液是有效的,且不良反应少.%Objective To evaluate the efficacy and side effects of the treatment using central venous catheter insertion drainage and the intrapleural administration of staphyloccal enterotoxin C injection plus low dose cisplatin for malignant pleural effusion.Methods Sixty-four patients were randomly divided into two groups.Test group 32 cases:staphyloccal enterotoxin C injection 20 ml combined with cisplatin 20 mg were infused into the thoracic cavity;control group (32 cases):bleomycin 60 mg were infused into the thoracic cavity.Results There was not statistical difference in the total response rate of pleural control and Karnofsky score between two groups(P>0.05).The side effects in test group were less than that in control group(P<0.05).Conclusion Placement of central venous catheter for drainage and intrapleural administration of staphyloccal enterotoxin C injection plus low dose cisplatin is effective for malignant pleural effusion,and the side effects less.

  5. Therapeutic evaluation of cisplatin, etoposide, and bleomycin chemotherapy regimen in high-risk gestational trophoblastic neoplasia%BEP方案治疗高危型妊娠滋养细胞肿瘤的疗效及安全性评价

    Institute of Scientific and Technical Information of China (English)

    宋水勤; 张国楠

    2012-01-01

    Objective To evaluate the effectiveness and safety of combination chemotherapy with bleomycin,etoposide and cisplatin (BEP) regimen on the patients with high-risk gestational trophoblastic neoplasia (GTN).Methods Forty-two patients with high-risk GTN admitted in Sichuan Cancer Hospital between Jan.1997 and Oct.2011 were analyzed retrospectively.The International Federation of Gynecology and Obstetrics (FIGO) prognostic score of all patients was more than 7.The mean age of patients was 30.2years (range 20 -49 years).All patients were treated with more than two cycles BEP regimen and followed up to the patients' death or at the end of Feb.2012.The clinical response,toxicity and the occurrence of secondary tumors were investigated.Results Forty-two high-risk GTN patients received the total of 251courses of the BEP regimen,the average number of courses for each patient was 6.0 courses.Thirty-seven patients achieved complete remission and 5 patients showed drug-resistant.The total complete remission rate of BEP regimen was 88% ( 37/42 ).Among the complete remission patients,the total courses of BEP regimen of cases getting normal serum β-hCG level was 129 courses ( average 3.5 courses),and the total courses of cases achieving complete remission was 227 courses (average 6.1 courses ).Among the 37 complete remission patients,31 cases were treated with BEP regimen chemotherapy alone,4 patients with BEP regimen chemotherapy combined with surgical treatment (1 case had no cancer after surgery) and 2 cases with BEP regimen chemotherapy combined with radiation therapy.Therefore,the complete remission rate of BEP regimen chemotherapy alone was 74% (31/42 ).There were 5 patients who showed drug-resistance after 24 courses of BEP regimen chemotherapy (average 4.8 courses),then received etoposide,methotrexate and dactinomycin( EMA )/cyclophosphamide and vincristine sulfate ( CO ) regimen chemotherapy after drugresistance,2 cases combined with radiation therapy,1 case combined

  6. Pharmacological targeting of protease-activated receptor 2 affords protection from bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    C. Lin (Cong); J. von der Thusen (Jan); J. Daalhuisen (Joost); M. Ten Brink (Marieke); B. Crestani (Bruno); T. van der Poll (Tom); K. Borensztajn (Keren); C. Arnold Spek (C.)

    2015-01-01

    textabstractIdiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whet

  7. A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity

    NARCIS (Netherlands)

    Gu, J.; Ye, Y.; Spitz, M.R.; Lin, J.; Kiemeney, L.A.L.M.; Xing, J.; Hildebrandt, M.A.T.; Ki Hong, W.; Amos, C.I.; Wu, X.

    2011-01-01

    Mutagen sensitivity, a measurement of chromatid breaks induced by various mutagens in short-term cultures of peripheral blood lymphocytes, is an established risk factor for a number of cancers and is highly heritable. The purpose of this study is to identify genetic predictors of mutagen sensitivity

  8. Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer

    DEFF Research Database (Denmark)

    Kier, Maria G; Lauritsen, Jakob; Mortensen, Mette S

    2016-01-01

    a small proportion of the patients received BEP. OBJECTIVE: To estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. DESIGN, SETTING, AND PARTICIPANTS: Of a Danish population-based cohort of GCC patients (1984-2007), 1889...... received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes measured were 5-yr progression......-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS AND LIMITATIONS: The 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC...

  9. Drugs Approved for Cervical Cancer

    Science.gov (United States)

    ... Human Papillomavirus (HPV) Nonavalent Vaccine Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine Drugs Approved to Treat Cervical Cancer Avastin (Bevacizumab) Bevacizumab Blenoxane (Bleomycin) Bleomycin Hycamtin (Topotecan ...

  10. Effect of radiation on the growth of normal and malignant human oesophageal explant cultures pre-treated with bleomycin

    Energy Technology Data Exchange (ETDEWEB)

    Seymour, C.B.; Cusack, A.; Mothersill, C.; Hennessy, T.P.

    1988-05-01

    A method has been developed for testing the response of oesophageal explants from tumour and surrounding normal tissue in the same patient to chemotherapy and ..gamma..-radiation, singly and in combination. The test allows treatment combinations, time and order of administration of agents to the tissue to be accurately controlled. Cytotoxicity, determined by measuring the area of outgrowth from an explant 2 weeks after plating, is the most useful short-term end-point, although many other are possible. Results showing differential cytotoxicity of belomycin with and without radiation in squamous and adenocarcinoma of the oesophagus and surrounding normal tissue from the same patient indicate tumour cells are relatively resistant to radiation alone, low levels of belomycin with or without radiation preferentially spare tumour cells and high levels, in combination with any radiation dose tested, but not without radiation, spare normal cells and give a significantly high amount of relative tumour cell kill. Belomycin must be added to the cells just before or just after irradiation to obtain the normal-tissue sparing effect.

  11. Paclitaxel and Carboplatin or Bleomycin Sulfate, Etoposide Phosphate, and Cisplatin in Treating Patients With Advanced or Recurrent Sex Cord-Ovarian Stromal Tumors

    Science.gov (United States)

    2016-03-16

    Ovarian Granulosa Cell Tumor; Ovarian Gynandroblastoma; Ovarian Sertoli-Leydig Cell Tumor; Ovarian Sex Cord Tumor With Annular Tubules; Ovarian Sex Cord-Stromal Tumor; Ovarian Sex Cord-Stromal Tumor of Mixed or Unclassified Cell Types; Ovarian Steroid Cell Tumor

  12. Efeitos da quercetina na lesão pulmonar induzida por bleomicina: um estudo preliminar Effects of quercetin on bleomycin-induced lung injury: a preliminary study

    Directory of Open Access Journals (Sweden)

    José Antônio Baddini Martinez

    2008-07-01

    Full Text Available OBJETIVO: Investigar os efeitos da quercetina em um modelo de inflamação pulmonar e fibrose induzidas por bleomicina. MÉTODOS: Setenta e nove hamsters machos adultos foram randomizados para aplicação de injeções pelas vias intratraqueal (IT e intraperitoneal (IP em quatro configurações: veículo IP/salina IT (grupo VS, n = 16; salina IT/quercetina IP (grupo QS, n = 16; bleomicina IT/veículo IP (grupo VB, n = 27; e bleomicina IT/quercetina IP (grupo QB, n = 20. A quercetina e a bleomicina foram aplicadas em doses de 30 mg/kg/dia e 10 U/kg, respectivamente.A quercetina foi iniciada/suspensa 3 dias antes/14 dias depois das injeções IT. RESULTADOS: A taxa de mortalidade do grupo VB foi significantemente superior à dos demais grupos (44% vs. VS: 0%; QS: 0%; QB: 15%. O grupo VB exibiu níveis pulmonares de substâncias reativas ao ácido tiobarbitúrico (× 10-2 nmol/mg significativamente maiores (6,6 ± 1,3 vs. VS: 5,5 ± 0,8; QS: 2,5 ± 0,6; e QB: 5,8 ± 0,6.Os grupos VB/QB mostraram níveis pulmonares de glutationa reduzida (× 10-2 nmol/mg significativamente menores que os dos grupos VS/QS (28,9 ± 13,8/28,6 ± 14,8 vs. 43,9 ± 16,0/51,1 ± 20,3 e níveis de hidroxiprolina (mg/g significativamente maiores (201,6 ± 37,3/177,6 ± 20,3 vs. 109,6 ± 26,1/117,5 ± 32,0. CONCLUSÕES: Em um modelo animal de lesão pulmonar, a quercetina exibiu efeitos antiinflamatórios que são relacionados, pelo menos em parte, a suas propriedades antioxidantes.OBJECTIVE: The aim of this study was to identify the best experimental model in which to observe the pulmonary alterations characterizing hepatopulmonary syndrome (HPS. METHODS: Male Wistar rats, with mean weight of 250 g, were used in four experimental models: inhaled carbon tetrachloride; intraperitoneal carbon tetrachloride; partial portal vein ligation; and bile duct ligation (BDL. The animals in all groups were divided into control and experimental subgroups. The following variables were measured: transaminase levels; blood gases; lipoperoxidation, using thiobarbituric acid reactive substances (TBARS and chemiluminescence; and levels of superoxide dismutase (SOD anti-oxidant activity. Anatomopathological examination of the lung was also performed. RESULTS: There were statistically significant differences between the BDL control and BDL experimental groups: aspartate aminotransferase (105.3 ± 43 vs. 500.5 ± 90.3 IU/L; alanine aminotransferase (78.75 ± 37.7 vs. 162.75 ± 35.4 IU/L; alkaline phosphatase (160 ± 20.45 vs. 373.25 ± 45.44 IU/L; arterial oxygen tension (85.25 ± 8.1 vs. 49.9 ± 22.5 mmHg; and oxygen saturation (95 ± 0.7 vs. 73.3 ± 12.07%. Lipoperoxidation and antioxidant activity also differed significantly between the two BDL groups (control vs. experimental: TBARS (0.87 ± 0.3 vs. 2.01 ± 0.9 nmol/mg protein; chemiluminescence (16008.41 ± 1171.45 vs. 20250.36 ± 827.82 cps/mg protein; and SOD (6.66 ± 1.34 vs. 16.06 ± 2.67 IU/mg protein. The anatomopathological examination confirmed pulmonary vasodilatation in the BDL model. In the other models, there were no alterations that were characteristic of HPS. CONCLUSIONS: The data obtained suggest that the BDL model can be used in future studies involving hepatic alterations related to oxidative stress and HPS.

  13. Synthesis, stability and reactivity of the first mononuclear nonheme oxoiron(IV) species with monoamido ligation: a putative reactive species generated from iron-bleomycin.

    Science.gov (United States)

    Hitomi, Yutaka; Arakawa, Kengo; Kodera, Masahito

    2014-07-18

    The preparation and characterisation of an oxoiron(IV) species with monoamido ligation are described. Reactivity studies revealed the important role of the amido ligand in enhancing the ability of oxoiron(IV) complexes to promote hydrogen atom transfer from external alkanes.

  14. Effect of expression of TGF-beta and TNF-alpha with Qidan granule treatment in rats by bleomycin-induced pulmonary fibrosis

    Institute of Scientific and Technical Information of China (English)

    辛洪涛; 宋秀杰; 靳长俊; 王静; 黄琛; 张欣; 王建平; 姜淑娟

    2003-01-01

    Objective: To evaluate the therapeutic effects and mechanisms of Qidan granule in blemycinA5-induced pulmonary interstitial fibrosis (PIF)in rats. Methods: PIF models were established by blemycinA5-induced in rats. They were treated by Qidan granule and Hydrocortisone respectively. The pathological changes and collagen protein disposition were observed, and the expression of TGF-β, TNF-α proteins were measured by immunohistochemical technique. Results: The pulmonary alveolitis and fibrosis were alleviated remarkably in Qidan granule group compared with those in the model control group and hydrocortisone group (P<0.01). The expression of TGF-β and TNF-α protein were higher in Qidan granule group than those in normal group ,and were significantly less than those in the model control group and in hydrocortisone group (P<0.01). Conclusion: Qidan granule would ameliorate the pulmonary alveolitis and fibrosis. TGF-β and TNF-α might play an important role in the development of alveolitis and fibrosis in rats.

  15. Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: Potential role in pulmonary fibrosis

    NARCIS (Netherlands)

    K. Borensztajn (Keren); P. Bresser (Paul); C.M. van der Loos (Chris); I. Bot (Ilze); B. van den Blink (Bernt); M.A. den Bakker (Michael); J. Daalhuisen (Joost); A.P. Groot (Angelique); M.P. Peppelenbosch (Maikel); J. von der Thusen (Jan); C.A. Spek (Arnold)

    2010-01-01

    textabstractIdiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recen

  16. Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury Potential Role in Pulmonary Fibrosis

    NARCIS (Netherlands)

    Borensztajn, Keren; Bresser, Paul; van der Loos, Chris; Bot, Ilze; van den Blink, Bernt; den Bakker, Michael A.; Daalhuisen, Joost; Groot, Angelique P.; Peppelenbosch, Maikel P.; von der Thusen, Jan H.; Spek, C. Arnold

    2010-01-01

    Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and re mains refractory to current therapies The coagula non cascade is frequently activated during pulmonary fibrosis but this observation has so far resisted a mechanistic explanation Recent data suggest

  17. Drug: D03229 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 301] 4 Agents affecting cellular function 42 Antineoplastics 423 Antibiotics 4234 Bleomycins D03229 Bleomyci...1] D03229 Bleomycin hydrochloride (JP16) Antineoplastics [BR:br08308] Natural products Antibiotics

  18. The Effects and Mechanisms of Erdosteine in Bleomycin-Induced Pulmonary Fibrosis in Rats%厄多司坦对博莱霉素致大鼠肺纤维化发生发展的干预作用

    Institute of Scientific and Technical Information of China (English)

    张蕾; 范龙梅

    2009-01-01

    目的:探讨厄多司坦对肺纤维化的干预作用及机制.方法:清洁级雄性SD大鼠24只,随机分为2组:博莱霉素组12只(气管内滴注博来霉素复制肺纤维化模型5mg/kg,0.2~0.3mL)、厄多司坦组12只(造模后用厄多司坦10mg/kg·d灌胃),各组于造模后第7、28d行肺功能检查后各处死6只,观察肺泡炎和肺纤维化的动态变化和肺组织匀浆中羟脯氨酸(HYP)、丙二醛(MDA)、髓过氧化物酶(MPO)含量及超氧化物歧化酶(SOD)活力.结果:①厄多司坦组大鼠肺泡炎、肺纤维化程度减轻,肺功能优于博来霉素组.②28d时肺组织匀浆中HYP含量厄多司坦组(5.93±0.24)显著低于博来霉素组(6.36±0.27)(P0.05).结论:①厄多司坦对博莱霉素致大鼠肺纤维化有干预作用,②厄多司坦干预肺纤维化的机制早期可能为通过使中性粒细胞扣压减少,增加自由基的清除使体内氧化-抗氧化系统恢复平衡,使脂质过氧化损伤减轻而实现的.

  19. 5例会厌皱襞血管瘤患者局部注射平阳霉素的护理%Nursing for 5 Patients with Epiglottis Plica Hemangioma Locally Injected with Bleomycin A5

    Institute of Scientific and Technical Information of China (English)

    杨徐静; 刘翠兰; 沈美琴

    2009-01-01

    总结了5例会厌皱襞血管瘤患者局部注射平阳零素的护理经验,包括术前良好的心理干预,术后加强对咽喉水肿、疼痛的观察护理,必要时遵医嘱局部雾化吸入糖皮质激素消肿;观察局部出血情况;观察平阳霉素的药物不良反应,如发热、胃肠道反应和过敏性休克;术后强调合理用嗓和合理进食,防止血管瘤过早破溃.

  20. Influência do biofármaco DNA-hsp65 na lesão pulmonar induzida por bleomicina Influence of a DNA-hsp65 vaccine on bleomycin-induced lung injury

    OpenAIRE

    Adriana Ignacio de Padua; Célio Lopes Silva; Simone Gusmão Ramos; Lúcia Helena Faccioli; José Antônio Baddini Martinez

    2008-01-01

    OBJETIVO: Avaliar a influência do biofármaco DNA-hsp65 em um modelo de distúrbio fibrosante pulmonar experimental. MÉTODOS: Foram estudados 120 camundongos machos C57BL/6, divididos em quatro grupos: grupo SS, animais tratados com salina (placebo) e injetados com salina intratraqueal (IT); grupo SB, tratados com salina (placebo) e injetados com bleomicina IT; grupo PB, tratados com plasmídeo, sem gene bacteriano, e injetados com bleomicina IT; e grupo BB, tratados com DNA-hsp65 e injetados co...

  1. ALTERNATING CYCLES OF PVB AND BEP IN THE TREATMENT OF PATIENTS WITH ADVANCED SEMINOMA

    NARCIS (Netherlands)

    GIETEMA, JA; WILLEMSE, PHB; MULDER, NH; OLDHOFF, J; DEVRIES, EGE; SLEIJFER, DT

    1991-01-01

    33 patients (median age 39 years) with advanced seminoma were treated with 4 courses of alternating cisplatin-containing chemotherapy PVB/BEP (cisplatin, vinblastine and bleomycin; bleomycin, etoposide and cisplatin). Patients were classified as stage IIC (n = 7), IID (n = 9), III (n = 13) and IV (n

  2. Effects of curcumin on bleomycin‑induced oxidative stress in malignant testicular germ cell tumors.

    Science.gov (United States)

    Cort, Aysegul; Ozdemir, Evrim; Timur, Mujgan; Ozben, Tomris

    2012-10-01

    Bleomycin is commonly used in the treatment of testicular cancer. Bleomycin generates oxygen radicals, induces the oxidative cleavage of DNA strands and induces cancer cell apoptosis. Curcumin (diferuloylmethane) is a potent antioxidant and chief component of the spice turmeric. No study investigating the effects of curcumin on intrinsic and bleomycin-induced oxidative stress in testicular germ cell tumors has been reported in the literature. For this reason, the present study aimed to examine the effects of curcumin on oxidative stress produced in wild-type NTera-2 and p53-mutant NCCIT testicular cancer cells incubated with bleomycin and the results were compared with cells treated with H2O2 which directly produces oxidative stress. The protein carbonyl content, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), 8-isoprostane, lipid hydroperoxide (LPO) levels and total antioxidant capacity in the two testicular cancer cell lines were determined. Results showed that bleomycin and H2O2 significantly increased protein carbonyl, TBARS, 8-isoprostane and LPO levels in the NTera-2 and NCCIT cell lines. Bleomycin and H2O2 significantly decreased the antioxidant capacity and GSH levels in NTera-2 cells. Curcumin significantly decreased LPO, 8-isoprostane and protein carbonyl content, and TBARS levels increased in cells treated with bleomycin and H2O2. Curcumin enhanced GSH levels and the antioxidant capacity of NTera-2 cells. In conclusion, curcumin inhibits bleomycin and H2O2-induced oxidative stress in human testicular cancer cells.

  3. Internalization of a thiazole-modified peptide in Sinorhizobium meliloti occurs by BacA-dependent and -independent mechanisms.

    Science.gov (United States)

    Wehmeier, Silvia; Arnold, Markus F F; Marlow, Victoria L; Aouida, Mustapha; Myka, Kamila K; Fletcher, Vivien; Benincasa, Monica; Scocchi, Marco; Ramotar, Dindial; Ferguson, Gail P

    2010-09-01

    BacA proteins play key roles in the chronic intracellular infections of Sinorhizobium meliloti, Brucella abortus and Mycobacterium tuberculosis within their respective hosts. S. meliloti, B. abortus and M. tuberculosis BacA-deficient mutants have increased resistance to the thiazole-modified peptide bleomycin. BacA has been previously hypothesized, but not experimentally verified, to be involved in bleomycin uptake. In this paper, we show that a BacA-dependent mechanism is the major route of bleomycin internalization in S. meliloti. We also determined that the B. abortus and S. meliloti BacA proteins are functional homologues and that the B. abortus BacA protein is involved in the uptake of both bleomycin and proline-rich peptides. Our findings also provide evidence that there is a second, BacA-independent minor mechanism for bleomycin internalization in S. meliloti. We determined that the BacA-dependent and -independent mechanisms of bleomycin uptake are energy-dependent, consistent with both mechanisms of bleomycin uptake involving transport systems.

  4. Effect of Pingyangmycin on human venous malformation endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Yi Fang Zhao; Zhi Jun Sun; Yu Lin Jia; Jun Jia; Ya Meng Si; Ji Hong Zhao; Wen Feng Zhang

    2008-01-01

    @@ Purpose: Venous malformations are common vascular anomalies with a propensity of the head and neck. Intralesional injection of Pingyangmycin (PYM, bleomycin A5 hydrochloride) is a widely used sclerotherapy method for the treatment of venous malformation.

  5. Protein (Cyanobacteria): 175290 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007131221.1 1117:3496 52604:2952 102115:797 102116:797 111780:797 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MINNQIIFHLAIPINDLAKAKEFYAQGLGCQIGRENST

  6. Protein (Cyanobacteria): 143489 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007131876.1 1117:2878 52604:682 102115:1231 102116:1231 111780:1231 glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MSFFCHDALVTIAALEYQKVIDFYRKLLSQEPQPYI

  7. Protein (Cyanobacteria): 175756 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007131410.1 1117:3497 52604:2652 102115:934 102116:934 111780:934 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MMHHVSIRTANIHRAIAFYEQLGFTVNERFTTGYTLAC

  8. Protein (Cyanobacteria): 175683 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007132840.1 1117:3497 52604:2654 102115:393 102116:393 111780:393 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MTDIGLTHIALPVSNLERSIKFYSTYAKMRVVHRRIDA

  9. Protein (Cyanobacteria): 175437 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007130757.1 1117:3496 52604:2653 102115:394 102116:394 111780:394 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MTVKPEIKSNSLRPGSLRKVHHIALNVKDMAASRHFYG

  10. Protein (Cyanobacteria): 175681 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007134225.1 1117:3497 52604:2654 102115:393 102116:393 111780:393 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MQITRLLHTAILVSDLAKAEHFYGEVLGLVKAEGRTSN

  11. Protein (Cyanobacteria): 175438 [PGDBj - Ortholog DB

    Lifescience Database Archive (English)

    Full Text Available YP_007131651.1 1117:3496 52604:2653 102115:394 102116:394 111780:394 Glyoxalase/bleomycin resistan...ce protein/dioxygenase Stanieria cyanosphaera PCC 7437 MNLSKIHHIAIICSNYQVSKHFYTEILGLKIIQETYRE

  12. Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

    Science.gov (United States)

    Gupta, Arjun; Sen, Shiraj; Naina, Harris

    2016-04-06

    Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury.

  13. Treatment Options for Testicular Cancer, by Type and Stage

    Science.gov (United States)

    ... nodes, chemo is often recommended. Chemotherapy with the BEP regimen (bleomycin, etoposide, and cisplatin) for 2 cycles. ... chemo is recommended, with either 3 cycles of BEP or 4 cycles of EP (etoposide and cisplatin). ...

  14. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005206 The pivotal role of CXCR3 in the patho-genesis of bleomycin-induced pulmonary fibrosis. GAO Jin-ming(高金明), Dept Respir Med, PUMC Hosp, PUMC & CAMS, Beijing 100730. Chin J Tu-berc Respir Dis, 2005; 28 (1): 28-32. Objective: To investigate the contribution of chemokine receptor-CXCR3 to the fibrotic disease process induced by bleomycin in CXCR3 gene defi-

  15. EFFECTS OF ADENOSINE REDUCED ON STROMAL NECROSIS CELL IN SPLEEN,BONE MARROW AND LUNG FIBROSIS INDUCED BY BLEOMYCIN%腺苷对博莱霉素所致肺纤维化以及脾与骨髓等基质细胞坏死的影响

    Institute of Scientific and Technical Information of China (English)

    楼皖玲; 潘家华; 陈兰举; 刘欣

    2002-01-01

    目的应用双哌达莫(DPM)、腺苷(ADO)与ADO拮抗剂茶碱(TH)治疗博莱霉素(BLE)肺纤维化小鼠,观察肺、脾等病理变化,探讨肺纤维化发病机理.方法实验第1天100只小鼠经气管注入BLE 8.5 mg*kg-1,随机分BLE、DPM、ADO和TH四组,第2天起分别给予NS(100μl*d-1)、DPM、ADO和TH,剂量均为50mg*kg-1*d-1,共 7天,第4~30天内处死动物,组织化学法观察肺内纤维变化与脾、胸腺、骨髓病理学改变.结果 BLE组和TH组第4~6天脾、胸腺髓质与骨髓中许多基质细胞坏死导致组织严重疏松.BLE组第20天后脾与胸腺逐渐萎缩,肺与脾内网状纤维大量增加.DPM组与ADO组第4~6天脾、骨髓坏死基质细胞较少,第30天肺未发生纤维化,淋巴器官未萎缩.结论 BLE能致脾、骨髓等基质细胞大量坏死与严重组织疏松.内、外源性ADO能轻度减少基质细胞坏死,促进淋巴组织与造血组织增生,抑制BLE诱导的肺纤维化与淋巴器官萎缩.

  16. 博来霉素致肺纤维化大鼠不同时间点吸人STAT1反义寡核苷酸的疗效比较%Therapeutic effects of aerosolized signal transducer and activator of transcription 1 antisense oligonucleotide administered at different time points on bleomycin-induced pulmonary fibrosis: experiment with rats

    Institute of Scientific and Technical Information of China (English)

    李晶; 曾鸣; 朱晨; 王文军; 湛晓勤; 范贤明

    2009-01-01

    目的 探讨雾化吸入信号转导和转录活化因子1(STAT1)反义寡核苷酸(ASON)干预肺纤维化的最佳给药时机.方法 Wistar雌性大鼠25只随机均分为博来霉素(BLM)组、ASON 0 d组、ASON 7 d组、ASON 14 d组和生理盐水(NS)组,前4组气管内灌注BLM建立肺纤维化模型,NS组气管内灌注NS.ASON 0、7、14 d组分别于气管内灌注BLM后立即、第7和14天开始雾化吸入STATI ASON;NS组和BLM组雾化吸入NS.气管内灌注BLM后第28天处死各组大鼠,取肺组织分别行HE和Masson染色,观察肺泡炎和纤维化情况并评分;酶联免疫吸附试验(ELISA)测定支气管肺泡灌洗液(BALF)中转化生长因子β(TGF-β)和肿瘤坏死因子α(TNF-α)浓度.结果 肺组织病理学观察显示ASON 0 d组大鼠肺泡炎和肺纤维化程度明显轻于BLM组和ASON 14 d组,肺泡炎评分(1.80±0.84)和肺纤维化评分(2.60±0.55)均明显低于BLM组(2.40±0.55、4.40±0.55)、ASON 7 d组(2.20±0.45、3.00 ±0.71)和ASON 14 d组(2.20±0.84、4.00±1.00)(均P<0.05);ASON 7 d组肺纤维化评分也明显低于BLM组和ASON 14 d组(均P<0.05).ASON 0 d组BALF中TGF-β与TNF-α浓度[(48.11±3.46)pg/ml、(1.93±0.14)ng/ml]均明显低于BLM组[(57.67±2.46)pg/ml、(2.45±0.25)ng/ml,均P<0.05],TGF-β浓度明显低于ASON 7 d组[(51.42±3.57)pg/ml]和ASON 14 d组[(55.83±1.79)pg/ml](均P<0.05);ASON 7 d组BALF中TGF-β浓度也明显低于BLM组和ASON 14d组(均P<0.05).结论 早期雾化吸入STAT1 ASON对BLM致肺纤维化大鼠的肺纤维化形成有明显阻抑作用,用药越早效果越好,提示雾化吸入STAT1 ASON有可能成为肺纤维化的早期干预手段.%Objective To investigate the curative effects of inhaling signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotide (ASON) on alveolitis and pulmonary fibrosis and the best administration time. Methods Twenty-five adult female Wistar rats were randomly divided into 5 equal groups: BLM group, undergoing intra-tracheal perfusion of BLM so as to establish animal models of alveolitis and pulmonary fibrosis and then inhaling aerosolized normal saline (NS); NS group undergoing intra-tracheal perfusion of NS and then inhaling aerosolized NS; ASON 0 d group, undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml immediately; ASON 7 d group, undergoing intra-tracheal perfusion of BLM and then inhaling STAT1 ASON 3 ml 7 days later; and ASON 14 d group undergoing intra-tracheal perfusion of BLM and then inhaling aerosolized STAT1 ASON 3 ml 14 days later. Aerosolized inhalation was repeated once every other day for 4 times. Twenty-eight days after intra-tracheal perfusion the rats were sacrificed with their lungs taken out to undergo pathological examination. NS was infused into the right lungs to get bronchoalveolar lavage fluid (BALF). ELISA was used to examine the concentrations of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) in the BALF. Results The pathology result of the lung tissues showed that compared with the BLM and ASON 14 d groups, the alveolitis and pulmonary fibrosis of the ASON 0 d group were obviously milder. The scores of alveolitis and pulmonary fibrosis of the ASON 0 d group were (1.80 ± 0. 84) and (2. 60 ± 0. 55) respectively, both significantly lower than those of the BLM group [(2.40 ± 0. 55) and (4. 40 ± 0. 55) respectively] and those of the ASON 7 d group [(2. 20 ±0. 45) and (3.00 ±0. 71) respectively] (all P < 0. 05). The scores of pulmonary fibrosis of the ASON 7 d group was significantly lower than those of the BLM and ASON 14 d groups (both P < 0. 05). The concentrations of TGF-β and TNF-α in BALF of the ASON 0 d group were (48. 11 ±3.46) pg/ml and (1.93 ± 0. 14) ng/ml respectively, both significantly lower than those of the BLM group [(57. 67 ± 2. 46) pg/ml and (2. 45 ± 0. 25) ng/ml respectively, both P < 0. 05]. The concentration of TGF-β in BALF of the ASON 0 d group was significantly lower than those of the ASON 7 d and ASON 14 d groups [(51.42 ±3. 57) pg/ml and (55.8

  17. Respuesta de ratones Balb/c frente a ciclofosfamida y bleomicina en el ensayo de la morfología de la cabeza del espermatozoide - Balb/c mice’s response against bleomycin and cyclophosphamide in the head sperm morphology assay

    OpenAIRE

    Rosario Fernández Luis Alfredo; Arencibia Arrebola Daniel Franciscoa

    2011-01-01

    ResumenEl ensayo de la morfología de la cabeza del espermatozoide permite el estudio del potencial genotóxico de muestras problemas a nivel celular. En este artículo se decidió evaluar y comparar en 16 ratones Balb/c machos por grupo, el efecto de dos sustancias mutagénicas en este ensayo.SummaryThe head sperm morphology assay, allows the study of the genotoxic potencial of samples at the cellular level problems. In this article we decide to evaluate and to compare in 16 Balb/c males mice per...

  18. Trichostatin A affects expression of NF-κB in mice with bleomycin-induced pulmonary fibrosis%曲古抑菌素A对博莱霉素致肺纤维化小鼠NF-κB表达的影响研究

    Institute of Scientific and Technical Information of China (English)

    黄旭晴; 徐长青; 李旭

    2016-01-01

    目的 观察曲古抑菌素A(TSA)对博莱霉素(BLM)诱导的肺纤维化小鼠核因子-κB(NF-κB)表达的影响.方法 96只健康雄性C57BL/6小鼠随机分为对照组、模型组、TSA早期干预组和TSA晚期干预组,各24只.模型组、TSA早期干预组和TSA晚期干预组小鼠均予以气管内滴注BLM(10mg/kg体重)溶液0.15ml诱导肺纤维化模型,对照组小鼠予0.9%氯化钠注射液0.15ml气管内滴注.建模后,TSA干预组分阶段(早期:第1~14天;晚期:第15~28天)予以TSA(40mg/kg体重)溶液腹腔注射,2次/周.模型组和对照组予以等体积二甲基亚砜腹腔注射作为溶媒对照.建模后第7、14、28天各组均随机分3批处死小鼠8只,留取右肺上叶组织行HE染色和Masson染色观察肺泡炎及肺纤维化程度,并行Szapiel评分,右肺中、下叶组织碱水解法检测羟脯氨酸(HYP)含量,免疫组化方法检测NF-κB表达水平.结果 病理学检查比较,对照组小鼠肺泡结构正常,模型组小鼠肺组织在第7天出现出血、渗出等肺泡炎性改变,第28天出现明显肺纤维化.模型组小鼠肺组织各时点肺泡炎Szapiel评分、HYP含量、NF-κB表达水平均高于对照组(均P<0.05);TSA早期干预组小鼠各时点以上指标均低于模型组(均P<0.05),而TSA晚期干预组与模型组比较均无统计学差异(均P >0.05).结论 早期应用TSA或能通过抑制NF-κB的表达发挥延缓肺纤维化的作用.

  19. The Role of Catalase in Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Takigawa Tomoko

    2010-12-01

    Full Text Available Abstract Background Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. Methods The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. Results In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12 compared to control lungs (n = 10. Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-β expression and total collagen content following bleomycin treatment compared to wild-type mice. Conclusions Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.

  20. Peculiarities of induction and persistence of hidden chromosome instability in peripheral blood lymphocytes of persons occupationally exposed to ionizing radiation.

    Science.gov (United States)

    Pilinska, M A; Dybsky, S S; Dybska, O B; Shvayko, L I; Sushko, V O

    2014-09-01

    Objective - to investigate the induction of hidden chromosome instability in persons occupationally exposed to ionizing radiation and its persistence in vitro in successive mitoses. Materials and methods. Using two tests ("G2-bleomycin sensitivity assay" and two-term cultivation of human peripheral blood lymphocytes) voluntary cytogenetic examination of 15 individuals participated in the conversion of the "Shelter" ("Chornobyl NPP") into ecologically safe system had been carried out. Total 24 034 metaphase had been analyzed, of which 12 243 - without additional mutagenic exposure, 11 791 - exposed to bleomycin in vitro at concentration of 0.05 μg/ml. Results. The magnitude and dynamics of background as well as bleomycin-induced cytogenetic effects in both terms of lymphocytes' cultivation in occupational group differed significantly from the group of comparison towards increasing of chromosome instability indices with significant interindividual fluctuations. Conclusion. Interindividual differences in persistence of radiation-induced hidden chromosome instability in successive generations of human somatic cells had been found.

  1. Photochemical internalization for the treatment of malignant gliomas

    Science.gov (United States)

    Madsen, Steen J.; Kharkhuu, Khishigzaya; Berg, Kristian; Hirschberg, Henry

    2007-02-01

    Photochemical internalization (PCI) is a technique to improve the utilization of macromolecules (e.g. chemotherapeutic agents) in cancer therapy in a site-specific manner. The concept is based on the use of specially designed photosensitizers which localize preferentially in the membranes of endocytic vesicles. Upon exposure to light the photosensitizers induce the formation of reactive oxygen species such as singlet molecular oxygen. The photooxidation of the endocytic membranes leads to the release of the contents of the vesicles into the cytosol. In this way, macromolecules encapsulated by the vesicles will reach the cytosol and exert their biological activity instead of being degraded by lysosomal hydrolases. The utility of PCI for the treatment of malignant gliomas was investigated in vitro using an F98 rat glioma cell line. The cytotoxicity of 5-aminolevulinic acid (ALA) based PCI of bleomycin was compared to: (1) ALA-PDT, and (2) bleomycin. In all cases, monolayers were incubated in ALA, bleomycin, or ALA + bleomycin for 4 hours and were subsequently exposed to 635 nm light. Toxicity was evaluated using colony formation assays. F98 rat glioma cells in monolayer were found to be susceptible to the effects of both ALA-PDT and bleomycin. ALA-PDT was found to be particularly effective when light was delivered at a low irradiance of 5 mW cm -2. In this case, a radiant exposure of 20 J cm -2 resulted in only 4% survival. Bleomycin was found to be toxic at relatively low concentrations, incubation of F98 cells in 10 μg ml -1 for 4 hours resulted in 1% survival. The PCI effect was found to be negligible for the parameters investigated in the F98 cell line suggesting that: (1) the incubation time was sub-optimal and/or (2) ALA was inappropriate for this application.

  2. Raynaud's phenomenon in a child with medulloblastoma as a late effect of chemotherapy.

    Science.gov (United States)

    Atas, Erman; Korkmazer, Nadir; Artik, Hatice A; Babacan, Oguzhan; Kesik, Vural

    2015-01-01

    There are a lot of early or late side effects of chemotherapies. One of them is Raynaud's phenomenon (RP). Vascular toxicity associated with antineoplastic agents is notified in bleomycin alone therapy or in combination with cisplatin, vinblastine, and vincristine. The mechanism of RP associated with antineoplastic agents is unknown. All children receiving vinblastine, vincristine, bleomycin and cisplatin therapy, are followed and questioned about their complaint on RP. Long-term follow-up of surviving patients is recommended. Oncologists should be aware of the potential late toxic effects of antineoplastic drugs.

  3. Survival and Toxicity in Patients With Disseminated Germ CellCancer Aged 40 Years and Older

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Bandak, Mikkel; Thomsen, Maria F

    2014-01-01

    , treatment related toxicity and survival in patients aged ≥40 years treated with standard chemotherapy for GCC compared with a younger control group that received similar treatment during the same period. METHODS: From 1984 to 2011, 135 patients aged ≥40 years with disseminated GCC treated with bleomycin...... followed until death or October 1, 2011. RESULTS: The cumulated doses of BEP were comparable between the two groups, however, more patients aged ≥40 years were reduced in bleomycin doses based on a decrease in carbon monoxide diffusion capacity corrected for haemoglobin (P = 0.03). No differences between...

  4. A Rationale for Synchrony Strategies in Chemotherapy,

    Science.gov (United States)

    1973-01-01

    Barranco et al. (1) which was used for the treatment of melanoma as a prototype. Sherakava et al. (4) This work was supported in part by the Office of...tant.to have enough treatments. BIBLIOGRAPHY (1) Barranco , S.C., Romsdahl, M.M., Luce, J.K. and Humphrey, R.N. (1973) Bleomycin as a possible...synchronizing agent for human tumor cells in vivo. Cancer Research 33:882-7. (2) Barranco , S.C. and Humphrey, R.M. (1971) The effects of bleomycin on survival

  5. Acute inferior ST segment elevation myocardial infarction due to chemotherapy in a young man with testicular cancer

    Directory of Open Access Journals (Sweden)

    Veysel Tosun

    2016-12-01

    Full Text Available Testicular cancer is the most common malignancy in men between 15 and 29 years of age. cisplatin, etoposide and bleomycin combination chemotherapy remains the mainstay of testicular cancer treatment. Acute myocardial infarction is a rare complication of these chemotherapeutics. In this case report, we present a case of 36-year-old male with acute inferior ST-segment elevation myocardial infarction after bleomycin injection. Because the patient had no significant risk factors for coronary artery disease, the infarction was likely caused by the chemotherapy regimen.

  6. Angiotensin-converting enzyme

    DEFF Research Database (Denmark)

    Sørensen, P G; Rømer, F K; Cortes, D

    1984-01-01

    In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiolog......In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical...

  7. Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

    LENUS (Irish Health Repository)

    Robb, W B

    2010-03-01

    The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

  8. 5. MUTAGEN SENSITIVITY AND DNA REPAIR CAPACITY (DRC) AS RISK FACTORS FOR NON-SMALL CELL LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@An alkaline single cell gel electrophoresis assay has been standardised by which mutagen sensitivity and DNA repair capacity (DRC) can be measured in cryopreserved peripheral blood lymphocytes following induction and repair of DNA damage induced by bleomycin. In an ongoing case-control study, we have applied this assay to Caucasian

  9. Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents.

    Science.gov (United States)

    Ludwig, Luciane Bitelo; Valiati, Victor Hugo; Palazzo, Roberta Passos; Jardim, Laura Bannach; da Rosa, Darlan Pase; Bona, Silvia; Rodrigues, Graziela; Marroni, Norma Possa; Prá, Daniel; Maluf, Sharbel Weidner

    2013-01-01

    Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective.

  10. Catalytic Oxidation with a Non-Heme Iron Complex That Generates a Low-Spin FeIIIOOH Intermediate

    NARCIS (Netherlands)

    Roelfes, Gerard; Lubben, Marcel; Hage, Ronald; Que, Jr.; Feringa, Bernard

    2000-01-01

    The antitumor drug bleomycin (BLM) is proposed to act via a low-spin iron(III) hydroperoxide intermediate called “activated bleomycin”. To gain more insight into the mechanistic aspects of catalytic oxidation by these intermediates we have studied the reactivity of [(N4Py)Fe(CH3CN)](ClO4)2 (1) (N4Py

  11. [Lung infiltrations in Hodgkin lymphoma].

    Science.gov (United States)

    Ciurea-Löchel, A; Ciurea, A; Stey, C; Pestalozzi, B

    2001-08-02

    We report the case of a young patient presenting with cervical lymphadenopathy and interstitial pulmonary infiltrates due to Hodgkin's Disease. Although lung involvement regressed under chemotherapy, we observed new alveolar infiltrates during treatment. Steroid administration after exclusion of an infectious cause was followed by rapid clinical and radiological improvement, indicating the probable presence of pulmonary bleomycine toxicity.

  12. Chemotherapy-induced hypercoagulability and biomarkers for prediction of thromboembolic events in patients with metastatic testicular cancer

    NARCIS (Netherlands)

    Lubberts, S.; Boer, H.; Altena, R.; Meijer, C.; Lefrandt, J.D.; Nuver, J.; Mulder, A.B.; Lisman, T.; Kamphuisen, P.W.; Gietema, J.A.

    2013-01-01

    The majority of patients with disseminated testicular cancer can be cured with combination chemotherapy consisting of bleomycin, etoposide and cisplatin (BEP). Because of this success, focus shifts to adverse effects of this treatment. The incidences of venous and arterial thromboembolism (VTE and A

  13. Effects of diterpene phenol extract of Rosmarinus Officinalis on TGFβ1 and mRNA expressions of its signaling pathway molecules in the lung tissue of pulmonary fibrosis rats

    Institute of Scientific and Technical Information of China (English)

    杨礼腾

    2013-01-01

    Objective To investigate the regulative mechanism of the diterpene phenol extract of Rosmarinus Officinalis (DERO) on the imbalance of collagen metabolism of the lung tissue in pulmonary fibrosis rats.Methods Fifty healthy Sprague-Dawley rats were randomly divided into normal saline group (NS) ,bleomycin-induced lung

  14. The effect of marrow mesenchymal stem cell transplantation on pulmonary fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    黄坤

    2012-01-01

    Objective To study the possible mechanisms of marrow mesenchymal stem cells(MSC) in therapy of bleomycin(BLM)-induced pulmonary fibrosis in rats. Methods Fifty-four female Wistar rats were randomly divided into a control group,a BLM group and a MSC group. The control group receivel intratracheal normal

  15. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009189 Therapeutic effects of aerosolized signal transducer and activator of transcription 1 antisense oligonucleotide administered at different time points on bleomycin-induced pulmonary fibrosis:experiment with rats. LJ Jing(李晶),et al.Dept Respir Med,Affili Hosp,Luzhou Med Coll,Luzhou 646000.Natl Med J China,2009;89(12):831-835.

  16. Ototoxicity following Vinblastine chemotherapy in a patient of Hodgkin′s Lymphoma

    Directory of Open Access Journals (Sweden)

    Raj Kumar Nirban

    2015-01-01

    Full Text Available Sudden hearing loss is a well-known complication of certain chemotherapeutic agents. However, vinblastine has seldom been implicated causing ototoxicity. We report a case of sudden bilateral hearing loss in a 36-year-old male patient of Mixed cellularity Hodgkin′s lymphoma following standard adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy.

  17. No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission

    DEFF Research Database (Denmark)

    Jakobsen, Lasse H; Hutchings, Martin; de Nully Brown, Peter;

    2016-01-01

    , vinblastine, dacarbazine)/BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) therapy, were included in the study. The cumulative progression rates in the first 2 years were 4% (95% confidence interval [CI] 1-7) for patients with stage I-II disease vs. 12% (95...

  18. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer

    NARCIS (Netherlands)

    Nuver, J; Smit, AJ; van der Meer, J; van den Berg, MP; van der Graaf, WTA; Meinardi, MT; Sleijfer, DT; Hoekstra, HJ; van Gessel, AI; van Roon, AM; Gietema, JA

    2005-01-01

    Purpose; After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. Patients and

  19. The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Tianju Liu

    Full Text Available FIZZ (found in inflammatory zone 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.

  20. Gallium-67-citrate uptake in a case of acne vulgaris

    Energy Technology Data Exchange (ETDEWEB)

    Kipper, M.S.; Taylor, A.; Ashburn, W.L.

    1981-09-01

    A case of increased Ga-67 uptake in a patient with active acne vulgaris is reported. The scan was requested in a search for metastatic testicular carcinoma or bleomycin pulmonary toxicity. Careful clinical evaluation including physical examination was necessary in order to avoid an erroneous scan interpretation.

  1. End-on and side-on peroxo derivatives of non-heme iron complexes with pentadentate ligands : Models for putative intermediates in biological iron/dioxygen chemistry

    NARCIS (Netherlands)

    Roelfes, G; Vrajmasu, [No Value; Ho, RYN; Rohde, JU; Zondervan, C; la Crois, RM; Schudde, EP; Lutz, M; Spek, AL; Hage, R; Feringa, BL; Munck, E; Que, L; Vrajmasu, Vladislav; Ho, Raymond Y.N.; Rohde, Jan-Uwe; Crois, Rene M. la; Spek, Anthony L.; Que, Jr.; Feringa, Bernard

    2003-01-01

    Mononuclear iron(III) species with end-on and side-on peroxide have been proposed or identified in the catalytic cycles of the antitumor drug bleomycin and a variety of enzymes, such as cytochrome P450 and Rieske dioxygenases, Only recently have biomimetic analogues of such reactive species been, ge

  2. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

    Science.gov (United States)

    Black, Katharine E; Berdyshev, Evgeny; Bain, Gretchen; Castelino, Flavia V; Shea, Barry S; Probst, Clemens K; Fontaine, Benjamin A; Bronova, Irina; Goulet, Lance; Lagares, David; Ahluwalia, Neil; Knipe, Rachel S; Natarajan, Viswanathan; Tager, Andrew M

    2016-06-01

    Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

  3. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury.

    Science.gov (United States)

    Sueblinvong, Viranuj; Neveu, Wendy A; Neujahr, David C; Mills, Stephen T; Rojas, Mauricio; Roman, Jesse; Guidot, David M

    2014-01-01

    Fibrotic lung diseases increase with age. Previously we determined that senescence increases tissue expression of fibronectin EDA (Fn-EDA) and decreases fibroblast expression of Thy-1, and that fibrocytes contribute to fibrosis following bleomycin-induced lung injury in mice. In this study we hypothesized that fibroblasts lacking Thy-1 expression produce an extracellular matrix that promotes fibrocyte retention and myofibroblast transdifferentiation, thereby promoting fibrogenesis. Young and old mice were treated with bleomycin intratracheally; fibrocytes in the bone marrow, blood, and lungs were quantified, and lung fibroblast Thy-1 expression assessed. Bone marrow-derived fibrocytes were cultured on matrices derived from Thy-1(+) or Thy-1(-) fibroblasts ± the pro-fibrotic cytokine TGFβ1. Older mice had more fibrocytes in their bone marrows at baseline and more fibrocytes in their lungs following bleomycin treatment. In parallel, lung fibroblasts in older mice had lower expression of Thy-1 at baseline that increased transiently 7 days after bleomycin treatment but then rapidly waned such that 14 days after bleomycin treatment Thy-1 expression was again markedly lower. Fibrocytes cultured on matrices derived from Thy-1(-) fibroblasts + TGFβ1 had increased gene expression for collagen type 1, fibronectin, Fn-EDA, and α-smooth muscle actin. In parallel, whereas the matrices derived from Thy-1(-) fibroblasts stimulated phosphorylation of Akt in cultured fibrocytes, the matrices derived from Thy-1(+) fibroblasts induced apoptosis. These findings suggest that senescence increases fibrocyte recruitment to the lung following injury and that loss of Thy-1 expression by lung fibroblasts promotes fibrocyte retention and myofibroblast trans-differentiation that renders the "aging lung" susceptible to fibrosis.

  4. Coordination chemistry and solution structure of Fe(II)-peplomycin. Two possible coordination geometries.

    Science.gov (United States)

    Li, Yang; Lehmann, Teresa

    2012-06-01

    The solution structure of Fe(II)-peplomycin was determined from NMR data collected for this molecule. As found previously for Fe(II)- and Co(II)-bound bleomycin; the coordination sphere of the metal is composed of the primary and secondary amines in β-aminoalanine, the pyrimidine and imidazole rings in the pyrimidinylpropionamide, and β-hydroxyhistidine moieties, respectively, the amine nitrogen in β-hydroxyhistidine, and either the carbamoyl group in mannose or a solvent molecule. The two most discussed coordination geometries for the aforementioned ligands in metallo-bleomycins have been tested against the NMR data generated for Fe(II)-peplomycin. The interpretation of the experimental evidence obtained through molecular dynamics indicates that both geometries are equally likely in solution for this compound in the absence of DNA, but arguments are offered to explain why one of these geometries is preferred in the presence of DNA.

  5. Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials.

    Science.gov (United States)

    Iwamoto, Naoki; Distler, Jörg H W; Distler, Oliver

    2011-02-01

    Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events.

  6. Preclinical validation of electrochemotherapy as an effective treatment for brain tumors

    DEFF Research Database (Denmark)

    Agerholm-Larsen, Birgit; Iversen, Helle K; Ibsen, Per

    2011-01-01

    Electrochemotherapy represents a strategy to enhance chemotherapeutic drug uptake by delivering electrical pulses which exceed the dielectric strength of the cell membrane, causing transient formation of structures that enhance permeabilization. Here we show that brain tumors in a rat model can...... treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment......, we found that 9 of 13 rats (69%) receiving electrochemotherapy displayed a complete elimination of tumor, in contrast to control rats treated with bleomycin only, pulses only, or untreated where tumor progression occurred in each case. Necrosis induced by electrochemotherapy was restricted...

  7. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale

    DEFF Research Database (Denmark)

    Gallamini, Andrea; Barrington, Sally F; Biggi, Alberto

    2014-01-01

    A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of 'interim' positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility...... of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin......, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently...

  8. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis

    Science.gov (United States)

    Kaminski, Naftali; Allard, John D.; Pittet, Jean F.; Zuo, Fengrong; Griffiths, Mark J. D.; Morris, David; Huang, Xiaozhu; Sheppard, Dean; Heller, Renu A.

    2000-02-01

    The molecular mechanisms of pulmonary fibrosis are poorly understood. We have used oligonucleotide arrays to analyze the gene expression programs that underlie pulmonary fibrosis in response to bleomycin, a drug that causes lung inflammation and fibrosis, in two strains of susceptible mice (129 and C57BL/6). We then compared the gene expression patterns in these mice with 129 mice carrying a null mutation in the epithelial-restricted integrin 6 subunit (6/-), which develop inflammation but are protected from pulmonary fibrosis. Cluster analysis identified two distinct groups of genes involved in the inflammatory and fibrotic responses. Analysis of gene expression at multiple time points after bleomycin administration revealed sequential induction of subsets of genes that characterize each response. The availability of this comprehensive data set should accelerate the development of more effective strategies for intervention at the various stages in the development of fibrotic diseases of the lungs and other organs.

  9. Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Taalman, R.D.F.M.; Scheres, J.M.J.C.; Hustinx, T.W.J. (Katholieke Univ. Nijmegen (Netherlands). Dept. of Human Genetics); Jaspers, N.G.J.; de Wit, J. (Erasmus Universiteit, Rotterdam (Netherlands). Lab. of Cell Biology and Genetics)

    1983-02-01

    The Nijmegen Breakage Syndrome (NBS) is a new chromosomal instability disorder different from ataxia telangiectasia (AT) and other chromosome-breakage syndromes. Cells from an NBS patient appeared hypersensitive to X-irradiation. X-rays induced significantly more chromosomal damage in NBS lymphocytes and fibroblasts than in normal cells. The difference was most pronounced after irradiation in G/sub 2/. Further, NBS fibroblasts were more readily by X-rays than normal fibroblasts. In addition, the DNA synthesis in NBS cells was more resistant to X-rays and bleomycin than that in normal cells. The reaction of NBS cells to X-rays and bleomycin was similar to that of cells from patients with ataxia telangiectasia. Our results indicate that NBS and AT, which also have similar chromosomal characteristics, must be closely related.

  10. Effect of solcoseryl on antitumour action and acute toxicity of some antineoplastic drugs.

    Science.gov (United States)

    Danysz, A; Sołtysiak-Pawluczuk, D; Czyzewska-Szafran, H; Jedrych, A; Jastrzebski, Z

    1991-01-01

    The in vivo effect of Solcoseryl on the antitumour activity and acute toxicity of some antineoplastic drugs was examined. It was found that Solcoseryl does not inhibit the antineoplastic effectiveness of the drugs against transplantable P 388 leukaemia in mice. Studies of the effect of Solcoseryl on acute toxicity of selected antineoplastic drugs in mice revealed that the biostimulator could exert a modifying influence. The prior administration of Solcoseryl significantly decreases the acute toxicity of methotrexate but has no effect on acute toxicity of 5-fluorouracil, increases the acute toxicity of bleomycin and vinblastine and has no effect on acute toxicity of methotrexate and mitoxantron. On the other hand, Solcoseryl administered simultaneously with the antineoplastic drugs increases acute toxicity of 5-fluorouracil, bleomycin and mitoxantron. The protective effect of the biostimulator noted exclusively against acute toxicity of 5-fluorouracil was also observed after multiple administration of this anticancer drug.

  11. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF-β signaling pathway.

    Science.gov (United States)

    Li, Li; Huang, Wenting; Li, Kunlin; Zhang, Kejun; Lin, Caiyu; Han, Rui; Lu, Conghua; Wang, Yubo; Chen, Hengyi; Sun, Fenfen; He, Yong

    2015-12-22

    Interstitial lung disease (ILD) is a serious side-effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Therefore, it is necessary to study underlying mechanisms for the development of pulmonary fibrosis induced by EGFR-TKI and potential approaches to attenuate it. Metformin is a well-established and widely prescribed oral hypoglycemic drug, and has gained attention for its potential anticancer effects. Recent reports have also demonstrated its role in inhibiting epithelial-mesenchymal transition and fibrosis. However, it is unknown whether metformin attenuates EGFR-TKI-induced pulmonary fibrosis. The effect of metformin on EGFR-TKI-induced exacerbation of pulmonary fibrosis was examined in vitro and in vivo using MTT, Ki67 incorporation assay, flow cytometry, immunostaining, Western blot analysis, and a bleomycin-induced pulmonary fibrosis rat model. We found that in lung HFL-1 fibroblast cells, TGF-β or conditioned medium from TKI-treated lung cancer PC-9 cells or conditioned medium from TKI-resistant PC-9GR cells, induced significant fibrosis, as shown by increased expression of Collegen1a1 and α-actin, while metformin inhibited expression of fibrosis markers. Moreover, metformin decreased activation of TGF-β signaling as shown by decreased expression of pSMAD2 and pSMAD3. In vivo, oral administration of gefitinib exacerbated bleomycin-induced pulmonary fibrosis in rats, as demonstrated by HE staining and Masson staining. Significantly, oral co-administration of metformin suppressed exacerbation of bleomycin-induced pulmonary fibrosis by gefitinib. We have shown that metformin attenuates gefitinib-induced exacerbation of TGF-β or bleomycin-induced pulmonary fibrosis. These observations indicate metformin may be combined with EGFR-TKI to treat NSCLC patients.

  12. Prognostic factors in the treatment of inoperable orofacial tumours with simultaneous radio- and intraarterial chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Szepesi, T.; Stadler, B.; Hohenberg, G.; Hollmann, K.; Mailath, G.; Kuehboeck, J.

    1985-05-01

    Between January 1973 and April 1982 66 evaluable patients with advanced inoperable orofacial tumours underwent intraarterial Bleomycin and Methotrexate with simultaneous radiotherapy in a prospective study. 32 patients had no previous treatment, 34 patients had initial surgery, radiotherapy and/or chemotherapy. 15 mg Bleomycin were administered through a catheter into the arteria externa carotis daily in the morning. 25 mg Methotrexate were given in the same way at night followed by 3 mg Calcium-Leucovorin i.m. every 8 hours. The cumulative dose was 300 mg Bleomycin and 500 mg Methotrexate. Four hours after the administration of Bleomycin the target volume was irradiated (single fraction 2 Gy, total dose 60 to 65 Gy). The overall response rate was 65% containing 17% complete and 48% partial remission. Destruction of the bone appeared to be the most important index at the start of the therapy. Further prognostic determinants as previous treatment, localisation of the primary tumours (maxilla and start of the therapy. Further prognostic determinants as previous treatment, localisation of the primary tumours (maxilla and mandibula respectively oral cavity and oropharynx) and local regional lymphonode stage missed statistically significance in the survival time, may be due to a possible radiosensitizing effect of the simultaneous chemotherapy. Complete remission turned out to be the most important prognostic factor after the end of treatment. Patients responding with complete remission show a mediam disease free survival of 56+months and a median survival time of 82 months. Acute reactions were reversibel. Only in 14% of the patients the treatment could not be finished. Better results could be obtained by electron-affinic radiosensitizers and high LET radiation.

  13. Efficient transformation of Penicillium chrysogenum mediated by Agrobacterium tumefaciens LBA4404 for cloning of Vitreoscilla hemoglobin gene

    OpenAIRE

    Sun,Chuan-Bao; Kong,Qiu-Lian; Xu,Wen-Si

    2002-01-01

    The vgb and bleomycin resistance genes could be efficiently transferred into the filamentous fungus Penicillium chrysogenum under help of T-DNA of Agrobacterium tumefaciens LBA4404 and the transferred genes were integrated at a chromosomal locus of P. chrysogenum. Transformation using A. tumefaciens LBA4404 could be enhanced in the presence of acetosyringone (AS) when being carried out in the conidiaand mycelium. The efficiencies of transformation could be improved up to 10 folds compared wit...

  14. Cordyceps Militaris Alleviates Severity of Murine Acute Lung Injury Through miRNAs-Mediated CXCR2 Inhibition

    Directory of Open Access Journals (Sweden)

    Sheng Liu

    2015-07-01

    Full Text Available Background/Aims: Acute lung injury (ALI and acute respiratory distress syndrome (ARDS are lethal diseases in humans, and the current treatments have limited therapeutic effects. Cordyceps militaris (CM is a caterpillar-grown traditional medicinal mushroom, and has been used as a natural invigorant for longevity, endurance, and vitality in China. Recently, purified extracts from CM have been shown to have beneficial effects on various diseases including cancer. Nevertheless, a role of CM in ALI has not been examined previously. Methods: Here, we used a bleomycin-induced ALI model to study the effects of CM on the severity of ALI in mice. The levels of CXCR2, a receptor for Interleukin 8 (IL-8 in pulmonary microvascular endothelial cells, were examined in different experimental groups. The levels of microRNA (miR-1321 and miR-3188 were also examined in lung samples and in CM. Adeno-associated viruses carrying miR-1321 and miR-3188 were injected into bleomycin-treated mice for evaluation their effects on the severity of ALI. Results: CM treatment significantly alleviated the severity of bleomycin-induced ALI in mice. The increases in lung CXCR2 by bleomycin were significantly reduced by CM at protein level, but not at mRNA level. CM contained high levels of 2 miRNAs (miR-1321 and miR-3188 that target 3'-UTR of CXCR2 mRNA to inhibit its expression. Overexpression of miR-1321 and miR-3188 in mouse lung through AAV-mediated gene therapy mimicked the effects of CM. Conclusion: CM may alleviate severity of murine ALI through miRNAs-mediated CXCR2 inhibition.

  15. Complementation of the Yeast Model System Reveals that Caenorhabditis elegans OCT-1 Is a Functional Transporter of Anthracyclines

    OpenAIRE

    Nicolas Brosseau; Emil Andreev; Dindial Ramotar

    2015-01-01

    The yeast plasma membrane protein Agp2 belongs to the family of amino acid transporters. It acts as a regulator that controls the expression of several uptake transporter genes such as DUR3 and SAM3 encoding two high-affinity polyamine permeases. agp2Δ mutants display extreme resistance to several cationic compounds including polyamines, the anticancer agent bleomycin, and cationic antifungal peptides. We propose that Agp2 might be involved in regulating the uptake of other cationic anticance...

  16. Isolated Femoral Muscle and Bone Metastases Rarely Encountered in Testicular Seminoma

    Directory of Open Access Journals (Sweden)

    Serkan Degirmencioglu

    2013-01-01

    Full Text Available Isolated muscle and bone metastases are rarely encountered in patients with testicular seminomas. In the present study, a patient who was admitted with pain, loss of motion, and swelling in the right leg 20 months following surgery for stage I seminoma was presented. Hypermetabolic lesion was detected in the right femoral muscle and bone via positron emission tomography. After the presence of metastasis from seminoma was confirmed by biopsy, bleomycin, cisplatin, and etoposide, combination chemotherapy was administered to the patient.

  17. Functional and Structural Study of the Dimeric Inner Membrane Protein SbmA

    OpenAIRE

    Corbalan, Natalia; Runti, Giulia; Adler, Conrado; Covaceuszach, Sonia; Ford, Robert C.; Lamba, Doriano; Beis, Konstantinos; Scocchi, Marco; Vincent, Paula A.

    2013-01-01

    SbmA protein has been proposed as a dimeric secondary transporter. The protein is involved in the transport of microcins B17 and J25, bleomycin, proline-rich antimicrobial peptides, antisense peptide phosphorodiamidate morpholino oligomers, and peptide nucleic acids into the Escherichia coli cytoplasm. The sbmA homologue is found in a variety of bacteria, though the physiological role of the protein is hitherto unknown. In this work, we carried out a functional and structural analysis to dete...

  18. Two Cases of Cerebral Sinus Venous Thrombosis Following Chemotherapy for Non-Seminomatous Germ Cell Tumor

    OpenAIRE

    Papet, C.; Gutzeit, A.; Pless, M.

    2011-01-01

    We report on two patients with cerebral sinus venous thrombosis following chemotherapy with cisplatin, bleomycin and etoposide for non-seminomatous germ cell tumor. Headache and neurological deficits were the leading symptoms. Cancer and cisplatin chemotherapy are well-known risk factors for thromboembolic events. The therapeutic strategy is an anticoagulant therapy. Symptoms are usually reversible within weeks under this therapy. Therefore, in patients with testicular cancer and chemotherapy...

  19. Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

    Science.gov (United States)

    2015-08-01

    Sun, Ph.D. CONTRACTING ORGANIZATION: Seattle Institute for Biomedical and Clinical Research Seattle, WA 98108-1532 REPORT DATE: August 2015 TYPE OF...NUMBERSeattle Institute for Biomedical and Clinical Research 1660 S Columbian Way, S-151F Seattle, WA 98108-1532 9. SPONSORING / MONITORING AGENCY NAME(S) AND...Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production. Am J Respir Cell Mol Biol. 42: 432

  20. p53 and miR-34a Feedback Promotes Lung Epithelial Injury and Pulmonary Fibrosis.

    Science.gov (United States)

    Shetty, Shwetha K; Tiwari, Nivedita; Marudamuthu, Amarnath S; Puthusseri, Bijesh; Bhandary, Yashodhar P; Fu, Jian; Levin, Jeffrey; Idell, Steven; Shetty, Sreerama

    2017-03-05

    Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. The pathogenesis of interstitial lung diseases, including its most common form, IPF, remains poorly understood. Alveolar epithelial cell (AEC) apoptosis, proliferation, and accumulation of myofibroblasts and extracellular matrix deposition results in progressive loss of lung function in IPF. We found induction of tumor suppressor protein, p53, and apoptosis with suppression of urokinase-type plasminogen activator (uPA) and the uPA receptor in AECs from the lungs of IPF patients, and in mice with bleomycin, cigarette smoke, silica, or sepsis-induced lung injury. Treatment with the caveolin-1 scaffolding domain peptide (CSP) reversed these effects. Consistent with induction of p53, AECs from IPF lungs or mice with diverse types of lung injuries showed increased p53 acetylation and miR-34a expression with reduction in Sirt1. This was significantly reduced after treatment of wild-type mice with CSP, and uPA-deficient mice were unresponsive. Bleomycin failed to induce miR-34a in p53- or plasminogen activator inhibitor-1 (PAI-1)-deficient mice. CSP-mediated inhibition of miR-34a restored Sirt1, suppressed p53 acetylation and apoptosis in injured AECs, and prevented pulmonary fibrosis (PF). AEC-specific suppression of miR-34a inhibited bleomycin-induced p53, PAI-1, and apoptosis and prevented PF, whereas overexpression of precursor-miR-34a increased p53, PAI-1, and apoptosis in AECs of mice unexposed to bleomycin. Our study validates p53-miR-34a feedback as a potential therapeutic target in PF.

  1. Haemolytic anaemia after cisplatin treatment.

    OpenAIRE

    Levi, J A; Aroney, R S; Dalley, D N

    1981-01-01

    Normochromic or normocytic anaemia is a common side effect of treatment with cisplatin. Two patients treated with cisplatin 100 mg/m2 in combination with vinblastine, bleomycin, and actinomycin D developed haemolytic anaemia. Neither patient had evidence of haemolysis before treatment, and in both cases severe haemolytic anaemia developed after several courses of cisplatin and when the cancer had regressed almost completely. The importance of haemolysis in the development of anaemia after cis...

  2. Hyaluronic Acid is Overexpressed in Fibrotic Lung Tissue and Promotes Collagen Expression

    Science.gov (United States)

    2009-04-01

    injured adult tissue (1-4). Periostin has also been shown to regulate inflammatory cell infiltration in allergic disease in the esophagus and lung (5...model for scleroderma lung disease because both bleomycin treatment and scleroderma lung disease produce inflammatory alveolitis and overproduction...t, a fibroblastic lineage 4. essential for cardiac healing after 5. ., ltration in allergic lung and esophageal responses. 6. r, D.E

  3. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

    Science.gov (United States)

    Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

    2015-07-21

    The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

  4. Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and Subset Distinctions

    Science.gov (United States)

    2015-09-01

    subsets. Methods Gene expression measured in skin from mice with sclerodermatous graft-versus-host disease (sclGVHD), bleomycin-induced fibrosis, Tsk1... penetrant .) In) addition) to) a) readily) apparent) skin ) fibrosis) resulting) from) ECM) anomalies,) Tsk2/+) mice) show) more) autoimmune) and... penetrant in Tsk2/þ heterozygotes and it is homozygous embryonic lethal. Tsk2/þ mice have many features of human disease including tight skin , dysregulated

  5. The Integrative Studies of Genetic and Environmental Factors in Systemic Sclerosis

    Science.gov (United States)

    2011-05-01

    same results. Notably, increased hair follicles were incon- sistently seen in Ctgf siRNA- and SPARC siRNA-treated bleomycin-induced skins. The lung...lymphocytes are central players in cell-mediated immunity, which usually stimulate target cells such as fibroblasts. Therefore, the combination of human...connective tissues are the major target of pathogens and/or primary sites of dysfunction. A typical pathological consequence of dysfunctional

  6. Concentration is more important than dose when using intralesional Pingyangmycin injection for treatment of vascular malformations

    Institute of Scientific and Technical Information of China (English)

    周琴; 郑家伟; 杨秀娟; 王延安

    2010-01-01

    @@ Vascular anomalies represent a wide spectrum of pathology with different clinico-pathological characteristics.Approximately 60% of them occur in the head and neck region.A variety of therapeutic modalities have been reported to manage vascular anomalies over the years,including surgical resection,laser therapy and sclerotherapy,etc.Bleomycin has been successfully used in intralesional injection treatment of cystic hydromas and haemangiomas,based specifically on a high sclerosing effect on vascular endothelium[1].

  7. Regulation of COLx1(1), LO and COX-1 mRNA Expression by Prostaglandin E2 in Human Embryonic Fibroblasts, IMR-90.

    Science.gov (United States)

    1998-01-01

    synthesis of LO [Roy et al., 1996] which is an active participant during collagen deposition [ Pinnell and Martin, 1968]. In * 2 addition, these two cytokines...groups of lysyl or hydroxylysyl residues in collagen fibrils to peptidyl o-aminoadipic-8-semialdehyde [ Pinnell and Martin, 1968]. This process yields...macrophage which is considered a central cell in the cytokine network of the lung [Scheule et al., 1992]. In any case , in a bleomycin-induced pulmonary

  8. Successful Treatment of Refractory Wart with a Topical Activated Vitamin D in a Renal Transplant Recipient

    Directory of Open Access Journals (Sweden)

    Luciano Moscarelli

    2011-01-01

    Full Text Available Warts are benign proliferations of the skin and mucosa caused by infection with human papillomavirus. They are commonly treated with destructive modalities such as cryotherapy with liquid nitrogen, local injection of bleomycin, electrocoagulation, topical application of glutaraldehyde, and local and systemic interferon-β therapy. These treatment modalities often cause pain and sometimes scarring or pigmentation after treatment. We herein report a case with a right index finger wart, which was successfully treated with a topical activated vitamin D.

  9. Worm-like thrombus in left main coronary artery after cytostatic treatment.

    Science.gov (United States)

    Karavelioglu, Yusuf; Ekicibasi, Erkan; Tanalp, Ali C; Karapinar, Hekim; Aung, Soe M

    2010-07-01

    This paper reports a 43-year-old patient who had a large, mobile, worm-like thrombus in the left main coronary artery after receiving a chemotherapy regimen containing cisplatin, bleomycin and etoposide for a nonseminomatous testes tumor. The patient was successfully treated with thrombolytic therapy. Physicians should be aware that thrombotic events may be observed after the administration of certain chemotherapeutic agents, particularly cisplatin.

  10. Pulmonary damage caused by cytostatics and paraquat

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, G.; Woeltjen, H.H.; Schauer, A.

    1981-09-01

    Substances which exercise a pulmonary toxic action will first of all produce alveolar and perivascular oedemas followed by fibrosis. Differential diagnosis is explained on the basis of two cases of a fatal mitomycin fibrosis of the lung, as well as the observation of fibrous changes following the administration of Bleomycin and Metothrexat. The course of pulmonary fibroses caused by paraquat is described for two cases of fatal paraquat intoxications.

  11. Intraperitoneal cytostatics impair early post-operative collagen synthesis in experimental intestinal anastomosesP6.

    OpenAIRE

    Martens, M F; Hendriks, T; Wobbes, T; DE PONT J.J.

    1992-01-01

    Collagen synthesis in intestinal anastomoses has been measured in rats after in vivo administration of cytostatics. The cytostatics were administered during 5 consecutive days either intravenously or intraperitoneally. On day 3 of the course the rats received both an ileal and a colonic anastomosis. The animals were sacrificed 3 and 7 days after operation. The cytostatics regimen used was a combination of 5-fluorouracil, bleomycin and cisplatinum in a dose of 10, 2 and 0.35 mg kg-1 day-1, res...

  12. Antimutagenic properties of Mangifera indica L. stem bark extract and evaluation of its effects on hepatic CYP1A1.

    Science.gov (United States)

    Morffi, Janet; Rodeiro, Idania; Hernández, Sandra Luz; González, Leonora; Herrera, Jose; Espinosa-Aguirre, J Javier

    2012-09-01

    Mangifera indica stem bark extract (MSBE) is a Cuban natural product which has shown strong antioxidant properties. In this work, the antimutagenic effect of MSBE was tested against 10 well-known mutagens/carcinogens in the Ames test in the absence or presence of metabolic fraction (S9). The chemical mutagens tested included: cyclophosphamide, mitomycin C, bleomycin, cisplatin, dimethylnitrosamine (DMNA), benzo[a]pyrene (BP), 2-acetylaminofluorene (2-AAF), sodium azide, 1-nitropyrene (1-NP) and picrolonic acid. Protective effects of the extract were also evaluated by comparing the efficiency of S9 fraction obtained from rats treated during 28 days with oral doses of MSBE (50-500 mg/kg) with that obtained from rats treated with vehicle (control) to activate bleomycin and cyclophosphamide in the Ames test. MSBE concentrations between 50 and 500 μg/plate significantly reduced the mutagenicity mediated by all the chemicals tested with the exception of sodium azide. Higher mutagenicity was found when bleomycin and cyclophosphamide (CP) were activated by control S9 than by MSBE S9. In addition, inhibition of CYP1A1 microsomal activity was observed in the presence of MSBE (10-20 μg/ml). We can conclude that besides its potent antioxidant activity previously reported, MSBE may also exert a chemoprotective effect due to its capacity to inhibit CYP activity.

  13. Rare cavernous lymphangioma of the bladder in an adult female:treatment and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Feng Qu; Jinyu Zheng; Yajun Xiao; Yifei Xing; Chuanguo Xiao

    2006-01-01

    Objective: Lymphangioma is a benign tumor representing a congenital malformation of the lymphatic channels. The cavernous lymphangioma of the bladder did not report before. Here we report 1 case of cavernous lymphangioma of the bladder in an adult female and review the literature in order to accumulate the experience of diagnosis and treatment for these diseases. Methods: In our case a 50-year-old woman presented with irritative voiding symptoms and had painless macroscopic hematuria at times. Cystoscopy showed a non-papillary tumor at apex vesicae and mucous membrane hyperaemia between the two orifices within the trigone. The pathologic diagnosis was cystitis glandularis with hyperplasia of urothelium and cavernous lymphangioma in lamina propria. Transurethral resection was performed and then bleomycin A5 was injected into lesion multipoint applying ureteral catheter with puncture needle. Results: Two months after operation the irritative voiding symptoms improved and the urine analysis was normal. Cystoscopy showed no residual tumor. Bleomycin A5 was injected into the lesion area again just like the operation before. All symptoms disappeared completely when the patient was examined a month later. There was no side effect after injection and no recurrence during the follow-up of 1 year. Conclusion: Lymphangioma of the bladder can be diagnosed exactly by cystoscopy and pathological examination. Surgery may be the best treatment. The bleomycin A5 intralesional sclerosant is also an effective therapy for the disease after surgical removal.

  14. Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis

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    Bramanti Placido

    2011-04-01

    Full Text Available Abstract Background Adrenomedullin (AM, a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. AM are widely distributed in various tissues and acts as a local vasoactive hormone in various conditions. Methods In the present study, we investigated the efficacy of AM on the animal model of bleomycin (BLM-induced lung injury. Mice were subjected to intratracheal administration of BLM and were assigned to receive AM daily by an intraperitoneal injection of 200 ngr/kg. Results and Discussion Myeloperoxidase activity, lung histology, immunohistochemical analyses for cytokines and adhesion molecules expression, inducible nitric oxide synthase (iNOS, nitrotyrosine, and poly (ADP-ribose polymerase (PARP were performed one week after fibrosis induction. Lung histology and transforming growth factor beta (TGF-β were performed 14 and 21 days after treatments. After bleomycin administration, AM-treated mice exhibited a reduced degree of lung damage and inflammation compared with BLM-treated mice, as shown by the reduction of (1 myeloperoxidase activity (MPO, (2 cytokines and adhesion molecules expression, (3 nitric oxide synthase expression, (4 the nitration of tyrosine residues, (5 poly (ADP-ribose (PAR formation, a product of the nuclear enzyme poly (ADP-ribose polymerase (PARP (6 transforming growth factor beta (TGF-β (7and the degree of lung injury. Conclusions Our results indicate that AM administration is able to prevent bleomycin induced lung injury through the down regulation of proinflammatory factors.

  15. Preliminary study of therapeutic effects of panax notoginside and methylprednisolone on pulmonary fibrosis in rats

    Institute of Scientific and Technical Information of China (English)

    CUI She-huai; LI Xue-jun

    2004-01-01

    Objective: To study the therapeutic effects of panax notoginside (PN) and methylprednisolone (MP) on pulmonary fibrosis in rats. Methods: Bleomycin was introduced into the bronchial tree of 75 Wistar male rats through a tracheal incision to establish a rat model of pulmonary fibrosis (PF). The rats were equally divided into 3 groups: PF group,PN treated group and MP treated group. Five rats of each group were killed 1, 3, 7, 14 and 28 d after the administration of bleomycin and the specimens of lung tissue and plasma were collected for the determination of content of collagen Ⅰ and Ⅲwith immunohistochemical method and the level of MIP-1α and MCP-1 with ELIZA. Results: The severity of PF, the content of collagen Ⅰ and Ⅲ and the level of MIP- 1 α and MCP- 1 were significantly decreased in PN and MP treated groups than in PF group ( P < 0.05). Conclusion: PN and MP are effective to control the development of PF induced with bleomycin in rats.

  16. Anticlastogenic potential and antioxidant effects of an aqueous extract of pulp from the pequi tree (Caryocar brasiliense Camb

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    Juliana Khouri

    2007-03-01

    Full Text Available The effectiveness of an aqueous extract of Caryocar brasiliense (Caryocaraceae Camb pulp, popularly known in Brazil as pequi, against clastogenicity induced by cyclophosphamide and bleomycin was evaluated using an in vivo mouse bone marrow cell micronuclei test, an in vitro Chinese hamster ovary cell (CHO-K1 chromosome aberration test and an in vitro antioxidant assay based on the oxidative damage to 2-deoxy-D-ribose (2-DR induced by hydroxyl radicals (•OH generated by the reaction between ascorbic acid and (Fe III-EDTA. In mouse bone marrow cells the extract showed a protective effect against micronuclei induced by cyclophosphamide and bleomycin but did not interfere with polychromatic bone marrow erythrocyte proliferation, except when the mice had been treated with the highest dose of cyclophosphamide. When CHO-K1 cells were pretreated by adding 0.01, 0.05 or 0.1 mL of extract per mL of cell culture medium 24 or 48 h before bleomycin or cyclophosphamide there was a protective effect against chromosome breaks and a significant decrease in the mitotic index (a measure of cytotoxicity of the CHO-K1 cells. The extract also had a protective effect against oxidative hydroxyl radical damage to 2-DR. This study suggests that C. brasiliense pulp aqueous extract has anticlastogenic potential, possibly due to its antioxidative properties.

  17. Effects of antineoplastic agents and ionizing irradiation on a human testicular cancer xenograft

    Energy Technology Data Exchange (ETDEWEB)

    Osieka, R.; Pfeiffer, R.; Glatte, P.; Schmidt, C.G.; Bamberg, M.; Scherer, E.

    1985-01-01

    Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease.

  18. mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis.

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    Yao-Song Gui

    Full Text Available The mammalian target of rapamycin (mTOR signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1(fx/+ (STT. Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.

  19. Targeting miR-155 to Treat Experimental Scleroderma.

    Science.gov (United States)

    Yan, Qingran; Chen, Jie; Li, Wei; Bao, Chunde; Fu, Qiong

    2016-02-01

    Scleroderma is a refractory autoimmune skin fibrotic disorder. Alterations of microRNAs in lesional skin could be a new approach to treating the disease. Here, we found that expression of miR-155 was up regulated in lesional skin tissue from patients with either systemic or localized scleroderma, and correlated with fibrosis area. Then we demonstrated the potential of miR-155 as a therapeutic target in pre-clinical scleroderma models. MiR-155(-/-) mice were resistant to bleomycin induced skin fibrosis. Moreover, topical antagomiR-155 could effectively treat mice primed with subcutaneous bleomycin. In primary skin fibroblast, miR-155 silencing could inhibit collagen synthesis function, as well as signaling intensity of two pro-fibrotic pathways, Wnt/β-catenin and Akt, simultaneously. We further showed that miR-155 could regulate the two pathways via directly targeting casein kinase 1α (CK1α) and Src homology 2-containing inositol phosphatase-1 (SHIP-1), as previous reports. Mice with miR-155 knockout or topical antagomir-155 treatment showed inhibited Wnt/β-catenin and Akt signaling in skin upon bleomycin challenge. Together, our data suggest the potential of miR-155 silencing as a promising treatment for dermal fibrosis, especially in topical applications.

  20. Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/- knockout mice.

    Directory of Open Access Journals (Sweden)

    Darrell Pilling

    Full Text Available Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis, myelofibrosis, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system. Fibrosis involves the accumulation and differentiation of many immune cells, including macrophages and fibroblast-like cells called fibrocytes. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2 inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP also promotes the formation of immuno-regulatory Mreg macrophages. To elucidate the endogenous function of SAP, we used bleomycin aspiration to induce pulmonary inflammation and fibrosis in mice lacking SAP. Compared to wildtype C57BL/6 mice, we find that in Apcs-/- "SAP knock-out" mice, bleomycin induces a more persistent inflammatory response and increased fibrosis. In both C57BL/6 and Apcs-/- mice, injections of exogenous SAP reduce the accumulation of inflammatory macrophages and prevent fibrosis. The types of inflammatory cells present in the lungs following bleomycin-aspiration appear similar between C57BL/6 and Apcs-/- mice, suggesting that the initial immune response is normal in the Apcs-/- mice, and that a key endogenous function of SAP is to promote the resolution of inflammation and fibrosis.

  1. Effect of P2X7 receptor knockout on AQP-5 expression of type I alveolar epithelial cells.

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    Georg Ebeling

    Full Text Available P2X7 receptors, ATP-gated cation channels, are specifically expressed in alveolar epithelial cells. The pathophysiological function of this lung cell type, except a recently reported putative involvement in surfactant secretion, is unknown. In addition, P2X7 receptor-deficient mice show reduced inflammation and lung fibrosis after exposure with bleomycin. To elucidate the role of the P2X7 receptor in alveolar epithelial type I cells we characterized the pulmonary phenotype of P2X7 receptor knockout mice by using immunohistochemistry, western blot analysis and real-time RT PCR. No pathomorphological signs of fibrosis were found. Results revealed, however, a remarkable loss of aquaporin-5 protein and mRNA in young knockout animals. Additional in vitro experiments with bleomycin treated precision cut lung slices showed a greater sensitivity of the P2X7 receptor knockout mice in terms of aquaporin-5 reduction as wild type animals. Finally, P2X7 receptor function was examined by using the alveolar epithelial cell lines E10 and MLE-12 for stimulation experiments with bleomycin. The in vitro activation of P2X7 receptor was connected with an increase of aquaporin-5, whereas the inhibition of the receptor with oxidized ATP resulted in down regulation of aquaporin-5. The early loss of aquaporin-5 which can be found in different pulmonary fibrosis models does not implicate a specific pathogenetic role during fibrogenesis.

  2. Enhancement of therapeutic drug and DNA delivery into cells by electroporation* Enhancement of therapeutic drug and DNA delivery into cells by electroporation

    Science.gov (United States)

    Rabussay, Dietmar; Dev, Nagendu B.; Fewell, Jason; Smith, Louis C.; Widera, Georg; Zhang, Lei

    2003-02-01

    The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as `electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing `pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm-1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

  3. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  4. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

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    Nora Semren

    Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

  5. Genetic analysis of the Rhizobium meliloti bacA gene: functional interchangeability with the Escherichia coli sbmA gene and phenotypes of mutants.

    Science.gov (United States)

    Ichige, A; Walker, G C

    1997-01-01

    The Rhizobium meliloti bacA gene encodes a function that is essential for bacterial differentiation into bacteroids within plant cells in the symbiosis between R. meliloti and alfalfa. An Escherichia coli homolog of BacA, SbmA, is implicated in the uptake of microcin B17, microcin J25 (formerly microcin 25), and bleomycin. When expressed in E. coli with the lacZ promoter, the R. meliloti bacA gene was found to suppress all the known defects of E. coli sbmA mutants, namely, increased resistance to microcin B17, microcin J25, and bleomycin, demonstrating the functional similarity between the two proteins. The R. meliloti bacA386::Tn(pho)A mutant, as well as a newly constructed bacA deletion mutant, was found to show increased resistance to bleomycin. However, it also showed increased resistance to certain aminoglycosides and increased sensitivity to ethanol and detergents, suggesting that the loss of bacA function causes some defect in membrane integrity. The E. coli sbmA gene suppressed all these bacA mutant phenotypes as well as the Fix- phenotype when placed under control of the bacA promoter. Taken together, these results strongly suggest that the BacA and SbmA proteins are functionally similar and thus provide support for our previous hypothesis that BacA may be required for uptake of some compound that plays an important role in bacteroid development. However, the additional phenotypes of bacA mutants identified in this study suggest the alternative possibility that BacA may be needed for membrane integrity, which is likely to be critically important during the early stages of bacterial differentiation within plant cells.

  6. MS80,a novel sulfated oligosaccharide,inhibits pulmonary fibrosis by targeting TGF-β1 both in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Han-dong JIANG; Hua-shi GUAN

    2009-01-01

    Aim:The pro-fibrogenic cytokine transforming growth factor-beta 1 (TGF-131) has attracted much attention for its potential role in the etiology of idiopathic pulmonary fibrosis (IPF).Here,we demonstrate that MS80,a novel sulfated oligosaccharide extracted from seaweed,can bind TGF-β1.The aim of the present study was to determine whether MSSO is capable of combating TGF-β1-mediated pulmonary fibrotic events both in vitro and in vivo,and to investigate the possible underlying mechanisms.Methods:Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-β.MTT assay,flow cytometry,Western blot analysis,BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80.The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model.Results:We report that MS80,a new kind of sulfated oligosaccharide extracted from seaweed,inhibits TGF-β1-induced pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis in vivo.Our results indicated that MS80 competitively inhibited heparin/HS-TGF-β1 interaction through its high binding affinity for TGF-β1.Moreover,MS80 arrested TGF-β1-induced human embryo pulmonary fibroblast (HEPF) cell proliferation,collagen deposition and matrix metalloproteinase (MMP) activity.Intriguingly,MS80 deactivated both the ERK and p38 signaling pathways.MS80 was also a potent suppressor of bleomycin-induced rat pulmonary fibrosis in vivo,as evidenced by improved pathological settings and decreased lung collagen contents.Conclusion:MS80 in particular,and perhaps oligosaccharide in general,offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.

  7. The Effect of 217 Hz Magnetic Field of Cell Phone with Different Intensities on Apoptosis of Normal and Cancerous Cells Treated with Chemotherapy Drug

    Directory of Open Access Journals (Sweden)

    Mahsa Mansourian

    2012-03-01

    Full Text Available Background: According to the increasing development of home and business electronic equipment in today's world, the biological effects of ELF magnetic fields have been studied at two molecular-cellular and animal- human levels. Considering the therapeutic viewpoint of this study regarding the effects of low-frequency fields of mobile phone, the effect of acute exposure to this field on chemotherapy will be studied.Materials and Methods: In this experimental study, based on measurement of the intensity of the magnetic fields from mobile phones in another research, flux densities of magnetic field of 159.44, 93.25 and 120µ tesla with frequency of 217Hz was generated in magnetic field generator system, and the apoptosis level in K562 cancer cells and healthy cells of lymphocytes was assessed after exposure to field using flow cytometry method. This evaluation method was also performed for the cells treated with bleomycin after exposure to this field.Results: 217 Hz magnetic field exposure significantly increases the rate of apoptosis percentage (p > 0.05 in K562 cancer cells and in two intensities of 120 and 159.44µ tesla compared to the control group, but such effect is not observed in lymphocyte cells. Bleomycin-induced apoptosis percentage following exposure to the mentioned magnetic field shows no significant difference compared to the group of treatment with drug and without field exposure. This lack of significant difference is observed between the groups of drug after field exposure and field alone as well as between groups exposed to field and groups treated with bleomycin.Conclusion: Study results showed that 217 Hz magnetic field of mobile phone can induce apoptosis on cancer cells, but it has no effect on healthy cells. Thus, in order to use mobile phone as an effective factor in their treatment, some studies should be conducted at animal-human level.

  8. Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.

    Directory of Open Access Journals (Sweden)

    Katsunari Makino

    Full Text Available Endothelin (ET-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF-α and connective tissue growth factor (CTGF were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.

  9. Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study.

    Science.gov (United States)

    Moodley, Yuben; Vaghjiani, Vijesh; Chan, James; Baltic, Svetlana; Ryan, Marisa; Tchongue, Jorge; Samuel, Chrishan S; Murthi, Padma; Parolini, Ornella; Manuelpillai, Ursula

    2013-01-01

    Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC), bone marrow MSC (BM-MSC) and human amniotic epithelial cells (hAEC) in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC), IL-6 (AM-MSC, BM-MSC, hAEC) and TNF-α (AM-MSC). The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC). IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro-fibrogenic cytokine TGF-β following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury.

  10. Anti-inflammatory effects of adult stem cells in sustained lung injury: a comparative study.

    Directory of Open Access Journals (Sweden)

    Yuben Moodley

    Full Text Available Lung diseases are a major cause of global morbidity and mortality that are treated with limited efficacy. Recently stem cell therapies have been shown to effectively treat animal models of lung disease. However, there are limitations to the translation of these cell therapies to clinical disease. Studies have shown that delayed treatment of animal models does not improve outcomes and that the models do not reflect the repeated injury that is present in most lung diseases. We tested the efficacy of amnion mesenchymal stem cells (AM-MSC, bone marrow MSC (BM-MSC and human amniotic epithelial cells (hAEC in C57BL/6 mice using a repeat dose bleomycin-induced model of lung injury that better reflects the repeat injury seen in lung diseases. The dual bleomycin dose led to significantly higher levels of inflammation and fibrosis in the mouse lung compared to a single bleomycin dose. Intravenously infused stem cells were present in the lung in similar numbers at days 7 and 21 post cell injection. In addition, stem cell injection resulted in a significant decrease in inflammatory cell infiltrate and a reduction in IL-1 (AM-MSC, IL-6 (AM-MSC, BM-MSC, hAEC and TNF-α (AM-MSC. The only trophic factor tested that increased following stem cell injection was IL-1RA (AM-MSC. IL-1RA levels may be modulated by GM-CSF produced by AM-MSC. Furthermore, only AM-MSC reduced collagen deposition and increased MMP-9 activity in the lung although there was a reduction of the pro-fibrogenic cytokine TGF-β following BM-MSC, AM-MSC and hAEC treatment. Therefore, AM-MSC may be more effective in reducing injury following delayed injection in the setting of repeated lung injury.

  11. Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.

    Science.gov (United States)

    Ahluwalia, Neil; Grasberger, Paula E; Mugo, Brian M; Feghali-Bostwick, Carol; Pardo, Annie; Selman, Moisés; Lagares, David; Tager, Andrew M

    2016-06-01

    Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.

  12. Male infertility in long-term survivors of pediatric cancer: A report from the Childhood Cancer Survivor Study

    Science.gov (United States)

    Wasilewski-Masker, K; Seidel, K D; Leisenring, W; Mertens, A C; Shnorhavorian, M; Ritenour, C W; Stovall, M; Green, D M; Sklar, C A; Armstrong, G T; Robison, L L; Meacham, L R

    2014-01-01

    Purpose The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. Methods Within the Childhood Cancer Survivor Study, 1622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1622; 57.8%) and siblings (174/274; 63.5%) who tried to become pregnant. Relative risks (RR) and 95% confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. Results Among those who provided self-report data, the prevalence of infertility was 46.0% in survivors versus 17.5% in siblings (RR=2.64, 95% CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37% had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose score (AAD) ≥ 3 (RR= 2.13, 95% CI 1.69-2.68 for AAD ≥ 3 versus AAD<3), surgical excision of any organ of the genital tract (RR=1.63, 95% CI 1.20-2.21), testicular radiation ≥ 4Gy (RR=1.99, 95% CI 1.52-2.61), and exposure to bleomycin (RR=1.55, 95% CI 1.20-2.01). Conclusion Many survivors who experience infertility father their own children suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. Implications for Cancer Survivors Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk. PMID:24711092

  13. Structure-Based Design of Tetrahydroisoquinoline-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors

    Science.gov (United States)

    2016-01-01

    The structure-based design of 1, 2, 3, 4-tetrahydroisoquinoline derivatives as selective DDR1 inhibitors is reported. One of the representative compounds, 6j, binds to DDR1 with a Kd value of 4.7 nM and suppresses its kinase activity with an IC50 value of 9.4 nM, but it is significantly less potent for a panel of 400 nonmutated kinases. 6j also demonstrated reasonable pharmacokinetic properties and a promising oral therapeutic effect in a bleomycin-induced mouse pulmonary fibrosis model. PMID:27219676

  14. Hodgkin's disease with leptomeningeal involvement. Report of a case with long survival

    Energy Technology Data Exchange (ETDEWEB)

    Orlowski, E.P.; Hansen, R.M.; Anderson, T.; Hanson, G.A.; Kun, L.E.; Pisciotta, A.V.

    1984-05-01

    A 30-year-old white man with Stage IV B Hodgkin's disease, mixed cellularity type, developed leptomeningeal involvement shortly after relapsing on nitrogen mustard, Oncovin (vincristine), procarbazine, and prednisone (MOPP), and while receiving Adriamycin (doxorubicin), bleomycin, Velban (vinblastine), and dacarbazine (ABVD). Whole brain irradiation and intrathecal methotrexate were successfully incorporated into his treatment program. The patient has now been in complete remission for more than 40 months. A review of this rare complication of Hodgkin's disease is presented.

  15. Klinefelter Syndrome with Poor Risk Extragonadal Germ Cell Tumor

    Directory of Open Access Journals (Sweden)

    Jeremy A. Konheim

    2017-01-01

    Full Text Available Germ cell tumors are the most common malignancy in men aged 15-35 years old, with a small percentage presenting in an extragonadal location. These tumors are seldom identified in the gastrointestinal tract. There is increased risk of extragonadal germ cell tumors (EGCT in men with Klinefelter syndrome (KS. We report a rare case of a 37-year-old male with KS and EGCT discovered in the duodenum and pelvis. After treatment with Bleomycin-Etoposide-Cisplatin (BEP, he developed growing teratoma syndrome (GTS and myelodysplasia. Despite surgical excision of the pelvic growing teratoma, he unfortunately died secondary to complications of severe bone marrow suppression.

  16. Klinefelter Syndrome with Poor Risk Extragonadal Germ Cell Tumor.

    Science.gov (United States)

    Konheim, Jeremy A; Israel, Jonathan A; Delacroix, Scott E

    2017-01-01

    Germ cell tumors are the most common malignancy in men aged 15-35 years old, with a small percentage presenting in an extragonadal location. These tumors are seldom identified in the gastrointestinal tract. There is increased risk of extragonadal germ cell tumors (EGCT) in men with Klinefelter syndrome (KS). We report a rare case of a 37-year-old male with KS and EGCT discovered in the duodenum and pelvis. After treatment with Bleomycin-Etoposide-Cisplatin (BEP), he developed growing teratoma syndrome (GTS) and myelodysplasia. Despite surgical excision of the pelvic growing teratoma, he unfortunately died secondary to complications of severe bone marrow suppression.

  17. Elektrokemoterapi til behandling af kutane metastaser

    DEFF Research Database (Denmark)

    Falk, Hanne; Matthiessen, Louise Wichmann; Dahlstrøm, Karin;

    2015-01-01

    effect by at least 300-fold. Electrochemotherapy is an efficient, once only treatment for cutaneous metastases with an objective response of 62-99%. Electrochemotherapy can reduce discomfort such as ulceration, oozing, bleeding and pain. Adverse events depend on the size of treatment area, but are very......Cutaneous metastases occur in up to 9% of all patients with cancer and may cause discomfort and stigmatization. Electrochemotherapy is a local treatment using electric pulses to permeabilize cell membranes, enabling chemotherapy, such as bleomycin, to enter the cells and increase the cytotoxic...

  18. Biological Bases of Space Radiation Risk

    Science.gov (United States)

    1997-01-01

    In this session, Session JP4, the discussion focuses on the following topics: Hematopoiesis Dynamics in Irradiated Mammals, Mathematical Modeling; Estimating Health Risks in Space from Galactic Cosmic Rays; Failure of Heavy Ions to Affect Physiological Integrity of the Corneal Endothelial Monolayer; Application of an Unbiased Two-Gel CDNA Library Screening Method to Expression Monitoring of Genes in Irradiated Versus Control Cells; Detection of Radiation-Induced DNA Strand Breaks in Mammalian Cells By Enzymatic Post-Labeling; Evaluation of Bleomycin-Induced Chromosome Aberrations Under Microgravity Conditions in Human Lymphocytes, Using "Fish" Techniques; Technical Description of the Space Exposure Biology Assembly Seba on ISS; and Cytogenetic Research in Biological Dosimetry.

  19. Interstitial lung disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930124 The effect of glycosaminoglycans inthe genesis of pulmonary interstitial fibrosis.LIBaoyu(李保玉),et al.Dept Pathol,Jilin MedColl,132001.Chin J Tuberc & Respir Dis 1992;15(4):204-205.The pulmonary interstitial fibrosis was causedby injecting Bleomycin into mouse trachea.Afterthe injection,the volume of glycosaminoglycans(GAG)in bronchoalveolar lavage fluid and lungtissues was increased.The observation underhistochemical stain and electron microscopeshowed that the distribution of GAG in lung tis-sues was varied at different time after the injec-tion,and related to the volume of collagen pro-teins and the formation of pulmonary interstitialfibrosis.

  20. Treatment of advanced head and neck cancer: multiple daily dose fractionated radiation therapy and sequential multimodal treatment approach.

    Science.gov (United States)

    Nissenbaum, M; Browde, S; Bezwoda, W R; de Moor, N G; Derman, D P

    1984-01-01

    Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing chemotherapy (DDP + bleomycin) alone, multiple daily fractionated radiation therapy, and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy. Multimodal therapy gave a significantly higher response rate (69%) than either single-treatment modality. The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days, and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity. Patients receiving multimodal therapy also survived significantly longer (median 50 weeks) than those receiving single-modality therapy (median 24 weeks).

  1. Symposium Entitled: Particle Lung Interactions: ’Overload’ Related Phenomena. A Journal of Aerosol Medicine - Deposition, Clearance, and Effects in the Lung. Volume 3, Supplement 1

    Science.gov (United States)

    1991-04-01

    bleomycin. J. Clin. Invest. 78:1150-1154. MURAD. S .. and PINNELL , S.R. 1987 Suppression of fibroblast proliferation and lysyl hydroxylase activity by...82170 SD 143 I 4 W . I~43II 4 - S m O211001gAi M 12100 p9I ’ T 11021000 mI Figure 2. Effect of 24 hr pretreatment with 500 u/al rat y- interferon on TiO2...Fe in the lungs and in other organs could not be ruled out. Hence, neither exclusive particle re- tention in the lungs nor estimates of S (t) were given

  2. A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974)

    DEFF Research Database (Denmark)

    Daugaard, G; Skoneczna, I; Aass, N

    2011-01-01

    To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor......-prognosis germ-cell cancer (GCC). Patient and methods: Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but closed with 137, due to slow accrual....

  3. Resistance Training Does Not Protect Against Increases in Plasma Cytokine Levels Among Germ Cell Cancer Patients During and After Chemotherapy

    DEFF Research Database (Denmark)

    Christensen, Jesper Frank; Tolver, Anders; Andersen, J.L.

    2014-01-01

    Abstract Context: Testicular germ cell cancer (GCC) patients treated with cisplatin-etoposide-bleomycin chemotherapy (BEP) have excellent prognosis but have an increased risk of late-occurring morbidities, which may be associated with changes in the inflammatory profile. Objective: The objective...... of the study was to explore plasma cytokine concentrations in GCC patients randomized to resistance training or usual care during BEP, in comparison with healthy controls. Design/Setting: This was a randomized controlled trial in GCC patients enrolled from an oncology clinic, including a healthy reference......). Changes in TNF-α correlated with pulmonary toxicity (P BEP display consistently elevated levels of systemic inflammatory markers compared with healthy...

  4. Hodgkin Lymphoma and Castleman Disease: When One Blood Disease Can Hide Another.

    Science.gov (United States)

    Filliatre-Clement, L; Busby-Venner, H; Moulin, C; Roth-Guepin, G; Perrot, A

    2017-01-01

    We describe a rare case of Castleman disease associated de novo with Hodgkin lymphoma. The incidence of Castleman disease is rare; only a few studies have described it in de novo association with Hodgkin lymphoma. The patient described here complained of unique evolutionary axillary adenopathy. A positron-emission tomography/computed tomography scan revealed hypermetabolic activity in this area. Diagnosis was based on a total excision biopsy of the adenopathy. The patient underwent complete remission with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy for treating Hodgkin lymphoma after surgical excision of the unicentric Castleman disease lesion.

  5. A young male with shortness of breath

    Directory of Open Access Journals (Sweden)

    Khan Fahmi

    2008-01-01

    Full Text Available We report a case of primary mediastinal seminoma, which presented initially with shortness of breath and a swelling in upper part of anterior chest wall. The diagnosis of primary mediastinal seminoma was established on the basis of histologic findings and was confirmed by immunohistochemical analysis. Abdominal, pelvis and cerebral CT scan, testicular ultrasound and TC-99 MDP bone scintigraphy were negative. Chemotherapy was initiated with B.E.P. protocol (Bleomycin, Etoposide, Cisplatinum; the patient received four cycles of chemotherapy. After 8 months, the patient was seen in the clinic; he was well.

  6. Hodgkin Lymphoma and Castleman Disease: When One Blood Disease Can Hide Another

    Directory of Open Access Journals (Sweden)

    L. Filliatre-Clement

    2017-01-01

    Full Text Available We describe a rare case of Castleman disease associated de novo with Hodgkin lymphoma. The incidence of Castleman disease is rare; only a few studies have described it in de novo association with Hodgkin lymphoma. The patient described here complained of unique evolutionary axillary adenopathy. A positron-emission tomography/computed tomography scan revealed hypermetabolic activity in this area. Diagnosis was based on a total excision biopsy of the adenopathy. The patient underwent complete remission with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy for treating Hodgkin lymphoma after surgical excision of the unicentric Castleman disease lesion.

  7. Immortalization of Werner syndrome and progeria fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Saito, H.; Moses, R.E. (Baylor College of Medicine, Houston, TX (USA))

    1991-02-01

    Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents.

  8. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

    2013-01-01

    The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  9. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Claude Jourdan Le Saux

    Full Text Available The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L, a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  10. Linear porokeratosis with multiple squamous cell carcinomas successfully treated by electrochemotherapy.

    Science.gov (United States)

    Sommerlad, M; Lock, A; Moir, G; McGregor, J; Bull, R; Cerio, R; Harwood, C

    2016-12-01

    Porokeratosis is a clonal epidermal disorder of keratinization characterized by annular lesions with an atrophic centre and a hyperkeratotic edge. The cornoid lamella is the histopathological hallmark. Six clinical variants are recognized: porokeratosis of Mibelli; disseminated superficial porokeratosis; disseminated superficial actinic porokeratosis (DSAP); porokeratosis plantaris et palmaris disseminata; punctate porokeratosis and linear porokeratosis. Linear porokeratosis is the type most frequently associated with malignant transformation into squamous cell carcinoma (SCC). It is thought to represent a mosaic form of DSAP and has an incidence of less than 1 in 200 000; treatment options are limited. We describe a patient with systematized linear porokeratosis and multiple SCCs who was successfully treated with bleomycin electrochemotherapy (ECT), a form of intralesional chemotherapy. In view of their large number, the individual SCCs were treated with bleomycin ECT. One year post-treatment the patient remains tumour free. To our knowledge, this is the first case of multiple SCCs treated by ECT in the context of systematized linear porokeratosis. Our case highlights the challenges associated with diagnosing and managing this unusual form of porokeratosis.

  11. Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma.

    Science.gov (United States)

    Usategui, Alicia; Criado, Gabriel; Del Rey, Manuel J; Faré, Regina; Pablos, José L

    2014-10-01

    Vitamin D analogues can reduce TGF-β pro-fibrotic signaling in dermal fibroblasts, but they may also induce a potentially pro-fibrotic thymic stromal lymphopoietin (TSLP)-dependent Th2 cytokine local response. We have analyzed the net effect of topical vitamin D analogue calcipotriol (CPT) on the cytokine profile and the development of fibrosis in experimental model of bleomycin-induced fibrosis. Mice were simultaneously treated with topical CPT or vehicle cream and skin fibrosis was measured by collagen deposition, Masson's trichrome staining and hydroxyproline content. Cytokine and TSLP gene expression was evaluated by quantitative RT-PCR. We showed that in bleomycin injected skin, CPT administration significantly enhanced TSLP and IL-13 gene expression, but did not modify the expression of other cytokines. Skin fibrosis and hydroxyproline content were significantly reduced in CPT compared to vehicle-treated mice. In normal skin, topical administration of CPT lacked a direct pro-fibrotic effect. Our results demonstrate that topical CPT superinduces the expression of the TSLP/IL-13 Th2 axis in fibrotic skin, but it has a net anti-fibrotic effect. These data support the therapeutic use of topical vitamin D analogues for skin fibrosis.

  12. Control of in vivo (cellular) phleomycin sensitivity by nuclear genotype, growth phase, and metal ions

    Energy Technology Data Exchange (ETDEWEB)

    Moore, C.W.

    1982-03-01

    Nuclear genotype, growth phase, and the presence of metal ions all proved to be important in controlling the lethal effects of phleomycin in eukaryotic Saccharomyces cerevisiae. Among 120 normal and radiation-sensitive strains compared for their sensitivities to lethal effects of phleomycin, all mutant strains exhibiting enhanced sensitivities to phleomycin killing were also sensitive to killing by ionizing radiation. Mutants exhibiting sensitivities to phleomycin similar to normal strains of the same ploidy were sensitive to ultraviolet radiation. We conclude that cellular recovery from phleomycin-induced damage in yeast depends upon the function of some or all of 13 independent genes and upon at least some of the same steps in cellular pathways for the biological repair of damage by ionizing radiation. In this respect, the action of phleomycin is similar to the action of its structurally similar analog, bleomycin, even though phleomycin was substantially more cytotoxic. Stationary-phase haploid yeast cells were more sensitive than exponentially growing cells to killing by phleomycin. Survival of stationary-phase yeast was reduced to 0.3 +/- 0.07% (S.E.) after 20-min exposures to phleomycin (1 microgram/ml; approximately 6.7 x 10(-7) M), but lethal effects of phleomycin were completely eradicated (98% survival) by the presence of 0.05 M ethylenediaminetetraacetate during the treatment period. The inactivation indicates an important role for one or more metal ion(s) in the in vivo toxicity of the phleomycin-bleomycin group of anticancer antibiotics.

  13. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  14. A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice.

    Science.gov (United States)

    Keith, Rebecca C; Powers, Jennifer L; Redente, Elizabeth F; Sergew, Amen; Martin, Richard J; Gizinski, Alison; Holers, V Michael; Sakaguchi, Shimon; Riches, David W H

    2012-03-01

    Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with increased mortality in up to 10% of patients with rheumatoid arthritis. Lung exposure to cigarette smoke has been implicated in disease development. Little is known about the mechanisms underlying the development of RA-ILD, in part due to the lack of an appropriate mouse model. The objectives of this study were (i) to test the suitability of SKG mice as a model of cellular and fibrotic interstitial pneumonia in the setting of autoimmune arthritis, and (ii) to determine the role of lung injury in the development of arthritis in SKG mice. Lung tissues were evaluated in arthritic SKG mice by quantifying cell accumulation in bronchoalveolar lavage, static compliance, collagen levels, and infiltrating cell phenotypes by flow cytometry and histology. Lung injury was induced by exposure to cigarette smoke or bleomycin. Arthritic SKG mice developed a patchy cellular and fibrotic interstitial pneumonia associated with reduced static compliance, increased collagen levels, and accumulation of inflammatory cells. Infiltrating cells comprised CD4+ T cells, B cells, macrophages, and neutrophils. Chronic exposure to cigarette smoke or initiation of lung injury with bleomycin did not cause arthritis. The pattern of lung disease suggests that arthritic SKG mice represent an authentic model of nonspecific interstitial pneumonia in RA-ILD patients. The lack of arthritis development after cigarette smoke or lung injury suggests that a model where breaches in immunologic tolerance are induced by lung inflammation and injury alone may be overly simplistic.

  15. Polycomb-group histone methyltransferase CLF is required for proper somatic recombination in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Na Chen; Wang-Bin Zhou; Ying-Xiang Wang; Ai-Wu Dong; Yu Yu

    2014-01-01

    Homologous recombination (HR) is a key process during meiosis in reproductive cells and the DNA damage repair process in somatic cells. Although chromatin structure is thought to be crucial for HR, only a smal number of chromatin modifiers have been studied in HR regulation so far. Here, we investigated the function of CURLY LEAF (CLF), a Polycomb-group (PcG) gene responsible for histone3 lysine 27 trimethy-lation (H3K27me3), in somatic and meiotic HR in Arabidopsis thaliana. Although fluorescent protein reporter assays in pol en and seeds showed that the frequency of meiotic cross-over in the loss-of-function mutant clf-29 was not significantly different from that in wild type, there was a lower frequency of HR in clf-29 than in wild type under normal conditions and under bleomycin treatment. The DNA damage levels were compara-ble between clf-29 and wild type, even though several DNA damage repair genes (e.g. ATM, BRCA2a, RAD50, RAD51, RAD54,and PARP2) were expressed at lower levels in clf-29. Under bleomycin treatment, the expression levels of DNA repair genes were similar in clf-29 and wild type, thus CLF may also regulate HR via other mechanisms. These findings expand the current knowledge of PcG function and contribute to general interests of epigenetic regulation in genome stability regulation.

  16. In vivo anticancer activity of vanillin, benzophenone and acetophenone thiosemicarbazones on Swiss albino mice

    Institute of Scientific and Technical Information of China (English)

    Sha Md. Shahan Shahriar; Shaikh M Mohsin Ali; Mele Jesmin; Md. Khairul Islam; Sarozit Mondal

    2014-01-01

    Objective: To study the anticancer activities of three schiff bases viz. vanillin thiosemicarbazone, benzophenone thiosemicarbazone and acetophenone thiosemicarbazone against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. Methods: Synthesized compounds have administrated into the intraperitoneal cavity of the EAC inoculated mice at two doses. The anticancer activities have studied by monitoring the parameters such as cell growth inhibition, tumor weight measurement, survival time of EAC bearing mice as well as the changes in depleted hematological parameters due to tumorgenesis. All such data have been compared with those of a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.).Results:It has been found that these bases enhanced life span, reduced average tumor weight and inhibited tumor cell growth of EAC cell bearing mice remarkably. The results were similar in potency to those obtained with bleomycin. It was also found that the depleted hematological parameters (red blood count, white blood count and haemoglobin content) were found to be restored gradually towards normal within few weeks after ceasing the treatment.Conclusions:The compounds can be primarily considered more or less as potent anticancer agents.

  17. Refractory Classical Hodgkin Lymphoma Presenting with Atypical Cutaneous Involvement and Diagnosis of ZZ Phenotype Alpha-1 Antitrypsin Deficiency

    Directory of Open Access Journals (Sweden)

    Mohamad Khawandanah

    2014-01-01

    Full Text Available Cutaneous Hodgkin lymphoma is a rare condition. Specific neoplastic involvement can be primary (confined to the skin or secondary to systemic involvement (metastatic. Cutaneous involvement by HL usually occurs late in the course and is associated with poor prognosis; however in some cases it can exhibit indolent behavior. Skin involvement with nonspecific cutaneous findings may represent a paraneoplastic syndrome. We describe a case of 46-year-old white male patient presented with rash and lymphadenopathy which led to the diagnosis of stage IVE mixed cellularity classical Hodgkin lymphoma with skin involvement. His disease was refractory to multiple lines of chemotherapy including (1 AVD (doxorubicin/bleomycin/dacarbazine, (2 brentuximab, and (3 bendamustine, he later achieved complete remission with (4 GCD (gemcitabine/carboplatin/dexamethasone salvage regimen. Bleomycin was not given secondary to poor pulmonary function tests. His treatment was complicated after AVD with multiple pneumothoraces which unmasked the diagnosis of ZZ phenotype alpha-1 antitrypsin (ATT deficiency. Simultaneous existence of Hodgkin lymphoma and ATT is rarely reported.

  18. Electrochemotherapy for the treatment of fibropapillomas in Chelonia mydas.

    Science.gov (United States)

    Brunner, Carlos Henrique Maciel; Dutra, Gustavo; Silva, Caroline Brunelli; Silveira, Lucia Maria Guedes; Martins, Maria de Fátima Monteiro

    2014-06-01

    Fibropapillomatosis continues to be an important cause of morbidity and mortality in sea turtles, particularly in Chelonia mydas. Turtles with this debilitating herpesvirus disease usually present with multiple, large, and ulcerated cutaneous masses that compromise both locomotion and feeding. There are very few available therapeutic strategies, with surgical excision being the most common. However, this surgical excision is associated with a high rate of local disease recurrence and secondary infections. Electrochemotherapy has been used for the treatment of epithelial neoplasm in several animal species. This technique is based on a combination of chemotherapy, usually with bleomycin or cisplatin, and electroporation. It consists of a series of short, high-voltage electric pulses that lead to increased membrane permeability and more efficient transport of antineoplastic drugs through the cellular membrane. Here, two C. mydas fibropapillomas were treated with a standard electrochemotherapy protocol using intralesional bleomycin sulfate injections followed by the application of electric pulses. Two sessions were performed, with a 33-day interval between sessions. Complete regression of lesions occurred without side effects or complications in each animal. There was no sign of local recurrence, even 1 yr after the end of treatment. Electrochemotherapy may be an effective therapeutic alternative for sea turtles with fibropapillomas.

  19. Activation of p53 in Human and Murine Cells by DNA-Damaging Agents Differentially Regulates Aryl Hydrocarbon Receptor Levels.

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Choubey, Divaker

    2015-01-01

    Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates multiple cellular processes. The anticancer drug doxorubicin (DOX) can activate AhR-mediated transcription of target genes. Because DOX in cells activates a DNA damage response involving ataxia telangiectasia-mutated (ATM)-mediated activation of p53, we investigated whether the activation of the p53 in cells by DNA-damaging agents such as DOX or bleomycin could regulate the AhR levels. Here we report that activation of p53 by DNA-damaging agents in human cells increased levels of AhR through a posttranscriptional mechanism. Accordingly, fibroblasts from ATM patients, which are defective in p53 activation, expressed reduced constitutive levels of AhR and treatment of cells with bleomycin did not appreciably increase the AhR levels. Further, activation of p53 in cells stimulated the expression of AhR target genes. In murine cells, activation of p53 reduced the levels of AhR messenger RNA and protein and reduced the expression of AhR target genes. Our observations revealed that activation of p53 in human and murine cells differentially regulates AhR levels.

  20. Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    François Huaux

    Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

  1. Chemical composition and antigenotoxic properties of Lippia alba essential oils

    Directory of Open Access Journals (Sweden)

    Molkary Andrea López

    2011-01-01

    Full Text Available The present work evaluated the chemical composition and the DNA protective effect of the essential oils (EOs from Lippia alba against bleomycin-induced genotoxicity. EO constituents were determined by Gas Chromatography/Mass Spectrometric (GC-MS analysis. The major compounds encountered being citral (33% geranial and 25% neral, geraniol (7% and trans-β-caryophyllene (7% for L. alba specimen COL512077, and carvone (38%, limonene (33% and bicyclosesquiphellandrene (8% for the other, COL512078. The genotoxicity and antigenotoxicity of EO and the compounds citral, carvone and limonene, were assayed using the SOS Chromotest in Escherichia coli. The EOs were not genotoxic in the SOS chromotest, but one of the major compound (limonene showed genotoxicity at doses between 97 and 1549 mM. Both EOs protected bacterial cells against bleomycin-induced genotoxicity. Antigenotoxicity in the two L. alba chemotypes was related to the major compounds, citral and carvone, respectively. The results were discussed in relation to the chemopreventive potential of L. alba EOs and its major compounds.

  2. Triphala, a formulation of traditional Ayurvedic medicine, shows protective effect against X-radiation in HeLa cells

    Indian Academy of Sciences (India)

    YUKI TAKAUJI; KENSUKE MIKI; JUMA MITA; MOHAMMAD NAZIR HOSSAIN; MASATAKE YAMAUCHI; MITOMU KIOI; DAI AYUSAWA; MICHIHIKO FUJII

    2016-12-01

    Ayurveda is a holistic medical system of traditional medicine, and Triphala is one of the most popular formulations inAyurveda. Triphala is composed of three kinds of herb, Terminalia chebula, Terminalia bellirica, and Emblicaofficinalis. Since Triphala is shown to exhibit a protective activity against ionizing radiation in mice, we investigatedits activity in HeLa cells. We found that Triphala showed the protective effects against X-radiation and bleomycin,both of which generate DNA strand breaks, in HeLa cells. Further, Triphala efficiently eliminated reactive oxygenspecies (ROS) in HeLa cells. Thus, the antioxidant activity of Triphala would likely play a role in its protective actionsagainst X-radiation and bleomycin because both agents damage DNA through the generation of ROS. Theseobservations suggested that the radioprotective activity of Triphala can be, at least partly, studied with the cellscultured in vitro. The simple bioassay system with human cultured cells would facilitate the understanding of themolecular basis for the beneficial effects of Triphala.

  3. An Innovative Cell Microincubator for Drug Discovery Based on 3D Silicon Structures

    Directory of Open Access Journals (Sweden)

    Francesca Aredia

    2016-01-01

    Full Text Available We recently employed three-dimensional (3D silicon microstructures (SMSs consisting in arrays of 3 μm-thick silicon walls separated by 50 μm-deep, 5 μm-wide gaps, as microincubators for monitoring the biomechanical properties of tumor cells. They were here applied to investigate the in vitro behavior of HT1080 human fibrosarcoma cells driven to apoptosis by the chemotherapeutic drug Bleomycin. Our results, obtained by fluorescence microscopy, demonstrated that HT1080 cells exhibited a great ability to colonize the narrow gaps. Remarkably, HT1080 cells grown on 3D-SMS, when treated with the DNA damaging agent Bleomycin under conditions leading to apoptosis, tended to shrink, reducing their volume and mimicking the normal behavior of apoptotic cells, and were prone to leave the gaps. Finally, we performed label-free detection of cells adherent to the vertical silicon wall, inside the gap of 3D-SMS, by exploiting optical low coherence reflectometry using infrared, low power radiation. This kind of approach may become a new tool for increasing automation in the drug discovery area. Our results open new perspectives in view of future applications of the 3D-SMS as the core element of a lab-on-a-chip suitable for screening the effect of new molecules potentially able to kill tumor cells.

  4. [Severe Acute Myocardial Infarction during Induction Chemotherapy for Retroperitoneal Germ Cell Tumor : A Case Report].

    Science.gov (United States)

    Sakka, Shotaro; Kawai, Koji; Tsujimoto, Ippei; Kurobe, Masahiro; Ichioka, Daishi; Kantori, Shuya; Kojima, Takahiro; Suetomi, Takahiro; Jouraku, Akira; Miyazaki, Jun; Hoshi, Tomoya; Nishiyama, Hiroyuki

    2016-09-01

    A 37-year-old man presented at our hospital. Pathological examination of a right orchiectomy specimen, radiographic examination, and tumor marker profile resulted in a diagnosis of retroperitoneal nonseminomatous germ cell tumor (intermediate risk according to IGCC classification). Laboratory testing revealed mild elevation of low density lipoprotein cholesterol. Induction chemotherapy with bleomycin, etoposide and cisplatin (BEP) was started, but he complained of chest pain on day 10 of the second cycle of BEP. We immediately started cardiac monitoring. One hour later, he suffered cardiac arrest due to ventricular fibrillation. Fortunately, sinus rhythm was restored after defibrillation. A diagnosis of acute myocardial infarction (AMI) with total occlusion at the mid-portion of the left anterior descending coronary artery was established by coronary angiography. After percutaneous transluminal coronary angioplasty was successfully performed, he recovered uneventfully. The induction chemotherapy was re-started 19 days after AMI. To avoid endothelial damage by bleomycin, we elected to treat with etoposide, ifosfamide, and cisplatin (VIP). After two further courses of VIP, the patient underwent resection of retoperitoneal tumor and achieved complete remission. The patient has remained disease-free during 3 years follow up without recurrence of AMI.

  5. Managing Risk in Hodgkin Lymphoma.

    Science.gov (United States)

    Armitage, James O; Chen, Robert W; Moskowitz, Craig H; Sweetenham, John

    2015-02-01

    Approximately 90% of patients with limited-stage Hodgkin lymphoma are cured. The cure rate in advanced-stage Hodgkin lymphoma is dramatically better than it once was, but it is still lower than the rate in patients with limited disease. The choice of treatment is based on several factors, including symptoms, disease stage, extent of tumor burden, and prognosis. Positron emission tomography scanning can be used to assess the patient's stage of disease, which can allow further individualization of therapy. Traditional frontline treatment options include doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and, for high-risk patients, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). Autologous stem cell transplantation cures approximately 50% of patients. The antibody-drug conjugate brentuximab vedotin is very active in relapsed/refractory Hodgkin lymphoma. Data presented at the 2014 meeting of the American Society of Hematology (ASH) showed that brentuximab vedotin was beneficial in several settings, including as consolidation therapy posttransplant in patients at high risk for relapse, as first-line salvage therapy in relapsed/refractory Hodgkin lymphoma prior to autologous hematopoietic cell transplantation, and in combination with bendamustine in relapsed/refractory disease. The ASH meeting also offered promising data on novel agents, such as the programmed cell death 1 (PD-1) inhibitors. In this monograph, 4 experts in the management of Hodgkin lymphoma discuss various aspects of the disease and provide their perspectives on the new data presented at the ASH meeting.

  6. Management of primary germ cell tumors of the mediastinum.

    Science.gov (United States)

    Economou, J S; Trump, D L; Holmes, E C; Eggleston, J E

    1982-05-01

    Twenty-eight patients with primary malignant germ cell tumors (GCT) of the mediastinum were treated at the University of California at Los Angeles and The Johns Hopkins Hospital in the past 30 years. Of 11 patients with pure seminomas, nine (82%) are free of disease from 6 months to 15 years following therapy. The primary treatment modality in these patients was mediastinal radiation; one patient with metastatic disease had a complete remission and prolonged survival following combination chemotherapy. Seventeen patients had GCT with nonseminomatous elements. Only three (18%) are alive and free of disease. One patient treated only surgically is alive at 15 years and two patients treated with combination chemotherapy and operation are alive and free of disease at 6 months and 3 years. When analyzed by a Kaplan-Meier actuarial survival estimate, patients with nonseminomatous GCT who were treated with cisplatin-bleomycin-based chemotherapy had a median survival of 14.0 months whereas those treated with chemotherapy regimens not employing these agents had a median survival of 4.0 months (generalized Wilcoxon test, p = 0.0495). Patients with pure seminomas are effectively treated with radiation therapy. Patients with nonseminomatous tumors have a much poorer prognosis and deserve aggressive multimodality therapy with cisplatin-bleomycin-based chemotherapy.

  7. Alternating chemotherapy of CHOP-Bleo and POEM-Bleo for diffuse large-cell lymphoma: a single-institutional study with a long-term follow-up.

    Science.gov (United States)

    Ohnoshi, T; Hayashi, K; Ueno, K; Tada, A; Mizuta, J; Tagawa, S; Matsutomo, S; Saito, S; Kawashima, K; Yoshino, T

    1993-08-01

    Diffuse large-cell lymphoma (DLCL) is a neoplasm that is curable with chemotherapy in an appreciable percentage of patients. However, not all patients are cured and the best drug combination and optimal dose intensity have not yet been established. In an attempt to improve complete response rate and survival with minimal toxicity, we devised an alternating combination chemotherapy consisting of CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisolone, and bleomycin) and POEM-Bleo (prednisolone, vincristine, etoposide, mitoxantrone, and bleomycin). Between March 1986 and October 1990, 30 newly-diagnosed patients with advanced DLCL were treated with the regimen. Of these 30 patients, 14 (47%) were 61 years of age or more, 15 (50%) had stage IV disease, 14 (47%) presented with constitutional symptoms, and 7 (23%) had T-cell lymphoma. After the completion of therapy, 23 (77%) achieved a complete response and 6 (20%) had a partial response. The actuarial relapse-free survival at 5 years is 52% and the overall survival projected to 5 years is 47%. Toxicity was generally mild and well tolerated. Although this alternating regimen had substantial activity as front-line chemotherapy for advanced DLCL, we conclude that the observed response rate and survival do not essentially differ from those achieved with conventional regimens and further clinical trials are thus not warranted.

  8. In vivo anticancer activity of vanillin semicarbazone

    Institute of Scientific and Technical Information of China (English)

    Shaikh M Mohsin Ali; M Abul Kalam Azad; Mele Jesmin; Shamim Ahsan; M Mijanur Rahman; Jahan Ara Khanam; M Nazrul Islam; Sha M Shahan Shahriar

    2012-01-01

    Objective:To evaluate the anticancer activity of vanillin semicarbazone (VSC) against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. Methods:The compound VSC at three doses (5, 7.5 and 10 mg/kg i.p.) was administered into the intraperitoneal cavity of the EAC inoculated mice to observe its efficiency by studying the cell growth inhibition, reduction of tumour weight, enhancement of survival time as well as the changes in depleted hematological parameters. All such parameters were also studied with a known standard drug bleomycin at the dose of 0.3 mg/kg (i.p.). Results:Among the doses studied, 10 mg/kg (i.p.) was found to be quite comparable in potency to that of bleomycin at the dose of 0.3 mg/kg (i.p.). The host toxic effects of VSC was found to be negligible. Conclusions: It can be concluded that VSC can therefore be considered as potent anticancer agent.

  9. Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor.

    Science.gov (United States)

    Yang, Jibing; Velikoff, Miranda; Canalis, Ernesto; Horowitz, Jeffrey C; Kim, Kevin K

    2014-04-15

    Fibrogenesis involves a pathological accumulation of activated fibroblasts and extensive matrix remodeling. Profibrotic cytokines, such as TGF-β, stimulate fibroblasts to overexpress fibrotic matrix proteins and induce further expression of profibrotic cytokines, resulting in progressive fibrosis. Connective tissue growth factor (CTGF) is a profibrotic cytokine that is indicative of fibroblast activation. Epithelial cells are abundant in the normal lung, but their contribution to fibrogenesis remains poorly defined. Profibrotic cytokines may activate epithelial cells with protein expression and functions that overlap with the functions of active fibroblasts. We found that alveolar epithelial cells undergoing TGF-β-mediated mesenchymal transition in vitro were also capable of activating lung fibroblasts through production of CTGF. Alveolar epithelial cell expression of CTGF was dramatically reduced by inhibition of Rho signaling. CTGF reporter mice demonstrated increased CTGF promoter activity by lung epithelial cells acutely after bleomycin in vivo. Furthermore, mice with lung epithelial cell-specific deletion of CTGF had an attenuated fibrotic response to bleomycin. These studies provide direct evidence that epithelial cell activation initiates a cycle of fibrogenic effector cell activation during progressive fibrosis. Therapy targeted at epithelial cell production of CTGF offers a novel pathway for abrogating this progressive cycle and limiting tissue fibrosis.

  10. Triphala, a formulation of traditional Ayurvedic medicine, shows protective effect against X-radiation in HeLa cells.

    Science.gov (United States)

    Takauji, Yuki; Miki, Kensuke; Mita, Juma; Hossain, Mohammad Nazir; Yamauchi, Masatake; Kioi, Mitomu; Ayusawa, Dai; Fujii, Michihiko

    2016-12-01

    Ayurveda is a holistic medical system of traditional medicine, and Triphala is one of the most popular formulations in Ayurveda. Triphala is composed of three kinds of herb, Terminalia chebula, Terminalia bellirica, and Emblica officinalis. Since Triphala is shown to exhibit a protective activity against ionizing radiation in mice, we investigated its activity in HeLa cells. We found that Triphala showed the protective effects against X-radiation and bleomycin, both of which generate DNA strand breaks, in HeLa cells. Further, Triphala efficiently eliminated reactive oxygen species (ROS) in HeLa cells. Thus, the antioxidant activity of Triphala would likely play a role in its protective actions against X-radiation and bleomycin because both agents damage DNA through the generation of ROS. These observations suggested that the radioprotective activity of Triphala can be, at least partly, studied with the cells cultured in vitro. The simple bioassay system with human cultured cells would facilitate the understanding of the molecular basis for the beneficial effects of Triphala.

  11. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Cong, E-mail: wangcongweihai@126.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Dai, Jinghong, E-mail: daijinghongnew@163.com [Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China); Sun, Zhaorui, E-mail: lanseyunduan@163.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Shi, Chaowen, E-mail: willscw@live.cn [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Cao, Honghui, E-mail: caohonghui92@gmail.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); and others

    2015-02-01

    In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.

  12. Chemical composition and antigenotoxic properties of Lippia alba essential oils.

    Science.gov (United States)

    López, Molkary Andrea; Stashenko, Elena E; Fuentes, Jorge Luis

    2011-07-01

    The present work evaluated the chemical composition and the DNA protective effect of the essential oils (EOs) from Lippia alba against bleomycin-induced genotoxicity. EO constituents were determined by Gas Chromatography/Mass Spectrometric (GC-MS) analysis. The major compounds encountered being citral (33% geranial and 25% neral), geraniol (7%) and trans-β-caryophyllene (7%) for L. alba specimen COL512077, and carvone (38%), limonene (33%) and bicyclosesquiphellandrene (8%) for the other, COL512078. The genotoxicity and antigenotoxicity of EO and the compounds citral, carvone and limonene, were assayed using the SOS Chromotest in Escherichia coli. The EOs were not genotoxic in the SOS chromotest, but one of the major compound (limonene) showed genotoxicity at doses between 97 and 1549 mM. Both EOs protected bacterial cells against bleomycin-induced genotoxicity. Antigenotoxicity in the two L. alba chemotypes was related to the major compounds, citral and carvone, respectively. The results were discussed in relation to the chemopreventive potential of L. alba EOs and its major compounds.

  13. Intralesional vincristine combined with cryotherapy for recalcitrant verrucas.

    Science.gov (United States)

    Lee, Jong-Rok; Youn, Jeong-Hwan; Roh, Joo-Young

    2011-01-01

    Verrucas are often recalcitrant to conventional cryotherapy. Since 1970, intralesional bleomycin has been used off-label by dermatologists. But in some cases, the results of intralesional bleomycin were disappointing. Vincristine is a well-known vinca alkaloid antiblastic drug that has been used for treating hematological neoplasm and nephroblastomas. It was reported good efficacy of intralesional vincristine for treating nodular lesion in classic Kaposi sarcoma. Its use in epithelial neoplasm and Kaposi sarcoma may support its efficacy in recalcitrant verrucas. The three patients selected for the study presented severe verrucas on foot, and they had already undergone cryotherapy several times and there was no improvement. They got intralesional vincristine injection on their verrucas. The target lesion was infiltrated with 0.03 mL of vincristine sulphate at a concentration of 1 µg/mL. The injected amount of vincristine was proportional to the diameter of the nodule. After two treatments had been completed, there was a great decrease of lesion size compared with the other lesions. The three patients complained of pain lasting for several days. This pain was generally well tolerated. Intralesional vincristine injection on verruca is an effective and rapid novel method, and when combined with cryotherapy, shows excellent therapeutic response.

  14. Paeoniflorin suppresses TGF-β mediated epithelial-mesenchymal transition in pulmonary fibrosis through a Smad-dependent pathway

    Science.gov (United States)

    Ji, Yu; Dou, Yan-nong; Zhao, Qian-wen; Zhang, Ji-zhou; Yang, Yan; Wang, Ting; Xia, Yu-feng; Dai, Yue; Wei, Zhi-feng

    2016-01-01

    Aim: Paeoniflorin has shown to attenuate bleomycin-induced pulmonary fibrosis (PF) in mice. Because the epithelial-mesenchymal transition (EMT) in type 2 lung endothelial cells contributes to excessive fibroblasts and myofibroblasts during multiple fibrosis of tissues, we investigated the effects of paeoniflorin on TGF-β mediated pulmonary EMT in bleomycin-induced PF mice. Methods: PF was induced in mice by intratracheal instillation of bleomycin (5 mg/kg). The mice were orally treated with paeoniflorin or prednisone for 21 d. After the mice were sacrificed, lung tissues were collected for analysis. An in vitro EMT model was established in alveolar epithelial cells (A549 cells) incubated with TGF-β1 (2 ng/mL). EMT identification and the expression of related proteins were performed using immunohistochemistry, transwell assay, ELISA, Western blot and RT-qPCR. Results: In PF mice, paeoniflorin (50, 100 mg·kg−1·d−1) or prednisone (6 mg·kg−1·d−1) significantly decreased the expression of FSP-1 and α-SMA, and increased the expression of E-cadherin in lung tissues. In A549 cells, TGF-β1 stimulation induced EMT, as shown by the changes in cell morphology, the increased cell migration, and the increased vimentin and α-SMA expression as well as type I and type III collagen levels, and by the decreased E-cadherin expression. In contrast, effects of paeoniflorin on EMT disappeared when the A549 cells were pretreated with TGF-β1 for 24 h. TGF-β1 stimulation markedly increased the expression of Snail and activated Smad2/3, Akt, ERK, JNK and p38 MAPK in A549 cells. Co-incubation with paeoniflorin (1–30 μmol/L) dose-dependently attenuated TGF-β1-induced expression of Snail and activation of Smad2/3, but slightly affected TGF-β1-induced activation of Akt, ERK, JNK and p38 MAPK. Moreover, paeoniflorin markedly increased Smad7 level, and decreased ALK5 level in A549 cells. Conclusion: Paeoniflorin suppresses the early stages of TGF-β mediated EMT in alveolar

  15. Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.

    Science.gov (United States)

    Fung, Chunkit; Sesso, Howard D; Williams, Annalynn M; Kerns, Sarah L; Monahan, Patrick; Abu Zaid, Mohammad; Feldman, Darren R; Hamilton, Robert J; Vaughn, David J; Beard, Clair J; Kollmannsberger, Christian K; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Lipshultz, Steve E; Einhorn, Lawrence H; Fossa, Sophie D; Travis, Lois B

    2017-04-10

    Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.

  16. 丹酚酸A对实验性肺纤维化大鼠的保护作用研究%Protection effect of Salvianolic acid A on pulmonary fibrosis of rat

    Institute of Scientific and Technical Information of China (English)

    孔勤; 刘瑞敏; 寿旗扬; 肖颖; 朱科燕; 陈民利

    2013-01-01

    目的 观察丹酚酸A对博来霉素诱导的肺纤维化大鼠的保护作用及可能机制.方法 气管单次给予博来霉素注射液复制大鼠肺纤维化模型,第2天开始给予丹酚酸A,连续28天,记录体重与一般体征变化;处死大鼠,测定血清自由基、肺功能及观察组织透射电镜等情况.结果 造模后给予丹酚酸A可改善肺纤维化大鼠一般体征状况;提高血清SOD、GSH-Px活性和降低MDA含量;改善肺功能;减轻肺泡炎症,缩小肺泡间隔宽度;电镜观察发现给予肺纤维化大鼠丹酚酸A后,胶原纤维生成减少,Ⅱ型肺泡上皮细胞增生减弱.结论 丹酚酸A对博来霉素诱导的实验性肺纤维化有一定的保护作用,其机制可能与丹酚酸A抗氧化作用有关.%Objective Investigate the effects of salvianolic acid A on rats of bleomycin -induced pulmonary fibrosis and potential mechanisms. Methods Single-dose bleomycin was given via intratracheal on Day 0 and rats were treated from Dayl daily with tail-vein injection of salvianolic acid A for 28 d. Record weights and observe general physical sign. Measure free radical ..pulmonary function and take electron microscopes. Results Salvianolic acid A could recover physical sign, enhance SOD and MDA activities and reduce MDA contents. Salvianolic acid A could minimize of alveolar spaces and alleviate the inflammation. Moreover, it could improve pulmonary function and decrease collagen expression, inhibits type Ⅱ alveolar epithelial cells hyperplasia in pulmonary fibrosis rats. Conclusion Salvianolic acid A could attenuate the bleomycin induced pulmonary fibrosis of rats and potential mechanism may be correlated with antioxidation of SAA.

  17. Effects of connective tissue growth factor and collagen type Ⅰ scleroderma

    Institute of Scientific and Technical Information of China (English)

    Xiaoning Yan; Jie Feng; Bingjun Shi

    2007-01-01

    Objective: To investigate the effects of connective tissue growth factor(CTGF) and collagen type Ⅰ(COL-I) on the pathogenesis of scleroderma and explore the relationship between the level of COL-I and CTGF. Methods: 12 mice model of scleroderma was established by the injection of Bleomycin. The level of CTGF and COL-I were detected by immunohistochemical method. The relationship was analyzed between CTGF and COL-I level. As control group, 12 healthy mice were selected. Results: The levels of CTGF and COL-I in sclerotic models were higher than in normal controls (P < 0.05). It was found that there was a correlation between the level of CTGF and COL-I. Conclusion: CTGF and COL-I played an important role in the hardening process of the skin lesions of the mice model, which may be involved in the pathogenesis of scleroderma.

  18. Hodgkin lymphoma in Tyrol-a population-based study.

    Science.gov (United States)

    Fong, Dominic; Steurer, Michael; Greil, Richard; Gunsilius, Eberhard; Spizzo, Gilbert; Gastl, Guenther; Tzankov, Alexandar

    2009-05-01

    We aimed to analyze the epidemiology, clinical characteristics, and outcome of patients with Hodgkin lymphoma (HL) diagnosed in Tyrol. All patients with newly diagnosed HL between 1993 and 2005 were included in this study. Among the 158 cases included, nodular lymphocytic predominant HL (nodular paragranuloma) was identified in ten cases (6%) whereas the majority of patients had classical Hodgkin lymphoma. Age (p Tyrol is comparable to other Western countries. Modern risk-adapted treatment results in excellent long-term prognosis but may be complicated by serious nonhematological side effects, in particular, infections and bleomycin-induced lung toxicity. Furthermore, 3% of HL patients had an antecedent malignant hematological disease before occurrence of HL.

  19. INTERVENTION CHEMOTHERAPY IN COMPREHENSIVE TREATMENT OF ADVANCED NASOPHARYNGEAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the use of interventional chemotherapy in comprehensive treatment for advanced nasopharyngeal carcinoma. Methods: Interventional chemotherapy with multi-drugs including cisplatin (DDP) 100 mg, 5-fluorouracil (5-FU) 1000 mg and bleomycin (BLM) 16 mg was used to treat 30 cases with advanced nasopharyngeal carcinoma before radiotherapy. 50 cases that received radiotherapy alone were used as a control group. The methods, time and dose schedule of radiotherapy were similar in the two groups. Results: The primary lesions in 16 cases and the cervical lymph nodes in 12 cases were reduced in size after interventional chemotherapy. Radiation doses of those in complete response in their primary lesion and cervical lymph nodes were lower than that of the control group (P<0.05). The complete response rate of study group was 83.3% and that of control group was 72.0% (P<0.05). Conclusion: Interventional chemotherapy plus radiotherapy is a valuable treatment method in advanced nasopharyngeal carcinoma.

  20. Predicting patients at risk for pain associated with electrochemotherapy

    DEFF Research Database (Denmark)

    Quaglino, Pietro; Matthiessen, Louise Wichmann; Curatolo, Pietro;

    2015-01-01

    BACKGROUND: Electrochemotherapy describes the use of electric pulses to enhance chemotherapy uptake, and has proven highly efficient in treating cutaneous metastases. Patients referred for electrochemotherapy present with diverse clinical pictures, from multiple small lesions to large, ulcerated...... lesions. Post-electrochemotherapy pain has been observed in some patients. The objectives of this study were to evaluate pain scores before and after electrochemotherapy, and to investigate if patients at risk of post-procedure pain could be identified. METHODS: Seven cancer centres in the International...... Network for Sharing Practices on Electrochemotherapy (INSPECT) consecutively and prospectively reported to a common database. Electrochemotherapy consisted of intratumoural or intravenous injection of bleomycin, followed by delivery of electric pulses in local or general anesthesia. RESULTS: Of 121...

  1. Intra-abdominal seminoma found incidentally during trauma workup in a man with bilateral cryptorchidism

    Directory of Open Access Journals (Sweden)

    Danielle Velez

    2015-01-01

    Full Text Available Bilateral cryptorchidism is a rare occurrence and seminoma is the most common germ cell tumor found in undescended testes when they occur. We present the case of a patient with bilateral cryptorchidism who presented to our trauma center after a motor vehicle collision and was found incidentally to have a 17-cm intra-abdominal mass. The mass was subsequently biopsied and proven to be seminoma. The patient completed three cycles of bleomycin/etoposide/cisplatin chemotherapy and successfully underwent a postchemo retroperitoneal lymph node dissection with no viable residual tumor or positive lymph nodes found in the surgical specimen. He also had an orchiopexy of the contralateral testicle. The patient recovered fully and has been found to be recurrence-free four months postoperatively. We highlight the importance of cisplatin-based chemotherapy and extensive tumor resection as the mainstay of initial cancer control.

  2. Lymphocyte Rich Hodgkin's Lymphoma Presented with Warm Hemolytic Anemia: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Jorge M. Hurtado-Cordovi

    2011-01-01

    Full Text Available Hodgkin's lymphoma accounts for ten percent of all lymphomas. In the United States, there are about 8000 new cases every year. This paper describes a case of lymphocyte-rich Hodgkin's lymphoma (LRHL manifested by autoimmune hemolytic anemia (AIHA. A 27-year-old Israeli male presented with dizziness associated with one month of low-grade fevers and night sweats; he also complained of persistent cough, pruritus, and ten-pound weight lost during this time. The CBC revealed hemoglobin of 5.9 gm/dL, and direct Coomb's test detected multiple nonspecific antibodies consistent with the diagnosis of AIHA. Chest, abdomen, and pelvic CT scan showed mediastinal lymphadenopathy and splenomegaly. Lymph node biopsy revealed classic LRHL. AIHA resolved after completion of the first cycle of chemotherapy with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD; after six cycles, he went into complete remission. Although infrequent, AIHA can be responsible for the presenting symptoms of HL.

  3. Advancements in Pharmacotherapy for Noncancerous Manifestations of HPV

    Directory of Open Access Journals (Sweden)

    Ramya Kollipara

    2015-04-01

    Full Text Available Human papillomavirus (HPV is the most common sexually transmitted disease. Via infection of the basal epithelial cells, HPV causes numerous malignancies and noncancerous cutaneous manifestations. Noncancerous cutaneous manifestations of HPV, including common, plantar, plane, and anogenital warts, are among the most common reasons for an office visit. Although there are various therapies available, they are notoriously difficult to treat. HPV treatments can be grouped into destructive (cantharidin, salicylic acid, virucidal (cidofovir, interferon-α, antimitotic (bleomycin, podophyllotoxin, 5-fluorouracil, immunotherapy (Candida antigen, contact allergen immunotherapy, imiquimod or miscellaneous (trichloroacetic acid, polyphenon E. The mechanism of action, recent efficacy data, safety profile and recommended regimen for each of these treatment modalities is discussed.

  4. [Biphasic pulmonary blastoma with germ cell differentiation: a challenge in diagnosis and treatment].

    Science.gov (United States)

    Teixeira, Alexandra; Vieira, Claúdia; Sousa, Nuno; Begonha, Rosa; Afonso, Mariana; Amaro, Teresina; Maurício, Joaquina

    2011-12-01

    Serviço de Oncologia Médica. Instituto Português de Oncologia Francisco Gentil. Porto. Portugal. A 27-year-old man, smoker, presented with three months history of fever. A left pulmonary mass inseparable from the heart was identified and serum alpha-fetoprotein was 4160 ng/ml. The morphologic aspects and immunohistochemistry of the biopsy specimen, in conjunction with the clinical findings were compatible with a diagnosis of pulmonary blastoma with germ cell differentiation. The tumour was considered unresectable. The patient was submitted to two cycles of primary chemotherapy with bleomycin, etoposide and cisplatin. Despite a reduction in serum alpha-fetoprotein, the tumor did not regress. Second line chemotherapy (with paclitaxel, ifosfamide and cisplatin) was instituted, but progressive disease was identified after 2 cycles. Six months after the diagnosis cerebral metastases were found and the patient died. This case illustrates a rare situation of difficult diagnosis and treatment.

  5. Treatment-related risk factors for premature menopause following Hodgkin lymphoma

    DEFF Research Database (Denmark)

    De Bruin, Marie L; Huisbrink, Jeannine; Hauptmann, Michael;

    2008-01-01

    We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40...... years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone......)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years...

  6. Effects of artichoke (Cynara scolymus) leaf and bloom head extracts on chemically induced DNA lesions in Drosophila melanogaster

    Science.gov (United States)

    Jacociunas, Laura Vicedo; Dihl, Rafael Rodrigues; Lehmann, Mauricio; de Barros Falcão Ferraz, Alexandre; Richter, Marc François; da Silva, Juliana; de Andrade, Heloísa Helena Rodrigues

    2014-01-01

    The genotoxicity of bloom head (BHE) and leaf (LE) extracts from artichoke (Cynara scolymus L.), and their ability to modulate the mutagenicity and recombinogenicity of two alkylating agents (ethyl methanesulfonate – EMS and mitomycin C – MMC) and the intercalating agent bleomycin (BLM), were examined using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Neither the mutagenicity nor the recombinogenicity of BLM or MMC was modified by co- or post-treatment with BHE or LE. In contrast, co-treatment with BHE significantly enhanced the EMS-induced genotoxicity involving mutagenic and/or recombinant events. Co-treatment with LE did not alter the genotoxicity of EMS whereas post-treatment with the highest dose of LE significantly increased this genotoxicity. This enhancement included a synergistic increase restricted to somatic recombination. These results show that artichoke extracts promote homologous recombination in proliferative cells of D. melanogaster. PMID:24688296

  7. Metastatic choriocarcinoma induced separate simultaneous intracerebral haemorrhages: a very rare occurrence and its novel association with Klinefelter syndrome.

    Science.gov (United States)

    Joret, Maximilian Olavi; Starke, Robert M; Scotter, John; Heppner, Peter

    2015-11-12

    Non-traumatic separate simultaneous intracerebral haemorrhages (SSIHs) are rare. Relevant aetiologies are diverse and their diagnosis challenging. We report a unique case of SSIH in an 18-year-old male with a background of previously undiagnosed testicular choriocarcinoma and Klinefelter syndrome. The patient was admitted to Auckland City Hospital with headaches, drowsiness and vomiting. A CT scan revealed SSIH in a background of tumorous lesions. His β human chorionic gonadotropin titre was elevated at 355 000 IU/L. The SSIH and the associated tumorous lesions were acutely surgically resected and the patient started on bleomycin, etoposide and cisplatin combination chemotherapy with excellent results. In this article, we underline choriocarcinoma as a rare aetiology of SSIH and present an example of the clinical presentation, investigation and management of this very rare pathological entity.

  8. Update on hypertrophic scar treatment

    Directory of Open Access Journals (Sweden)

    Felipe Bettini Rabello

    2014-08-01

    Full Text Available Scar formation is a consequence of the wound healing process that occurs when body tissues are damaged by a physical injury. Hypertrophic scars and keloids are pathological scars resulting from abnormal responses to trauma and can be itchy and painful, causing serious functional and cosmetic disability. The current review will focus on the definition of hypertrophic scars, distinguishing them from keloids and on the various methods for treating hypertrophic scarring that have been described in the literature, including treatments with clearly proven efficiency and therapies with doubtful benefits. Numerous methods have been described for the treatment of abnormal scars, but to date, the optimal treatment method has not been established. This review will explore the differences between different types of nonsurgical management of hypertrophic scars, focusing on the indications, uses, mechanisms of action, associations and efficacies of the following therapies: silicone, pressure garments, onion extract, intralesional corticoid injections and bleomycin.

  9. Biological effects of DNA damage in the hyperthermophilic archaeon Sulfolobus acidocaldarius.

    Science.gov (United States)

    Reilly, Michelle S; Grogan, Dennis W

    2002-02-19

    To investigate the generality of efficient double-strand break repair and damage-induced mutagenesis in hyperthermophilic archaea, we systematically measured the effects of five DNA-damaging agents on Sulfolobus acidocaldarius and compared the results to those obtained for Escherichia coli under corresponding conditions. The observed lethality of gamma-radiation was very similar for S. acidocaldarius and E. coli, arguing against unusually efficient double-strand break repair in S. acidocaldarius. In addition, DNA-strand-breaking agents (gamma-radiation or bleomycin), as well as DNA-cross-linking agents (mechlorethamine, butadiene diepoxide or cisplatin) stimulated forward mutation, reverse mutation, and formation of recombinants via conjugation in Sulfolobus cells. Although two of the five DNA-damaging agents failed to revert the E. coli auxotrophs under these conditions, all five reverted S. acidocaldarius auxotrophs.

  10. [Non-edematous spontaneously resolving cerebellar softening. Diagnostic possibilities and value (author's transl)].

    Science.gov (United States)

    Samson, M; Parain, D; Mihout, B

    1980-01-01

    Non edematous cerebellar softenings are usually unrecognized even though their relatively high frequency of occurrence is proved by systematic anatomical studies. They should be suspected when an acute late-onset vestibular syndrome is noted, in which there is a particular type of homolateral disequilibrium and nystagmus, good vestibular reactivity, and possible association with a cerebellar syndrome. Softening can usually be confirmed after several days by the complementary examinations presently available: computer tomography of the posterior fossa and scintigraphy with labelled bleomycin. Non-edematous forms are spontaneously resolving disorders but surveillance during the first few days is necessary together with anti-edematous therapy as early signs are common to those of edematous softening, responsible for rapid involvement of the brain stem and blocking of fluid pathways.

  11. Ultrasound guided electrochemotherapy for the treatment of a clear cell thymoma in a cat

    Science.gov (United States)

    Spugnini, Enrico Pierluigi; Menicagli, Francesco; Pettorali, Michela; Baldi, Alfonso

    2017-01-01

    A twelve-year-old male castrated domestic shorthair cat was presented for rapidly progressing respiratory distress. The cat was depressed, tachypneic and moderately responsive. Ultrasonography showed a mediastinal mass associated with a significant pleural effusion that needed tapping every five to seven days. Ultrasound guided biopsy yielded a diagnosis of clear cell thymoma upon histopathology. After complete staging procedures, the owner elected to treat the cat with electrochemotherapy (ECT) using systemic bleomycin. Two sessions of ultrasound guided ECT were performed at two week intervals with trains of biphasic electric pulses applied using needle electrodes until complete coverage of the area was achieved. The treatment was well tolerated and resulted in partial remission (PR). Additional sessions were performed on a monthly basis. The cat is still in PR after fourteen months. ECT resulted in improved local control and should be considered among the available adjuvant treatments in pets carrying visceral tumors. PMID:28331834

  12. Interplay between mutagen sensitivity and epidemiological factors in modulatinglung cancer risk.

    Science.gov (United States)

    Wu, Xifeng; Lin, Jie; Etzel, Carol J; Dong, Qiong; Gorlova, Olga Y; Zhang, Qing; Amos, Christopher I; Spitz, Margaret R

    2007-06-15

    Few studies have assessed mutagen sensitivity and lung cancer (LC) risk associations in the context of multiple epidemiological risk factors. We evaluated mutagen sensitivity as a susceptibility marker and explored the interplay of the genetic marker and multiple epidemiologic risk factors in modulating LC risk. This largest case-control study included 977 newly diagnosed LC patients and 977 controls, matched by age, gender, ethnicity and smoking status. Cases exhibited significantly higher mutagen sensitivity than controls in bleomycin (0.76 vs. 0.62 breaks/cell, p Mutagen sensitivity also exhibited dose-response relationship with LC risk in quartile analysis (p for trend mutagen sensitivity as a predisposition factor for LC and demonstrates the importance of assessing multiple risk factors to comprehensively assess LC risk. This new integrative approach should facilitate identification of high-risk subgroups and has important implications in LC prevention.

  13. Adaptive Response in Animals Exposed to Non-Ionizing Radiofrequency Fields: Some Underlying Mechanisms

    Directory of Open Access Journals (Sweden)

    Yi Cao

    2014-04-01

    Full Text Available During the last few years, our research group has been investigating the phenomenon of adaptive response in animals exposed to non-ionizing radiofrequency fields. The results from several separate studies indicated a significant increase in survival, decreases in genetic damage as well as oxidative damage and, alterations in several cellular processes in mice pre-exposed to radiofrequency fields and subsequently subjected to sub-lethal or lethal doses of γ-radiation or injected with bleomycin, a radiomimetic chemical mutagen. These observations indicated the induction of adaptive response providing the animals the ability to resist subsequent damage. Similar studies conducted by independent researchers in mice and rats have supported our observation on increased survival. In this paper, we have presented a brief review of all of our own and other independent investigations on radiofrequency fields-induced adaptive response and some underlying mechanisms discussed.

  14. Cellular senescence mediates fibrotic pulmonary disease

    Science.gov (United States)

    Schafer, Marissa J.; White, Thomas A.; Iijima, Koji; Haak, Andrew J.; Ligresti, Giovanni; Atkinson, Elizabeth J.; Oberg, Ann L.; Birch, Jodie; Salmonowicz, Hanna; Zhu, Yi; Mazula, Daniel L.; Brooks, Robert W.; Fuhrmann-Stroissnigg, Heike; Pirtskhalava, Tamar; Prakash, Y. S.; Tchkonia, Tamara; Robbins, Paul D.; Aubry, Marie Christine; Passos, João F.; Kirkland, James L.; Tschumperlin, Daniel J.; Kita, Hirohito; LeBrasseur, Nathan K.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function. PMID:28230051

  15. Management of craniopharyngiomas: Role of conservative strategies

    Directory of Open Access Journals (Sweden)

    Shibu Pillai

    2013-01-01

    Full Text Available Craniopharyngiomas are uncommon tumors and their management remains controversial. Despite gross total resection, recurrences can occur in 15-43% during long-term follow-up of more than 10 years. Furthermore, radical surgery can be associated with complications associated with hypothalamic damage, which can lead to a poor quality-of-life. Limited surgery followed by adjuvant radiotherapy (RT can provide excellent long-term tumor control with minimum complications and good functional outcome. RT can however, produce insidious onset of hypopituitarism and vasculopathy. Secondary malignancies are a rare complication of RT. Modern radiation techniques and intracystic radiation can reduce these complications. Intracystic radiation is highly effective for cystic craniopharyngiomas. Intracystic bleomycin (ICB and interferon alpha (IFN are rarely curative, but can produce long lasting control of tumor cysts and this is very useful in very young children who may not tolerate radical surgery or RT. IFN has fewer toxicity issues compared to ICB.

  16. Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer.

    Science.gov (United States)

    Delbès, Geraldine; Chan, Donovan; Hales, Barbara F; Trasler, Jacquetta M; Robaire, Bernard

    2013-04-01

    Chemotherapeutic drugs can affect DNA in male germ cells, thereby impacting on the integrity of the genome transmitted to offspring. Drug metabolizing enzymes can protect cells from xenobiotic insult. We analyzed the expression pattern of such enzymes in isolated round spermatids from rats exposed to drugs used to treat testicular cancer: bleomycin, etoposide, and cisplatin (BEP). The number of isozymes expressed and the overall relative expression values were highest for the glutathione S-transferases (GSTs). Moreover, BEP treatment significantly increased the expression of 8 GSTs and 3 aldehyde dehydrogenases. Increased expression of GST isozymes was confirmed by qRT-PCR and Western blot analysis. Although Gst genes can be targets for epigenetic modifications, promoter DNA methylation was not affected by BEP treatment. As GSTs are involved in drug resistance mechanisms, we hypothesize that BEP induction of GST expression may lead to the survival of damaged germ cells and the production of abnormal sperm.

  17. An improved brine shrimp larvae lethality microwell test method.

    Science.gov (United States)

    Zhang, Yi; Mu, Jun; Han, Jinyuan; Gu, Xiaojie

    2012-01-01

    This article described an improved brine shrimp larvae lethality microwell test method. A simply designed connecting vessel with alternative photoperiod was used to culture and collect high yield of active Artemia parthenogenetica nauplii for brine shrimp larvae lethality microwell test. Using this method, pure A. parthenogenetica nauplii suspension was easily cultured and harvested with high density about 100-150 larvae per milliliter and the natural mortality was reduced to near zero by elimination of unnecessary artificial disturbance. And its sensitivity was validated by determination of LC(50)-24 h of different reference toxicants including five antitumor agents, two pesticides, three organic pollutants, and four heavy metals salts, most of which exhibited LC(50)-24 h between 0.07 and 58.43 mg/L except for bleomycin and mitomycin C with LC(50)-24 h over 300 mg/L.

  18. Effects of Long-Term Exposure to 60 GHz Millimeter-Wavelength Radiation on the Genotoxicity and Heat Shock Protein (Hsp Expression of Cells Derived from Human Eye

    Directory of Open Access Journals (Sweden)

    Shin Koyama

    2016-08-01

    Full Text Available Human corneal epithelial (HCE-T and human lens epithelial (SRA01/04 cells derived from the human eye were exposed to 60 gigahertz (GHz millimeter-wavelength radiation for 24 h. There was no statistically significant increase in the micronucleus (MN frequency in cells exposed to 60 GHz millimeter-wavelength radiation at 1 mW/cm2 compared with sham-exposed controls and incubator controls. The MN frequency of cells treated with bleomycin for 1 h provided positive controls. The comet assay, used to detect DNA strand breaks, and heat shock protein (Hsp expression also showed no statistically significant effects of exposure. These results indicate that exposure to millimeter-wavelength radiation has no effect on genotoxicity in human eye cells.

  19. A Case of Recalcitrant Plantar Warts Associated with Statin Use

    Directory of Open Access Journals (Sweden)

    Aaron G. Wernham

    2015-01-01

    Full Text Available Background. Plantar warts are a common presenting skin complaint caused by the human papillomavirus. 1st line therapies include cryotherapy and topical salicylic acid. Where there is resistance to these treatments, consideration is made for 2nd line therapies, including intralesional bleomycin, imiquimod, 5-fluorouracil, and photodynamic therapy. We present a case of bilateral persistent plantar warts, resistant to treatment with repeated cryotherapy and topical salicylic acid over a 6-year period. Following a patient initiated decision to discontinue their statin medication, we observed rapid clearance of plantar warts without change to standard therapy or their environment. This case correlates with emerging literature demonstrating a link between statin medication and proliferation of HPV through increased levels of FOXP3+ regulatory T cells.

  20. Genotoxin Induced Mutagenesis in the Model Plant Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Marcela Holá

    2013-01-01

    Full Text Available The moss Physcomitrella patens is unique for the high frequency of homologous recombination, haploid state, and filamentous growth during early stages of the vegetative growth, which makes it an excellent model plant to study DNA damage responses. We used single cell gel electrophoresis (comet assay to determine kinetics of response to Bleomycin induced DNA oxidative damage and single and double strand breaks in wild type and mutant lig4 Physcomitrella lines. Moreover, APT gene when inactivated by induced mutations was used as selectable marker to ascertain mutational background at nucleotide level by sequencing of the APT locus. We show that extensive repair of DSBs occurs also in the absence of the functional LIG4, whereas repair of SSBs is seriously compromised. From analysis of induced mutations we conclude that their accumulation rather than remaining lesions in DNA and blocking progression through cell cycle is incompatible with normal plant growth and development and leads to sensitive phenotype.

  1. Retroperitoneal schwannoma mimicking metastatic seminoma:case report and literature review

    Institute of Scientific and Technical Information of China (English)

    Shi-Qiang Zhang; Song Wu; Kai Yao; Pei Dong; Yong-Hong Li; Zhi-Ling Zhang; Xian-Xin Li

    2013-01-01

    If a testicular cancer pat ient has a mass in the retroperitoneum,a metastasis is often the first suspicion,probably leading to improper diagnosis and overtreatment.Here we report a case of retroperitoneal schwannoma mimicking metastatic seminoma.A 29-year-old man,who had a history of seminoma,presented with a single retroperitoneal mass suspected to be a metastasis.Because the patient refused radiotherapy,3 cycles of cisplatin,etoposide,and bleomycin were offered.Post-chemotherapy computed tomography scan revealed persistence of the retroperitoneal mass,with no change in tumor size or characteristics.Subsequently,retroperitoneal lymph node dissection was performed.The dissected tissue contained negative lymph nodes but a single mass in the attached fat.Pathology revealed retroperitoneal schwannoma,which was confirmed by immunohistochemistry.Thus,clinicians should be aware of retroperitoneal schwannoma and its distinction from metastatic seminoma to avoid misdiagnosis and ensure proper treatment.

  2. Photothermal enhancement of chemotherapy mediated by gold-silica nanoshell-loaded macrophages: in vitro squamous cell carcinoma study

    Science.gov (United States)

    Madsen, Steen J.; Shih, En-Chung; Peng, Qian; Christie, Catherine; Krasieva, Tatiana; Hirschberg, Henry

    2016-01-01

    Moderate hyperthermia (MHT) has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of commonly used chemotherapeutic agents with MHT induced by near-infrared (NIR) activation of gold nanoshell (AuNS)-loaded macrophages (Ma). AuNS-loaded murine Ma combined with human FaDu squamous cells, in hybrid monolayers, were subjected to three cytotoxic drugs (doxorubicin, bleomycin, cisplatin) with or without NIR laser irradiation. For all three drugs, efficacy was increased by NIR activation of AuNS-loaded Ma. The results of this in vitro study provide proof-of-concept for the use of AuNS-loaded Ma for photothermal enhancement of the effects of chemotherapy on squamous cell carcinoma.

  3. Calcium Electroporation

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gibot, Laure; Madi, Moinecha;

    2015-01-01

    BACKGROUND: Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill...... efficacy-and normal cell sensitivity. METHODS: Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different human cancer cell lines: a colorectal adenocarcinoma (HT29), a bladder transitional cell carcinoma (SW780......), and a breast adenocarcinoma (MDA-MB231), as well as on primary normal human dermal fibroblasts (HDF-n). RESULTS: The results showed a clear reduction in spheroid size in all three cancer cell spheroids three days after treatment with respectively calcium electroporation (p

  4. A pre-validation trial - testing genotoxicity of several chemicals using standard, medium- and high-throughput comet formats.

    Directory of Open Access Journals (Sweden)

    Kristine Bjerve Gutzkow

    2015-06-01

    Results obtained with the three systems (standard, medium- and high-throughput were essentially the same. The 96-minigel format was analysed with the fully automated scoring system IMSTAR and comparable results were achieved with the semi-automated scoring system from Perceptives. The known genotoxic chemicals MNU, B(aP, 4-NQO and cyclophosphamide showed little consistent sign of genotoxicity at concentrations causing limited cytotoxicity. D-mannitol and Triton X-100 were, as expected, non-genotoxic (though Triton X-100, at high concentrations, caused DNA breaks as an apparent secondary effect of cytotoxicity. Etoposide and bleomycin gave significant increase in DNA strand break at borderline cytotoxic concentrations. The limitation of the assay to detect damaged bases by known genotoxins may be overcome by incorporating a DNA repair enzyme, such as formamidopyrimidine-DNA-glycosylase (FPG, to convert damaged bases into breaks as shown by Azqueta A et al., Mutagenesis vol. 28 no. 3 pp. 271–277, 2013 .

  5. Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

    DEFF Research Database (Denmark)

    Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua

    2016-01-01

    Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface......, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent...... within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180...

  6. A critical role for the mTORC2 pathway in lung fibrosis.

    Directory of Open Access Journals (Sweden)

    Wenteh Chang

    Full Text Available A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-β and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-β of pro-fibrotic pathways. Recent studies show that mTORC2, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis. We examined the effect of MLN0128 on TGF-β-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-β-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-β induces the Rictor component of mTORC2 in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it (1 inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-β-stimulated IPF fibroblasts; (2 inhibited fibrosis in a murine bleomycin lung model; and (3 protected lung epithelial cells from injury caused by TGF-β-stimulated IPF fibroblasts. Our findings support a role for mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.

  7. Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats.

    Science.gov (United States)

    Wang, Y; Huang, G; Mo, B; Wang, C

    2016-06-03

    The aim of this study was to determine the effect of artesunate on extracellular matrix (ECM) accumulation and the expression of collagen-IV, matrix metalloproteinase (MMP), and tissue inhibitor of matrix metalloproteinase (TIMP) to understand the pharmacological role of artesunate in pulmonary fibrosis. Eighty Sprague-Dawley rats were randomly assigned to four groups that were administered saline alone, bleomycin (BLM) alone, BLM + artesunate, or artesunate alone for 28 days. Lung tissues from 10 rats in each group were used to obtain lung fibroblast (LF) primary cells, and the rest were used to analyze protein expression. The mRNA expression of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 in lung fibroblasts was detected by real-time quantitative reverse transcriptase polymerase chain reaction. The protein levels of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 protein in lung tissues were analyzed by western blotting. Artesunate treatment alleviated alveolitis and pulmonary fibrosis induced by bleomycin in rats, as indicated by a decreased lung coefficient and improvement of lung tissue morphology. Artesunate treatment also led to decreased collagen-IV protein levels, which might be a result of its downregulated expression and increased MMP-2 and MMP-9 protein and mRNA levels. Increased TIMP-1 and TIMP- 2 protein and mRNA levels were detected after artesunate treatment in lung tissues and primary lung fibroblast cells and may contribute to enhanced activity of MMP-2 and -9. These findings suggested that artesunate attenuates alveolitis and pulmonary fibrosis by regulating expression of collagen-IV, TIMP-1 and 2, as well as MMP-2 and -9, to reduce ECM accumulation.

  8. Application of Translational Medicine Concept in Chinese Materia Medica:Effect and Mechanism of Mahuang and Wuweizi on Pulmonary Fibrosis

    Institute of Scientific and Technical Information of China (English)

    QIN Hai-zhi; DONG Wei-tao

    2015-01-01

    Objective:To explore the effect and mechanism of Mahuang (Herba Ephedra) and Wuweizi (Schisandra Chinesis) on pulmonary ifbrosis based on translation medicine theory. Methods: Totally 90 Wistar rats were divided into 6 groups. Pulmonary ifbrosis models of rats were established by drip of bleomycin A5 through trachea while sham-operation group was infused with equivalent normal saline instead of bleomycin A5 into trachea. Sham-operation group and negative control group were performed with normal saline gavage while positive control group with subcutaneous injection of hydrocortisone, Mahuang group and Wuweizi group with gavage of Mahuang and Wuweizi concentrated decoction, respectively, whereas combined group was treated with gavage of Mahuang concentrated decoction during the ifrst 7 days and with Wuweizi concentrated decoction in the ensuing 21 days. On the 7th day and 28th day, pulmonary alveolitis and fibrosis in different groups were observed and the expression levels of serum vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), thrombospondin-1 (TSP-1), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α) were detected and compared. Results: All models of groups were successfully established. Compared with negative control group, the levels of VEGF, Ang-2, MCP-1 and MIP-1α decreased in different degrees but TSP-1 increased in other groups after medication for 7 days and 28 days. Conclusion: Mahuang and Wuweizi have intervention effects on pulmonary fibrosis, the mechanism of which might be related to the inhibition of excessive angiogenesis through inhibiting the expression of MCP-1 and MIP-1α, lowering the level of proangiogenic factors (Ang-2 and BEGF), and enhancing the level of angiogenesis inhibiting factor (TSP-1).

  9. The role of the receptor for advanced glycation end-products in a murine model of silicosis.

    Directory of Open Access Journals (Sweden)

    Lasse Ramsgaard

    Full Text Available BACKGROUND: The role of the receptor for advanced glycation end-products (RAGE has been shown to differ in two different mouse models of asbestos and bleomycin induced pulmonary fibrosis. RAGE knockout (KO mice get worse fibrosis when challenged with asbestos, whereas in the bleomycin model they are largely protected against fibrosis. In the current study the role of RAGE in a mouse model of silica induced pulmonary fibrosis was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Wild type (WT and RAGE KO mice received a single intratracheal (i.t. instillation of silica in saline or saline alone as vehicle control. Fourteen days after treatment mice were subjected to a lung mechanistic study and the lungs were lavaged and inflammatory cells, protein and TGF-beta levels in lavage fluid determined. Lungs were subsequently either fixed for histology or excised for biochemical assessment of fibrosis and determination of RAGE protein- and mRNA levels. There was no difference in the inflammatory response or degree of fibrosis (hydroxyproline levels in the lungs between WT and RAGE KO mice after silica injury. However, histologically the fibrotic lesions in the RAGE KO mice had a more diffuse alveolar septal fibrosis compared to the nodular fibrosis in WT mice. Furthermore, RAGE KO mice had a significantly higher histologic score, a measure of affected areas of the lung, compared to WT silica treated mice. A lung mechanistic study revealed a significant decrease in lung function after silica compared to control, but no difference between WT and RAGE KO. While a dose response study showed similar degrees of fibrosis after silica treatment in the two strains, the RAGE KO mice had some differences in the inflammatory response compared to WT mice. CONCLUSIONS/SIGNIFICANCE: Aside from the difference in the fibrotic pattern, these studies showed no indicators of RAGE having an effect on the severity of pulmonary fibrosis following silica injury.

  10. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.

    Science.gov (United States)

    Park, Chan Sun; Bang, Bo-Ram; Kwon, Hyouk-Soo; Moon, Keun-Ai; Kim, Tae-Bum; Lee, Ki-Young; Moon, Hee-Bom; Cho, You Sook

    2012-12-15

    Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma.

  11. Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin's lymphoma (NHL): the 1980-1985 EORTC trial. The EORTC Lymphoma Group.

    Science.gov (United States)

    Carde, P; Meerwaldt, J H; van Glabbeke, M; Somers, R; Monconduit, M; Thomas, J; de Wolf-Peeters, C; de Pauw, B; Tanguy, A; Kluin-Nelemans, J C

    1991-06-01

    A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.

  12. Correlation of Clinical and Dosimetric Factors With Adverse Pulmonary Outcomes in Children After Lung Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Venkatramani, Rajkumar, E-mail: rvenkatramani@chla.usc.edu [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Kamath, Sunil [Department of Pulmonology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Wong, Kenneth [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Olch, Arthur J. [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Radiation Oncology, University of Southern California, Los Angeles, California (United States); Malvar, Jemily [Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Sposto, Richard [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Goodarzian, Fariba [Department of Radiology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Freyer, David R. [Division of Hematology/Oncology, Children' s Hospital Los Angeles, Los Angeles, California (United States); Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Keens, Thomas G. [Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California (United States); Department of Pulmonology, Children' s Hospital Los Angeles, Los Angeles, California (United States); and others

    2013-08-01

    Purpose: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. Methods and Materials: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. Results: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The following pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V{sub 22} (volume of lung exposed to a radiation dose ≥22 Gy) and V{sub 30} (volume of lung exposed to a radiation dose ≥30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and V{sub dose} (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). Conclusions: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed

  13. Effect of TGF-β/Smad signaling pathway on lung myofibroblast differentiation

    Institute of Scientific and Technical Information of China (English)

    Li GU; Yuan-jue ZHU; Xiao YANG; Zi-Jian GUO; Wen-bing XU; Xin-lun TIAN

    2007-01-01

    Aim: Myofibroblasts play important roles in the pathogenesis of lung fibrosis.Transforming growth factor (TGF)-β1 has been widely recognized as a key fibrogenic cytokine. The major signaling pathway of TGF-β1 is through cytoplas-mic Smad proteins. Our study investigated the role of individual TGF-β1/Smad signal proteins in mediating α-smooth muscle actin (α-SMA) gene expression,which is a well-known key marker of myofibroblast differentiation. Methods: We transiently cotransfected α-SMA promoter-luciferase fusion plasmid (p895-Luc)and Smad expression plasmids and measured Luc activity in TGF-β1-treated hu-man fetal lung fibroblasts. We induced Smad3 knockout mice lung fibrosis by bleomycin, α-SMA protein expression was assessed by Western blotting. Col-lagen protein was analyzed by measuring hydroxyprolin. Myofibroblast morphol-ogy was assessed by immunohistochemistry. Results: We found that the overexpression of Smad3, not Smad2 markedly increased TGF-β1-induced α-SMA promoter activity and α-SMA protein expression in vitro, whereas the over-expression of dominant negative mutant Smad3 and Smad7 repressed TGF-β1 induced α-SMA gene expression. Compared to wild-type mice, Smad3 knockout mice showed attenuated lung fibrosis after bleomycin treatment, manifested by lower collagen production and myofibroblast differentiation. Conclusion: Our study suggested TGF-β1/Smad3 is a major pathway which regulated the myofibroblast differentiation. This result indicates a potential significance for future attempts of attenuating the progression of human lung fibrosis by the inhibition of the Smad3 cascade.

  14. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

    Science.gov (United States)

    Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H

    2014-04-01

    Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

  15. The anti-fibrotic effect of inhibition of TGFβ-ALK5 signalling in experimental pulmonary fibrosis in mice is attenuated in the presence of concurrent γ-herpesvirus infection

    Directory of Open Access Journals (Sweden)

    Natalia Smoktunowicz

    2015-09-01

    Full Text Available TGFβ-ALK5 pro-fibrotic signalling and herpesvirus infections have been implicated in the pathogenesis and exacerbation of pulmonary fibrosis. In this study we addressed the role of TGFβ-ALK5 signalling during the progression of fibrosis in a two-hit mouse model of murine γ-herpesvirus 68 (MHV-68 infection on the background of pre-existing bleomycin-induced pulmonary fibrosis. Assessment of total lung collagen levels in combination with ex vivo micro-computed tomography (µCT analysis of whole lungs demonstrated that MHV-68 infection did not enhance lung collagen deposition in this two-hit model but led to a persistent and exacerbated inflammatory response. Moreover, µCT reconstruction and analysis of the two-hit model revealed distinguishing features of diffuse ground-glass opacities and consolidation superimposed on pre-existing fibrosis that were reminiscent of those observed in acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF. Virally-infected murine fibrotic lungs further displayed evidence of extensive inflammatory cell infiltration and increased levels of CCL2, TNFα, IL-1β and IL-10. Blockade of TGFβ-ALK5 signalling attenuated lung collagen accumulation in bleomycin-alone injured mice, but this anti-fibrotic effect was reduced in the presence of concomitant viral infection. In contrast, inhibition of TGFβ-ALK5 signalling in virally-infected fibrotic lungs was associated with reduced inflammatory cell aggregates and increased levels of the antiviral cytokine IFNγ. These data reveal newly identified intricacies for the TGFβ-ALK5 signalling axis in experimental lung fibrosis, with different outcomes in response to ALK5 inhibition depending on the presence of viral infection. These findings raise important considerations for the targeting of TGFβ signalling responses in the context of pulmonary fibrosis.

  16. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale.

    Science.gov (United States)

    Gallamini, Andrea; Barrington, Sally F; Biggi, Alberto; Chauvie, Stephane; Kostakoglu, Lale; Gregianin, Michele; Meignan, Michel; Mikhaeel, George N; Loft, Annika; Zaucha, Jan M; Seymour, John F; Hofman, Michael S; Rigacci, Luigi; Pulsoni, Alessandro; Coleman, Morton; Dann, Eldad J; Trentin, Livio; Casasnovas, Olivier; Rusconi, Chiara; Brice, Pauline; Bolis, Silvia; Viviani, Simonetta; Salvi, Flavia; Luminari, Stefano; Hutchings, Martin

    2014-06-01

    A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of 'interim' positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2-110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (Pinterim positron emission tomography scans for predicting treatment outcome were 0.73, 0.94, 0.94 and 0.73, respectively. Binary concordance amongst reviewers was good (Cohen's kappa 0.69-0.84). In conclusion, the prognostic role and validity of the Deauville five-point scale for interpretation of interim positron emission tomography scans have been confirmed by the present study.

  17. Posttranslational modifications in microcin B17 define an additional class of DNA gyrase inhibitor.

    Science.gov (United States)

    Yorgey, P; Lee, J; Kördel, J; Vivas, E; Warner, P; Jebaratnam, D; Kolter, R

    1994-05-10

    Drugs that inhibit the activity of DNA gyrase fall almost exclusively into two structural classes, the quinolones and the coumarins. A third class of DNA gyrase inhibitor is defined by the ribosomally synthesized peptide antibiotic microcin B17 (MccB17). MccB17 contains 43 amino acid residues, but 14 of these are posttranslationally modified. Here we describe the characterization of the structure of these modifications. We propose that four cysteine and four serine side chains undergo condensation with the carbonyl group of the preceding residue, followed by alpha/beta dehydrogenation to yield four thiazole and four oxazole rings, respectively. The three proteins implicated in catalyzing these modifications (McbBCD) would constitute the only thiazole/oxazole biosynthetic enzymes identified. These results open up possibilities for the design of DNA gyrase inhibitors and add to the repertoire of posttranslational modifications with potential for protein engineering. Escherichia coli sbmA mutants, which lack the inner membrane protein (SbmA) involved in MccB17 uptake, were found to be resistant to bleomycin. Bleomycin is structurally unrelated to MccB17 except for the fact that it contains two thiazole rings. This suggests that thiazole rings are part of the MccB17 structure recognized by SbmA. This observation and the finding that SbmA homologs are widely conserved and can play developmental roles [Glazebrook, J., Ichige, A. & Walker, G. C. (1993) Genes Dev. 7, 1485-1497] suggest that thiazole- and oxazole-containing compounds may serve as signaling molecules for a wide variety of bacteria in diverse environments, including pathogen interactions with plant and animal hosts.

  18. Pyrrhocoricin, a proline-rich antimicrobial peptide derived from insect, inhibits the translation process in the cell-free Escherichia coli protein synthesis system.

    Science.gov (United States)

    Taniguchi, Masayuki; Ochiai, Akihito; Kondo, Hiroshi; Fukuda, Shun; Ishiyama, Yohei; Saitoh, Eiichi; Kato, Tetsuo; Tanaka, Takaaki

    2016-05-01

    Previous studies have shown that pyrrhocoricin, a proline-rich antimicrobial peptide (PrAMP), killed sensitive species in a dose-dependent manner by specifically binding to DnaK. Here, on the basis of the finding that DnaK-deficient Escherichia coli strains are susceptible to PrAMPs, we used pyrrhocoricin to investigate internal targets other than DnaK. Using conventional antibiotics (bleomycin, streptomycin, and fosfomycin) that have known modes of action, first, we validated the availability of an assay using a cell-free rapid translation system (RTS), which is an in vitro protein synthesis system based on E. coli lysate, for evaluating inhibition of protein synthesis. We found that, similarly to bleomycin and streptomycin, pyrrhocoricin inhibited GFP synthesis in RTS in a concentration-dependent manner. In addition, blockage of transcription and translation steps in RTS was individually estimated using RT-PCR after gene expression to determine mRNA products and using sodium dodecyl sulfate-polyacrylamide gel electrophoresis to determine the amounts of GFP expressed from purified mRNA, respectively. The results demonstrated that this inhibition of GFP synthesis by pyrrhocoricin did not occur at the transcription step but rather at the translation step, in a manner similar to that of GFP synthesis by streptomycin, an inhibitor of the translation step by causing misreading of tRNA. These results suggest that RTS is a powerful assay system for determining if antimicrobial peptides inhibit protein synthesis and its transcription and/or translation steps. This is the first study to have shown that pyrrhocoricin inhibited protein synthesis by specifically repressing the translation step.

  19. ABVE-PC and modified BEACOPP regimen in Indian children with Hodgkin lymphoma: Feasibility and efficacy

    Directory of Open Access Journals (Sweden)

    Somasundaram Jayabose

    2016-01-01

    Full Text Available Aims: To study the toxicity of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide and modified-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, prednisone in intermediate-risk and high-risk Hodgkin lymphoma patients. Methods: High-risk patients received 4 cycles of modified-BEACOPP (m-BEACOPP plus 4 cycles of ABVD. Intermediate-risk patients received 4 cycles of ABVE-PC plus 2 cycles of ABVD. Results: From 2010 to 2014, 17 patients received 66 cycles of m-BEACOPP and 9 patients received 40 cycles of ABVE-PC. In the m-BEACOPP and ABVE-PC courses, respectively, significant thrombocytopenia (<50,000/mm3 occurred in 10.6% vs 0% of courses; anemia (Hb. <8 gm/dl in 27.3% vs 15%; neutropenia (ANC<500/mm3 in 46.9% vs 32.5%; and febrile neutropenia in 33.3% vs. 22.5%. Only episode of documented infection (hepatic abscess occurred in ABVE-PC. There were no episodes of sepsis, typhlitis or pneumonia in either group. All 26 patients are in remission with a median follow-up of 35 months (range, 17-61; and there have been no relapses. Two of 26 (7.7% patients failed to achieve rapid early response after 2 cycles and complete remission after 4 cycles of chemotherapy; both achieved remission with more intensive regimens followed by radiation. The remaining 24 patients did not receive radiation therapy. Conclusions: Both m-BEACOPP and ABVE-PC regimens have acceptable toxicity; and thus can be used in most centres with optimum supportive care facilities. They offer promising response rate and relapse free survival without the need for radiation therapy in most patients; and thus may be considered for children with high-risk and intermediate-risk Hodgkin lymphoma.

  20. TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis

    Directory of Open Access Journals (Sweden)

    Luckhardt Tracy R

    2011-08-01

    Full Text Available Abstract Background We have shown previously that murine gammaherpesvirus 68 (γHV68 infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c and TLR-9-/- mice. Results We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis. This was not associated with increased viral load in TLR-9-/- mice or with major alterations in T helper (Th1 and Th2 cytokines. We examined alveolar epithelial-cell apoptosis in both strains, but this could not explain the altered fibrotic outcomes. As expected, TLR-9-/- mice had a defect in the production of interferon (IFN-β after viral infection. Balb/c fibroblasts infected with γHV68 in vitro produced more IFN-β than did infected TLR-9-/- fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9-/- fibroblasts did not. Finally, therapeutic administration of CpG oligodeoxynucleotides ameliorated bleomycin-induced fibrosis in wild-type mice. Conclusions These results show a protective role for TLR-9 signaling in murine models of lung fibrosis, and highlight differences in the biology of TLR-9 between mice and humans.

  1. Inhomogeneity of local stiffness in the extracellular matrix scaffold of fibrotic mouse lungs.

    Science.gov (United States)

    Melo, Esther; Cárdenes, Nayra; Garreta, Elena; Luque, Tomas; Rojas, Mauricio; Navajas, Daniel; Farré, Ramon

    2014-09-01

    Lung disease models are useful to study how cell engraftment, proliferation and differentiation are modulated in lung bioengineering. The aim of this work was to characterize the local stiffness of decellularized lungs in aged and fibrotic mice. Mice (2- and 24-month old; 14 of each) with lung fibrosis (N=20) and healthy controls (N=8) were euthanized after 11 days of intratracheal bleomycin (fibrosis) or saline (controls) infusion. The lungs were excised, decellularized by a conventional detergent-based (sodium-dodecyl sulfate) procedure and slices of the acellular lungs were prepared to measure the local stiffness by means of atomic force microscopy. The local stiffness of the different sites in acellular fibrotic lungs was very inhomogeneous within the lung and increased according to the degree of the structural fibrotic lesion. Local stiffness of the acellular lungs did not show statistically significant differences caused by age. The group of mice most affected by fibrosis exhibited local stiffness that were ~2-fold higher than in the control mice: from 27.2±1.64 to 64.8±7.1kPa in the alveolar septa, from 56.6±4.6 to 99.9±11.7kPa in the visceral pleura, from 41.1±8.0 to 105.2±13.6kPa in the tunica adventitia, and from 79.3±7.2 to 146.6±28.8kPa in the tunica intima. Since acellular lungs from mice with bleomycin-induced fibrosis present considerable micromechanical inhomogeneity, this model can be a useful tool to better investigate how different degrees of extracellular matrix lesion modulate cell fate in the process of organ bioengineering from decellularized lungs.

  2. Treatment of vascular tumors and vascular malformations with Pingyangmycin%平阳霉素治疗血管瘤与脉管畸形临床观察

    Institute of Scientific and Technical Information of China (English)

    卢新华; 刘海涛; 叶明华; 夏刚; 陈羿

    2011-01-01

    目的 总结平阳霉素治疗血管瘤及脉管畸形所致不良反应及并发症,探讨其发生的原因及防治措施.方法 用平阳霉素或平阳霉素联合其他药物瘤内注射治疗血管瘤及脉管畸形234例,治疗期间观察并防治不良反应及并发症.结果 234例患者中28例出现不良反应,不良反应率为12.0%,主要为发热、食欲不振、皮疹、局部溃疡、过敏性休克.结论 注射平阳霉素前肌内注射地塞米松或平阳霉素混合地塞米松注射,可预防或减少平阳霉素发热反应,注射前平阳霉素皮肤试验可预防过敏反应发生.%Objective To evaluate the treatment of vascular tumors and vascular malformations with Pingyangmycin, including adverse reactions and complications. Methods Totally 234 cases of vascular tumors and vascular malformations were treated by Pingyangmycin or intratumoral injection in combination with other drugs. Adverse reactions and complications during treatment were observed. Results Two hundred thirty-four patients had adverse reactions( 12.0% ) which included fever, loss of appetite, rash, local ulceration and anaphylactic shock.Conclusion The intramuscular injection of dexamethasone or Pingyangmycin before mixing dexamethasone injection can prevent or reduce fever bleomycin. Meanwhile bleomycin skin test prior to injection can prevent allergic reactions.

  3. The Transcriptional Response to DNA-Double-Strand Breaks in Physcomitrella patens

    Science.gov (United States)

    Kamisugi, Yasuko; Whitaker, John W.

    2016-01-01

    The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting. Transcripts encoding DNA repair proteins active in multiple repair pathways were significantly up-regulated. These included Rad51, CtIP, DNA ligase 1, Replication protein A and ATR in homology-dependent repair, Xrcc4, DNA ligase 4, Ku70 and Ku80 in non-homologous end-joining and Rad1, Tebichi/polymerase theta, PARP in microhomology-mediated end-joining. Differentially regulated cell-cycle components included up-regulated Rad9 and Hus1 DNA-damage-related checkpoint proteins and down-regulated D-type cyclins and B-type CDKs, commensurate with the imposition of a checkpoint at G2 of the cell cycle characteristic of homology-dependent DNA-DSB repair. Candidate genes, including ATP-dependent chromatin remodelling helicases associated with repair and recombination, were knocked out and analysed for growth defects, hypersensitivity to DNA damage and reduced GT efficiency. Targeted knockout of PpCtIP, a cell-cycle activated mediator of homology-dependent DSB resection, resulted in bleomycin-hypersensitivity and greatly reduced GT efficiency. PMID:27537368

  4. Effect of curcumin on the expression of collagen type I protein and transforming growth factor-β1mRNA in pulmonary fibrosis rats%姜黄素对肺纤维化大鼠I型胶原蛋白和转化生长因子β1mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    陈碧; 张德平; 高蔚

    2008-01-01

    Objective To study the eitects ot curcumin on the expressions of collagen type I protein and transtorming growth factor-β1 mRNA in lung tissues of rats with pulmonary fibrosis.Methods 96 male SD rats were randomly divided into four groups with 24 rats in each group:the normal control group,the model group,the prednisone treated group,and the curcumin treated group.Pulmonary fibrosis was induced by intrabronchial injection of bleomycin A5.From the 15th day after bleomycin administration,rats in the prednisone treated group and the curcumin treated group were given prednisone(5 mg/kg)or curcumin(300 mg/kg) respectively once daily by intragastric administration.In the same way,rats in the normal control group and the model group were given 1% Sodium Carboxymethyl Cellulose(10 ml/kg)once daily.The histological changes of lung tissue were evaluated by Haematoxylin-eosin(HE)and Masson's trichrome.The rats were randomly sacrificed on the 21st,28th,42nd and 56th day after bleomycin administration.The type I collagen expression was analyzed by immunohistochemistry.The transforming growth factor-β1(TG-β1)mRNA expression of lung was detected by the semi-quantitative reverse transcription polymerase chain reaction(RT-PCR).Results Pulmonary fibrosis in the eurcumin treated group was significantly reduced as cornpared with the model group and the prednisone treated group on the 42nd and 56th day(P<0.05).The expression of type I collagen protein in the ourcumin treated group was significantly decreased than that in the model group and the prednisone treated group on the 28th,42nd and 56th day after bleomycin administration(P<0.05).The TGF-β1 mRNA expression in the curcunfin treated group was O.61±0.09 and 0.48±0.16 respectively on the 21st and 28th day after bleomycin administration(P<0.05).It was significantly decreased than that in the model group on the 21st,28th day after blenmycin administration and lower as compared with the prednisone treated group on the 21st

  5. Effects of Hirudo on the Expression of Plasminogen Activator Inhibitor-1 in Rats with Pulmonary Fibrosis%水蛭对肺纤维化大鼠PAI-1的影响

    Institute of Scientific and Technical Information of China (English)

    李晓娟; 张骞云; 蔡志刚; 崔卫正; 石玉珍

    2012-01-01

    Objective; To investigate the effects of hirudo on the expression of plasminogen activator inhibitor -1 (PAI-1) in rats with pulmonary fibrosis, and to explore the mechanisms. Methods; The pulmonary fibrosis rat model was established by intratracheal instillation of bleomycin. Model rats were divided into bleomycin group (group MD) and hirudo group (group HD) with 8 rats in each group, and control group (group NC) composed of 8 healthy rats was set up. The rats of group MD were given normal saline 6 ml/d by gavage. The rats of group HD were given hirudo power 4g/( kg o d) by ga-vage. Plasma PAI-1 level and its activity were detected by ELISA, and hydroxyproline (HYP) contents of lung tissues were detected. Results; The PAI-1 level and its activity in group NC were significantly lower than those in the other two groups (P<0. 01). The PAI-1 level and its activity in group MD were higher than those in group HD (P < 0. 01). The HYP content in group NC and group HD were lower than that in MD group (P < 0. 01). Conclusions; Hirudo can protect the lung tissue of rats with bleomycin-induced pulmonary fibrosis by decreasing thrombin expression in the lungs, inhibiting PAI-1 generation and its activity, increasing urokinase plasminogen activator(uPA) activity and reducing the fibrous protein deposition.Objective: To observe the effect of fluoride on the expressions of Twist mRNA and protein in bone tissue of rats, and to explore the role of Twist in pathogenesis of skeletal fluorosis. Methods; Thirty-six SD rats were randomly divided into 3 groups with 12 rats in each and half male half female. Controls were fed with tap water, rats of low fluoride and high fluoride groups were fed with water containing fluoride 5 mg/L and 50 mg/L respectively to establish fluorosis models. Rats were sacrificed in 6 months by femoral artery exsanguination. Urinary fluoride and bone fluoride contents of rats were detected by fluoride ion-selective electrode method. HE staining was used to

  6. 不同诱导剂致慢性阻塞性肺疾病模型小鼠氧化应激损伤的实验研究%Experimental Observation of Lung Oxidative Stress Injury in Mice Model of Chronic Obstructive Pulmonary Disease Induced by Different Inducers

    Institute of Scientific and Technical Information of China (English)

    覃文慧; 杨柯; 邓家刚; 张帅; 黄思诗

    2014-01-01

    This study was aimed to observe the intervention effect of oxidation/antioxidation at different time point among mice induced by lipopolysaccharide (LPS) and bleomycin. It provided experimental basis for the establishment of chronic obstructive pulmonary disease (COPD) animal model with qi-deficiency and phlegm-obstructing pattern with inducers mentioned above. A total of 96 mice were randomly divided into the normal control group, bleomycin group, and LPS group, with 32 mice in each group. In the bleomycin group and LPS group, 40 μL of nasal drops were given with bleomycin at the concentration of 3.75 μg/μL or LPS at the concentration of 5 μg/μL, respectively to establish the COPD animal model with qi-deficiency and phlegm-obstructing pattern. On the 1st day, 7th day, 14th day and 28th day after the model establishment, the general status and activities of mice were recorded. And traditional Chinese medicine (TCM) signs such as skin color of the four limbs, skin color under the tongue and color of the tail were also collected when the animal model was sacrificed. At each time point, 8 mice were sacrificed. The lung tissues were removed. And the contents of GSH, MDA, SOD and T-AOC were detected in the homogenate of lung tissues. The results showed that compared with the normal control group, mice in the bleomycin group had slightly dull eyes, dry hair without burnish, upright and fluffy hair, dark purple skin color of the auricle and four claws, tiredness, inactivity, occasional cough, asthma or rapid breathing. The GSH content of lung tissues on the 7th day, 14th day and 28th day was obviously reduced (P< 0.05, or P< 0.01). The MDA, SOD and T-AOC contents on the 1st day, 7th day, 14th day and 28th day were obviously reduced (P< 0.05, or P< 0.01). Compared with the normal control group, mice in the LPS group had slightly dull eyes, soft hair with slight burnish, pale red skin color of the auricle and four claws, tiredness; some mice preferred to gather

  7. Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

    Energy Technology Data Exchange (ETDEWEB)

    Dharmarajan, Kavita V. [Mount Sinai Medical Center, New York, New York (United States); Friedman, Debra L. [Vanderbilt University, Nashville, Tennessee (United States); Schwartz, Cindy L. [MD Anderson Cancer Center, Houston, Texas (United States); Chen, Lu [Children' s Oncology Group, Arcadia, California (United States); FitzGerald, T.J. [Quality Assurance Review Center, Lincoln, Rhode Island (United States); McCarten, Kathleen M. [Rhode Island Hospital/Warren Alpert Medical School at Brown University, Providence, Rhode Island (United States); Kessel, Sandy K.; Iandoli, Matt [Quality Assurance Review Center, Lincoln, Rhode Island (United States); Constine, Louis S. [University of Rochester Medical Center, Rochester, New York (United States); Wolden, Suzanne L., E-mail: woldens@mskcc.org [Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2015-05-01

    Purpose: The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. Patients and Methods: From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. Results: At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. Conclusion: Although

  8. Efficacy of neoadjuvant chemotherapy and radiotherapy for the histology-confirmed intracranial germinoma-preliminary report

    Energy Technology Data Exchange (ETDEWEB)

    Noh, Young Ju; Kim, Hak Jae; Heo, Dae Seog; Shin, Hee Yung; Kim, Il Han [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2002-06-15

    We intended to decrease late CNS reaction after radical radiotherapy for an intracranial germinoma by using combined neoadjuvant chemotherapy and involved-field radiotherapy. The efficacy in terms of its acute toxicity and short-term relapse patterns was analyzed. Eighteen patients were treated with combined neoadjuvant chemotherapy and radiotherapy between 1995 and 2001. The chemotherapy regimen used was the Children's Cancer Group (CCG) 9921A (cisplatin, cyclophosphamide, VP-16, vincristine) for 5 patients younger than 16 years, BEP(bleomycin, VP-16, cisplatin) for 12 patients, and EP (VP-16, cisplatin) for 1 patient. The radiotherapy covered the whole craniospinal axis for 5 patients, the whole brain for 1, and the partial brain (involved field) for 12. the primary lesion received tumour doses between 3,960 and 5,400 cGy. The male to female ratio was 16:2 and the median age was 16 years old. The tumors were located in the pineal gland in 12 patients, in the suprasellar region in 1, in the basal ganglia in 1, in the thalamus in 1. Three patients had multiple lesions and ventricular seedings were shown at MRI. In 3 patients, tumor cells were detected in the cerebrospinal fluid and MRI detected a spinal seeding in 2 patients. The response to neoadjuvant chemotherapy was complete remission in 5 patients, partial remission in 12, and no response in 1. However, after radiotherapy, all except 1 patient experienced complete remission. The toxicity during or after chemotherapy greater than or equal to grade III was remarkable; hematologic toxicity was observed in 11 patients, liver toxicity in none, kidney toxicity in none, and gastrointestinal toxicity in one. One patient suffered from bleomycin-induced pneumonitis. Radiotherapy was therefore stopped and the patient eventually died of respiratory failure. The other 17 are alive without any evidence of disease or relapse during an average of 20 months follow-up. A high response rate and disease control was

  9. Surgical Treatment Combined with Postoperative Adjuvant Chemotherapy Offer a Viable Option to the Cervical Cancer in Stage ⅠB ~ⅡA with Moderate and High-Risk Factor for Recurrence

    Institute of Scientific and Technical Information of China (English)

    MA Ke; LIU Tongyu; HUANG Weiping; WEN Hongwu; LIAO Qinping

    2012-01-01

    To determine the effectiveness of surgical therapy combined with postoperative adjuvant chemotherapy for cervical cancer with moderate and high-risk factors.Methods:68 patients with cervical cancer in stage Ⅰ B ~ ⅡA were enrolled and initially treated with radical hysterectomy and pelvic lymphadenectomy from January 1999 to December 2009.37 patients were assigned into moderate-risk group (stromal invasion > 50%,poor differentiation,max diameter of tumor ≥ 4 cm,positive LVSI,n =37),and 31patients assigned into high-risk group (positive surgical margin,parametrial invasion,lymph node involvement,n =31).In all cases,chemotherapy was administered adjuvantly:three to four courses of chemotherapy were administered adjuvantly to patients in moderate-risk group and four to six courses to patients in high-risk group.Chemotherapy regimen was BIP (Bleomycin + Ifosfamide + Cisplatin/Carboplatin)for squamous and adenosquamous cancer,and TP (Paclitaxel + Cisplatin/Carboplatin) for adenocarcinoma.Disease-free survival rates and complications of the combined therapy were recorded in follow-up.Results:Estimated 3-year disease-free survival rate was 93.1% for the patientsin moderate-risk group,and 85.4% for the patients in high-risk group (P > 0.05).The recurrence rate was 10.3% for the total 68 patients,and was 8.1% and 12.9% for the patients in moderate-risk group and high-risk group,respectively.The incidence of locoregional recurrence was 5.4% and 6.5% in the moderate-risk group and the high-risk group,respectively.Side effects of chemotherapy and complications of the combined therapy were limited,and no severe bleomycin-related pulmonary toxicity was observed.Conclusions:our results indicate that surgical therapy combined with postoperative adjuvant chemotherapy offers a viable option to the cervical cancer in stage Ⅰ B ~ Ⅱ A.Patients can tolerate the side effects of chemotherapy and get better efficacy.

  10. Effects of benzo(a)pyrene on telomere length in human bronchial epithelial cells%苯并(a)芘对人支气管上皮细胞端粒长度的影响

    Institute of Scientific and Technical Information of China (English)

    宾萍; 段化伟; 王亚东; 戴宇飞; 牛勇; 刘清君; 陈泓; 刘庆; 郑玉新

    2011-01-01

    Objective To investigate the effects of Benzo(a) pyrene[B(a) P] on telomere length in human bronchial epithelial cells in vitro. Methods Human bronchial epithelial cell lines(16HBE) were treated with B(a) P in vitro. Real-time polymerase chain reaction (RT-PCR) was used to evaluate the telomere length of genomic DNA in cells, and the changes of relative telomere length were marked. The positive control was 4 μg/ml Bleomycin (BLM). Results Compared to the group of 0μmol/L B(a) P, the groups of 1 μmol/L,4μmol/L and positive control group, the telomere length were significantly shorter (P < 0. 05 ), but no significant difference was found between group of 16 μmol/L B(a) P and control. Conclusion The data showed that B(a) P had influence on the telomere length of genomic DNA in 16HBE cells. It might lead to short telomere length in a certain range of dosage.%目的 体外探讨苯并(a)芘[Benzo(a)pyrene,B(a)P]对人支气管上皮细胞端粒长度的影响.方法 应用人支气管上皮细胞株16HBE,给予不同浓度的B(a)P处理,采用定量PCR方法测定细胞全基因组DNA的相对端粒长度,观察细胞全基因组DNA相对端粒长度的变化情况.以4μg/ml博来霉素(Bleomycin,BLM)为阳性对照.结果 与0μmol/L组比较,1和4μmol/L B(a)P染毒组,以及阳性对照组的相对端粒长度较短,差异有统计学意义(P0.05).结论 B(a)P可对人支气管上皮细胞16HBE的全基因组DNA端粒长度产生影响,在一定剂量内会导致细胞全基因组DNA端粒长度缩短.

  11. Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

    Energy Technology Data Exchange (ETDEWEB)

    Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Flampouri, Stella [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Zaiden, Robert [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Jacksonville, Florida (United States); Slayton, William [Department of Pediatrics, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Sandler, Eric [Department of Pediatrics, Division of Hematology/Oncology Nemours Children' s Clinic, Jacksonville, Florida (United States); Ozdemir, Savas [Department of Radiology, Division of Functional and Molecular Imaging, University of Florida College of Medicine, Jacksonville, Florida (United States); Dang, Nam H.; Lynch, James W. [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P. [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States)

    2014-08-01

    Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

  12. Fibrocytes in the Fibrotic Lung: Altered Phenotype Detected by Flow Cytometry

    Directory of Open Access Journals (Sweden)

    Charles eReese

    2014-06-01

    Full Text Available Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells before recruitment into target tissues. While most previous studies focused on circulating fibrocytes, here we focus on the fibrocyte phenotype in fibrotic tissue. The study’s relevance to human disease is heightened by use of a model in which bleomycin is delivered systemically, recapitulating several features of human scleroderma including multi-organ fibrosis not observed when bleomycin is delivered directly into the lungs. Using flow cytometry, we find in the fibrotic lung a large population of CD45high fibrocytes (called Region I rarely found in vehicle-treated control mice. A second population of CD45+ fibrocytes (called Region II is observed in both control and fibrotic lung. The level of CD45 in circulating fibrocytes is far lower than in either Region I or II lung fibrocytes. The chemokine receptors CXCR4 and CCR5 are expressed at higher levels in Region I than in Region II and are present at very low levels in all other lung cells including CD45+/collagen I- leucocytes. The collagen chaperone HSP47 is present at similar high levels in both Regions I and II, but at a higher level in fibrotic lung than in control lung. There is also a major population of HSP47high/CD45- cells in fibrotic lung not present in control lung. CD44 is present at higher levels in Region I than in Region II and at much lower levels in all other cells including CD45+/collagen I- leucocytes. When lung fibrosis is inhibited by restoring caveolin-1 activity using a caveolin-1 scaffolding domain peptide (CSD, a strong correlation is observed between fibrocyte number and fibrosis score. In summary, the distinctive phenotype of fibrotic lung fibrocytes suggests that fibrocyte differentiation occurs primarily within the

  13. 微创技术在口腔颌面的应用研究%MinimallyInvasiveTechniquesintheApplicationofOralandMaxillofacialRegion

    Institute of Scientific and Technical Information of China (English)

    刘韬

    2013-01-01

    Objective:Minimally invasive techniques oral and maxillofacial vascular malformation clinical research. Methods:According to the actual situation of vascular malformations, Adopt a"color Doppler ultrasound to guide minimally invasive treatment line bleomycin injection, digital subtraction angiography is mediated super-selective arterial embolization minimally invasive treatment, super-selective arterial embolization combined pingyangmycin minimally invasive treatment“and other means comprehensive treatment of oral and maxillofacial vascular malformations. Results: Interrupted after 1 year, Comprehensive treatment of the total efficiency 76.19%, Including color Doppler ultrasound to guide the line bleomycin injection minimally invasive treatment group was 71.43%, Digital subtraction angiography is mediated by a selective arterial embolization minimally invasive treatment group was 71.43%, Intervention super-selective intra-arterial embolization combined pingyangmycin minimally invasive treatment group was 85.71%.Conclusion:Color Doppler ultrasound guidance, super-selective arterial embolization is safe and effective oral and maxillofacial vascular malformations, Simplify treatment procedures, Reduce tissue trauma.%目的:探讨微创技术对口腔颌面处血管畸形的临床治疗研究。方法:依血管畸形实际状况,采取“CDU为引导行PYM注射的微创治疗、DSA为介导行SAE微创治疗、SAE+PYM联合微创治疗”等手段综合治疗口腔颌面血管畸形。结果:术后追访1年,综合治疗总有效率76.19%,其中CDU为引导行PYM注射的微创治疗组为71.43%,DSA为介导行SAE微创治疗组为71.43%,介入SAE+PYM联合微创治疗组为85.71%。结论:CDU引导、SAE治疗口腔颌面血管畸形安全有效,简化治疗程序,降低组织创伤。

  14. TAZ contributes to pulmonary fibrosis by activating profibrotic functions of lung fibroblasts

    Science.gov (United States)

    Noguchi, Satoshi; Saito, Akira; Mikami, Yu; Urushiyama, Hirokazu; Horie, Masafumi; Matsuzaki, Hirotaka; Takeshima, Hideyuki; Makita, Kosuke; Miyashita, Naoya; Mitani, Akihisa; Jo, Taisuke; Yamauchi, Yasuhiro; Terasaki, Yasuhiro; Nagase, Takahide

    2017-01-01

    Transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes. Nuclear translocation and activation of TAZ are regulated by multiple mechanisms, including actin cytoskeleton and mechanical forces. TAZ is involved in lung alveolarization during lung development and Taz-heterozygous mice are resistant to bleomycin-induced lung fibrosis. In this study, we explored the roles of TAZ in the pathogenesis of idiopathic pulmonary fibrosis (IPF) through histological analyses of human lung tissues and cell culture experiments. TAZ was highly expressed in the fibroblastic foci of lungs from patients with IPF. TAZ controlled myofibroblast marker expression, proliferation, migration, and matrix contraction in cultured lung fibroblasts. Importantly, actin stress fibers and nuclear accumulation of TAZ were more evident when cultured on a stiff matrix, suggesting a feedback mechanism to accelerate fibrotic responses. Gene expression profiling revealed TAZ-mediated regulation of connective tissue growth factor (CTGF) and type I collagen. Clinical relevance of TAZ-regulated gene signature was further assessed using publicly available transcriptome data. These findings suggest that TAZ is involved in the pathogenesis of IPF through multifaceted effects on lung fibroblasts. PMID:28195168

  15. Canine Oral Eosinophilic Granuloma Treated with Electrochemotherapy

    Directory of Open Access Journals (Sweden)

    Matías Nicolás Tellado

    2014-01-01

    Full Text Available A case of a canine oral eosinophilic granuloma in a 14-year-old female crossbred is described. The dog was presented with a history of ptyalism, halitosis, local pain, decreased appetite, and blood staining noted on food and water bowls. Clinical, hematologic, and biochemical examinations, abdominal ultrasonography, and 3-view chest radiographs were performed, and no metastases were found. Histopathologic examination of two 6 mm punch biopsies from the oral lesion revealed the presence of eosinophilic granulomatous lesions in the submucosa. After treatment with corticosteroids and wide spectrum antibiotics no significant changes in clinical signs and lesion size were observed. Electrochemotherapy (ECT, a novel tumor treatment routinely used for cutaneous and subcutaneous tumors in human patients in the European Union since 2006, was used to treat the eosinophilic granuloma. The procedure was performed under general anesthesia, followed by intravenous administration of bleomycin. Six weeks after treatment a complete response with disappearance of the mass and improvement of clinical signs were observed.

  16. Preoperative Arterial Interventional Chemotherapy on Cervical Cancer

    Institute of Scientific and Technical Information of China (English)

    WANG Hui; LING HU-Hua; TANG Liang-dan; ZHANG Xing-hua

    2008-01-01

    Objective:To discuss the therapeutic effect of preoperative interventional chemotherapy on cervical cancer.Methods:Preoperative interventional chemotherapy by femoral intubation was performed in 25 patients with bulky cervical cancer.The patients received bleomycin 45 mg and cisplatin or oxaliplatin 80 mg/m2.Results:25 cases(including 8 cases with stage Ⅰ and 17 cases with stage Ⅱ)received one or two courses of preoperative interventional chemotherapy.The size of the focal lesions was decreased greatly and radical hysterectomy and lymphadenectomy were performed successfully in all the patients.All of the specimens were sent for pathological examination.Lymphocyte infiltration was found more obvious in the cancer tissues as compared with their counterpart before treatment.As a result,relevant vaginal bleeding was stopped completely shortly after the treatment.Conclusion:Arterial interventional chemotherapy was proved to reduce the local size of cervical cancer and thus control the hemorrhage efficiently.The patients with cervical cancer can receive radical hysterectomy therapy after the interventional chemotherapy.

  17. Radiologic imaging and percutaneous treatment of pelvic lymphocele

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    Karcaaltincaba, Musturay [Department of Radiology, Division of Abdominal and Interventional Radiology, Hacettepe University School of Medicine, Sihhiye, Ankara 06100 (Turkey); Akhan, Okan [Department of Radiology, Division of Abdominal and Interventional Radiology, Hacettepe University School of Medicine, Sihhiye, Ankara 06100 (Turkey)]. E-mail: oakhan@hacettepe.edu.tr

    2005-09-01

    Pelvic lymphocele, also known as lymphocyst, is a cystic structure caused by lymphatic injury usually secondary to pelvic lymphadenectomy and renal transplantation. Lymphoceles can cause morbidity and rarely mortality by compression of adjacent structures and infectious complications. This review discusses etiology and treatment options for pelvic lymphoceles including surgical and percutaneous methods with emphasis on percutaneous techniques particularly in conjunction with sclerotherapy. Percutaneous catheter drainage with sclerotherapy procedure with various sclerosing agents is described in detail. Ethanol, povidone-iodine, tetracycline, doxycycline, bleomycin, talc and fibrin glue can be used as sclerosing agents. Combination of sclerosing agents to percutaneous catheter drainage significantly improves success rate in the treatment of pelvic lymphoceles. Infected lymphoceles are usually treated solely with percutaneous catheter drainage. Percutaneous treatment can be tailored according to volume of lymphoceles. We generally prefer single session sclerotherapy and 1 day catheter drainage in lymphoceles less than 150 mL, and larger ones are treated by multi-session sclerotherapy until daily drainage decreases below 10 mL. Percutaneous treatment preferably with sclerotherapy should be considered as the first-line treatment modality for pelvic lymphoceles due to its effectiveness, widespread applicability on an outpatient basis, ease of procedure and low complication rate.

  18. Implementation of a single quad MS detector in routine QC analysis of peptide drugs

    Directory of Open Access Journals (Sweden)

    Matthias D’Hondt

    2016-02-01

    Full Text Available A newly developed single quad mass spectrometry (MS detector was coupled to a ultra-high performance liquid chromatography (UPLC system and implemented in the routine quality control (QC and impurity analysis of four therapeutic peptides, namely bleomycin sulfate, tyrothricin, vancomycin HCl and bacitracin, which were selected given their multi-component drug nature and their closely structurally related impurity profiles. The QC and impurity profiling results obtained using the ultra-high performance liquid chromatography ultraviolet/mass spectrometry (UPLC-UV/MS detection system were analyzed against the results obtained using traditional high performance liquid chromatography-ultraviolet detection (HPLC-UV methods derived from pharmacopoeial methods. In general, the used stationary phases of sub-2 µm particle (UPLC technology resulted in lower limits of detection and higher resolution separations, which resulted in more detected impurities and shorter overall run times contrasting the traditional HPLC columns. Moreover, online coupling with a single quad MS detector allowed direct peak identification of the main compounds as well as small impurities, hereby increasing the information content without the need of reference standards.

  19. Biomarker expression in lung of rabbit with pulmonary fibrosis induced by ammonium perchlorate.

    Science.gov (United States)

    Wu, Feng-hong; Guo, Hui-xia; Lin, Ming-fang; Chen, Zhi-ze; Zhou, Xuan; Peng, Kai-liang

    2011-04-01

    Ammonium perchlorate (AP), an oxidizer, has been used in solid propellants. Although AP exposure has been suspected as a risk factor for the development of pulmonary fibrosis, data are still inconclusive. To evaluate the pulmonary toxicity and the potential pulmonary fibrosis caused by occupational exposure to this compound, 25 male rabbits were randomly allocated into five groups to receive AP or bleomycin or saline by intratracheal injection. All rabbits were sacrificed and total RNA from the lungs was extracted. Expressions of types I and III collagens, transforming growth factor-β(1) (TGF-β(1)) and tumour necrosis factor-α (TNF-α) messenger RNA (mRNA) were measured by reverse transcription-polymerase chain reaction (RT-PCR). The expressions of type I and III collagen mRNA in low, moderate and high dose AP groups were significantly higher (p < 0.01 or p < 0.05) than that in the saline group. There was also a significant increased level of TGF-β(1) and TNF-α mRNA in the three AP groups compared with saline control group (p < 0.01 or p < 0.05). These results reveal that AP can increase gene expressions of types I, III collagens, TGF-β(1) and TNF-α in lung of rabbits exposed to AP. The overexpression of these biomarkers were considered as effective indicator linking to the development of pulmonary fibrosis and finally demonstrated that AP has potential to induce pulmonary fibrosis.

  20. Overexpression of a Rrp1 transgene reduces the somatic mutation and recombination frequency induced by oxidative DNA damage in Drosophila melanogaster.

    Science.gov (United States)

    Szakmary, A; Huang, S M; Chang, D T; Beachy, P A; Sander, M

    1996-02-20

    Recombination repair protein 1 (Rrp1) includes a C-terminal region homologous to several DNA repair proteins, including Escherichia coli exonuclease III and human APE, that repair oxidative and alkylation damage to DNA. The nuclease activities of Rrp1 include apurinic/apyrimidinic endonuclease, 3'-phosphodiesterase, 3'-phosphatase, and 3'-exonuclease. As shown previously, the C-terminal nuclease region of Rrp1 is sufficient to repair oxidative- and alkylation-induced DNA damage in repair-deficient E. coli mutants. DNA strand-transfer and single-stranded DNA renaturation activities are associated with the unique N-terminal region of Rrp1, which suggests possible additional functions that include recombinational repair or homologous recombination. By using the Drosophila w/w+ mosaic eye system, which detects loss of heterozygosity as changes in eye pigmentation, somatic mutation and recombination frequencies were determined in transgenic flies overexpressing wild-type Rrp1 protein from a heat-shock-inducible transgene. A large decrease in mosaic clone frequency is observed when Rrp1 overexpression precedes treatment with gamma-rays, bleomycin, or paraquat. In contrast, Rrp1 overexpression does not alter the spot frequency after treatment with the alkylating agents methyl methanesulfonate or methyl nitrosourea. A reduction in mosaic clone frequency depends on the expression of the Rrp1 transgene and on the nature of the induced DNA damage. These data suggest a lesion-specific involvement of Rrp1 in the repair of oxidative DNA damage.

  1. Combinatorial synthesis, in silico, molecular and biochemical studies of tetrazole-derived organic selenides with increased selectivity against hepatocellular carcinoma.

    Science.gov (United States)

    Shaaban, Saad; Negm, Amr; Ashmawy, Abeer M; Ahmed, Dalia M; Wessjohann, Ludger A

    2016-10-21

    Novel tetrazole-based diselenides and selenoquinones were synthesized via azido-Ugi and sequential nucleophilic substitution (SN) strategy. Molecular docking study into mammalian TrxR1 was used to predict the anticancer potential of the newly synthesized compounds. The cytotoxic activity of the compounds was evaluated using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cancer cells and compared with their cytotoxicity in normal fibroblast (WI-38) cells. The corresponding redox properties of the synthesized compounds were assessed employing 2,2-diphenyl-1-picrylhydrazyl (DPPH), glutathione peroxidase (GPx)-like activity and bleomycin dependent DNA damage. In general, diselenides showed preferential cytotoxicity to HepG2 compared to MCF-7 cells. These compounds exhibited also good GPx catalytic activity compared to ebselen (up to 5 fold). Selenoquinones 18, 21, 22 and 23 were selected to monitor the expression levels of caspase-8, Bcl-2 and Ki-67 molecular biomarkers. Interestingly, these compounds downregulated the Bcl-2 and Ki-67 expression levels and activated the expression of caspase-8 in HepG2 cells compared to untreated cells. These results indicate that some of the newly synthesized compounds possess anti-HepG2 activity.

  2. Genetic characterization of two fully sequenced multi-drug resistant plasmids pP10164-2 and pP10164-3 from Leclercia adecarboxylata

    Science.gov (United States)

    Sun, Fengjun; Zhou, Dongsheng; Sun, Qiang; Luo, Wenbo; Tong, Yigang; Zhang, Defu; Wang, Qian; Feng, Wei; Chen, Weijun; Fan, Yahan; Xia, Peiyuan

    2016-01-01

    We previously reported the complete sequence of the resistance plasmid pP10164-NDM, harboring blaNDM (conferring carbapenem resistance) and bleMBL (conferring bleomycin resistance), which is recovered from a clinical Leclercia adecarboxylata isolate P10164 from China. This follow-up work disclosed that there were still two multidrug-resistant (MDR) plasmids pP10164-2 and pP10164-3 coexisting in this strain. pP10164-2 and pP10164-3 were completely sequenced and shown to carry a wealth of resistance genes, which encoded the resistance to at least 10 classes of antibiotics (β-lactams. macrolides, quinolones, aminoglycosides, tetracyclines, amphenicols, quaternary ammonium compounds, sulphonamides, trimethoprim, and rifampicin) and 7 kinds of heavy mental (mercury, silver, copper, nickel, chromate, arsenic, and tellurium). All of these antibiotic resistance genes are associated with mobile elements such as transposons, integrons, and insertion sequence-based transposable units, constituting a total of three novel MDR regions, two in pP10164-2 and the other one in pP10164-3. Coexistence of three resistance plasmids pP10164-NDM, pP10164-2 and pP10164-3 makes L. adecarboxylata P10164 tend to become extensively drug-resistant. PMID:27658354

  3. HPV Carcinomas in Immunocompromised Patients

    Directory of Open Access Journals (Sweden)

    Nicole M. Reusser

    2015-01-01

    Full Text Available Human papillomavirus (HPV infection is the most common sexually transmitted disease worldwide and can result in pre-malignancies or overt malignancies of the skin and mucosal surfaces. HPV-related illnesses are an important personal and public health problem causing physical, mental, sexual and financial detriments. Moreover, this set of malignancies severely affects the immunosuppressed population, particularly HIV-positive patients and organ-transplant recipients. There is growing incidence of HPV-associated anogenital malignancies as well as a decrease in the average age of affected patients, likely related to the rising number of high-risk individuals. Squamous cell carcinoma is the most common type of HPV-related malignancy. Current treatment options for HPV infection and subsequent disease manifestations include imiquimod, retinoids, intralesional bleomycin, and cidofovir; however, primary prevention with HPV vaccination remains the most effective strategy. This review will discuss anogenital lesions in immunocompromised patients, cutaneous warts at nongenital sites, the association of HPV with skin cancer in immunocompromised patients, warts and carcinomas in organ-transplant patients, HIV-positive patients with HPV infections, and the management of cutaneous disease in the immunocompromised patient.

  4. Antioxidation of quercetin against spinal cord injury in rats

    Institute of Scientific and Technical Information of China (English)

    LIU Jin-bo; TANG Tian-si; YANG Hui-lin

    2006-01-01

    Objective: To observe the effect of quercetin on experimental spinal cord injury (SCI) in rats.Methods: Sixty Sprague-Dawley rats were randomly divided into four groups: Group A only for laminectomy,Group B for laminectomy with SCI, Group C for SCI and intraperitoneal injection with a bolus of 200 mg/kg quercetin and Group D for SCI and intraperitoneal injection of saline. SCI model was made by using modified Allen's method on T12. Six rats of each group were killed at4 h after injury and the levels of free iron and malondialdehyde (MDA) of the involved spinal cord segments were measured by bleomycin and thiobarbituric acid (TBA) assays separately. The recovery of hind limb function was assessed by Modified Tarlov's scale and inclined plane method at 7 d,14 d and 21 d after SCI. The histological changes of the damaged spinal cord were also examined at 7 d after SCI.Results: After SCI, the levels of free iron and MDA were significantly increased in Groups B and D, while not in Group C. The Modified Tarlov's score and the inclined plane angles were significantly decreased in Groups B, C and D. The histological findings were not improved.Conclusions: After SCI, quercetin can reduce the level of lipid peroxidation, but not improve recovery of function.

  5. c-Myc regulates proliferation and Fgf10 expression in airway smooth muscle after airway epithelial injury in mouse.

    Directory of Open Access Journals (Sweden)

    Thomas Volckaert

    Full Text Available During lung development, Fibroblast growth factor 10 (Fgf10, which is expressed in the distal mesenchyme and regulated by Wnt signaling, acts on the distal epithelial progenitors to maintain them and prevent them from differentiating into proximal (airway epithelial cells. Fgf10-expressing cells in the distal mesenchyme are progenitors for parabronchial smooth muscle cells (PSMCs. After naphthalene, ozone or bleomycin-induced airway epithelial injury, surviving epithelial cells secrete Wnt7b which then activates the PSMC niche to induce Fgf10 expression. This Fgf10 secreted by the niche then acts on a subset of Clara stem cells to break quiescence, induce proliferation and initiate epithelial repair. Here we show that conditional deletion of the Wnt target gene c-Myc from the lung mesenchyme during development does not affect proper epithelial or mesenchymal differentiation. However, in the adult lung we show that after naphthalene-mediated airway epithelial injury c-Myc is important for the activation of the PSMC niche and as such induces proliferation and Fgf10 expression in PSMCs. Our data indicate that conditional deletion of c-Myc from PSMCs inhibits airway epithelial repair, whereas c-Myc ablation from Clara cells has no effect on airway epithelial regeneration. These findings may have important implications for understanding the misregulation of lung repair in asthma and COPD.

  6. Twenty Four-Hour Exposure to a 0.12 THz Electromagnetic Field Does Not Affect the Genotoxicity, Morphological Changes, or Expression of Heat Shock Protein in HCE-T Cells

    Science.gov (United States)

    Koyama, Shin; Narita, Eijiro; Shimizu, Yoko; Shiina, Takeo; Taki, Masao; Shinohara, Naoki; Miyakoshi, Junji

    2016-01-01

    To investigate the cellular effects of terahertz (THz) exposure, human corneal epithelial (HCE-T) cells derived from human eye were exposed to 0.12 THz radiation at 5 mW/cm2 for 24 h, then the genotoxicity, morphological changes, and heat shock protein (Hsp) expression of the cells were examined. There was no statistically significant increase in the micronucleus (MN) frequency of cells exposed to 0.12 THz radiation compared with sham-exposed controls and incubator controls, whereas the MN frequency of cells treated with bleomycin for 1 h (positive control) did increase significantly. Similarly, there were no significant morphological changes in cells exposed to 0.12 THz radiation compared to sham-exposed controls and incubator controls, and Hsp expression (Hsp27, Hsp70, and Hsp90α) was also not significantly different between the three treatments. These results indicate that exposure to 0.12 THz radiation using the present conditions appears to have no or very little effect on MN formation, morphological changes, and Hsp expression in cells derived from human eye. PMID:27527204

  7. Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A.

    Science.gov (United States)

    Kach, Jacob; Sandbo, Nathan; La, Jennifer; Denner, Darcy; Reed, Eleanor B; Akimova, Olga; Koltsova, Svetlana; Orlov, Sergei N; Dulin, Nickolai O

    2014-03-14

    Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF-β-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-β-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts.

  8. Removal of reactive oxygen species induced 3’-blocked ends by XPF-ERCC1

    Science.gov (United States)

    Fisher, Laura A.; Samson, Laura; Bessho, Tadayoshi

    2011-01-01

    XPF-ERCC1 is a structure-specific endonuclease that is essential for nucleotide excision repair and DNA interstrand cross-link repair in mammalian cells. The yeast counterpart of XPF-ERCC1, Rad1-Rad10, plays multiple roles in DNA repair. Rad1-Rad10 is implicated to be involved in the repair of oxidative DNA damage. To explore the role(s) of XPF-ERCC1 in the repair of DNA damage induced by reactive oxygen species (ROS), cellular sensitivity of the XPF-deficient Chinese hamster ovary cell-line UV41 to ROS was investigated. The XPF-deficient UV41 showed sensitivity to hydrogen peroxide, bleomycin and paraquat. Furthermore, XPF-ERCC1 showed an ability to remove 3’-blocked ends such as 3’-phosphoglycolate from the 3’-end of DNA in vitro. These data suggest that XPF-ERCC1 plays a role in the repair of ROS-induced DNA damage by trimming 3’-blocked ends. The accumulation of various types of DNA damage, including ROS-induced DNA damage due to defects in multiple XPF-ERCC1-mediated DNA repair pathways, could contribute to the accelerated aging phenotypes observed in an XPF-ERCC1 deficient patient. PMID:22007867

  9. Role of {sup 18}F-FDG PET-CT in monitoring the cyclophosphamide induced pulmonary toxicity in patients with breast cancer - 2 Case Reports

    Energy Technology Data Exchange (ETDEWEB)

    Taywade, Sameer Kamalakar; Kumar, Rakesh; Bhethanabhotla, Sainath; Bal, Chandrasekhar [A.I.I.M.S, New Delhi (India)

    2016-09-15

    Drug induced pulmonary toxicity is not uncommon with the use of various chemotherapeutic agents. Cyclophosphamide is a widely used chemotherapeutic drug in the treatment of breast cancer. Although rare, lung toxicity has been reported with cyclophosphamide use. Detection of bleomycin induced pulmonary toxicity and pattern of {sup 18}F-fluorodeoxyglucose ({sup 18}F-FDG) uptake in lungs on fluorodeoxyglucose positron emission tomography-computed tomography ({sup 18}F-FDG PET-CT) has been elicited in literature in relation to lymphoma. However, limited data is available regarding the role of {sup 18}F-FDG PET-CT in monitoring drug induced pulmonary toxicity in breast cancer. We here present two cases of cyclophosphamide induced drug toxicity. Interim {sup 18}F-FDG PET-CT demonstrated diffusely increased tracer uptake in bilateral lung fields in both these patients. Subsequently there was resolution of lung uptake on {sup 18}F-FDG PET-CT scan post completion of chemotherapy. These patients did not develop significant respiratory symptoms during chemotherapy treatment and in follow up.

  10. Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.

    Science.gov (United States)

    Choi, Jung Eun; Choe, A Reum; Yoon, Sang Eun; Nam, Eun Mi; Park, Heejung; Lee, Kyoung Eun

    2017-01-01

    The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'.

  11. DNA repair and gene therapy: implications for translational uses.

    Science.gov (United States)

    Limp-Foster, M; Kelley, M R

    2000-01-01

    Gene therapy has been proposed to have implications in the treatment of cancer. By genetically manipulating the hematopoietic stem cell compartment with genes that confer resistance to chemotherapeutic agents, the dose escalation that is necessary to effectively treat the cancers could potentially be achieved. DNA repair genes are some of the potential candidates to confer increased resistance to chemotherapeutic agents. Although initial focus in this area has been on the direct reversal protein (MGMT), its protective ability is limited to those agents that produce O(6)-methylGuanine cross-links-agents that are not extensively used clinically (e.g., nitrosoureas). Furthermore, most alkylating agents attack more sites in DNA other than O(6)-methylGuanine, such that the protections afforded by MGMT may prevent the initial cytotoxicity, but at a price of increased mutational burden and potential secondary leukemias. Therefore, some of the genes that are being tested as candidates for gene transfer are base excision repair (BER) genes. We and others have found that overexpression of selective BER genes confers resistance to chemotherapeutic agents such as thiotepa, ionizing radiation, bleomycin, and other agents. As these "proof of concept" analyses mature, many more clinically relevant chemotherapeutic agents can be tested for BER protective ability.

  12. Cytogenetic studies in human cells exposed in vitro to GSM-900 MHz radiofrequency radiation using R-banded karyotyping.

    Science.gov (United States)

    Bourthoumieu, S; Joubert, V; Marin, B; Collin, A; Leveque, P; Terro, F; Yardin, C

    2010-12-01

    It is important to determine the possible effects of exposure to radiofrequency (RF) radiation on the genetic material of cells since damage to the DNA of somatic cells may be linked to cancer development or cell death and damage to germ cells may lead to genetic damage in next and subsequent generations. The objective of this study was to investigate whether exposure to radiofrequency radiation similar to that emitted by mobile phones of second-generation standard Global System for Mobile Communication (GSM) induces genotoxic effects in cultured human cells. The cytogenetic effects of GSM-900 MHz (GSM-900) RF radiation were investigated using R-banded karyotyping after in vitro exposure of human cells (amniotic cells) for 24 h. The average specific absorption rate (SAR) was 0.25 W/kg. The exposures were carried out in wire-patch cells (WPCs) under strictly controlled conditions of temperature. The genotoxic effect was assessed immediately or 24 h after exposure using four different samples. One hundred metaphase cells were analyzed per assay. Positive controls were provided by using bleomycin. We found no direct cytogenetic effects of GSM-900 either 0 h or 24 h after exposure. To the best of our knowledge, our work is the first to study genotoxicity using complete R-banded karyotyping, which allows visualizing all the chromosomal rearrangements, either numerical or structural.

  13. Rapid, noninvasive quantitation of skin disease in systemic sclerosis using optical coherence elastography

    Science.gov (United States)

    Du, Yong; Liu, Chih-Hao; Lei, Ling; Singh, Manmohan; Li, Jiasong; Hicks, M. John; Larin, Kirill V.; Mohan, Chandra

    2016-04-01

    Systemic sclerosis (SSc) is a connective tissue disease that results in excessive accumulation of collagen in the skin and internal organs. Overall, SSc has a rare morbidity (276 cases per million adults in the United States), but has a 10-year survival rate of 55%. Currently, the modified Rodnan skin score (mRSS) is assessed by palpation on 17 sites on the body. However, the mRSS assessed score is subjective and may be influenced by the experience of the rheumatologists. In addition, the inherent elasticity of skin may bias the mRSS assessment in the early stage of SSc, such as oedematous. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess mechanical contrast in tissues with micrometer spatial resolution. In this work, the OCE technique is applied to assess the mechanical properties of skin in both control and bleomycin (BLM) induced SSc-like disease noninvasively. Young's modulus of the BLM-SSc skin was found be significantly higher than that of normal skin, in both the in vivo and in vitro studies (p<0.05). Thus, OCE is able to differentiate healthy and fibrotic skin using mechanical contrast. It is a promising new technology for quantifying skin involvement in SSc in a rapid, unbiased, and noninvasive manner.

  14. Twenty Four-Hour Exposure to a 0.12 THz Electromagnetic Field Does Not Affect the Genotoxicity, Morphological Changes, or Expression of Heat Shock Protein in HCE-T Cells.

    Science.gov (United States)

    Koyama, Shin; Narita, Eijiro; Shimizu, Yoko; Shiina, Takeo; Taki, Masao; Shinohara, Naoki; Miyakoshi, Junji

    2016-08-05

    To investigate the cellular effects of terahertz (THz) exposure, human corneal epithelial (HCE-T) cells derived from human eye were exposed to 0.12 THz radiation at 5 mW/cm² for 24 h, then the genotoxicity, morphological changes, and heat shock protein (Hsp) expression of the cells were examined. There was no statistically significant increase in the micronucleus (MN) frequency of cells exposed to 0.12 THz radiation compared with sham-exposed controls and incubator controls, whereas the MN frequency of cells treated with bleomycin for 1 h (positive control) did increase significantly. Similarly, there were no significant morphological changes in cells exposed to 0.12 THz radiation compared to sham-exposed controls and incubator controls, and Hsp expression (Hsp27, Hsp70, and Hsp90α) was also not significantly different between the three treatments. These results indicate that exposure to 0.12 THz radiation using the present conditions appears to have no or very little effect on MN formation, morphological changes, and Hsp expression in cells derived from human eye.

  15. Effects of cytostatic drugs on plasma level and renal excretion of beta-acetyldigoxin.

    Science.gov (United States)

    Kuhlmann, J; Zilly, W; Wilke, J

    1981-10-01

    Mucosal defects decrease digoxin absorption in patients with malabsorption syndromes. Since the intestinal mucosa can be damaged by cytostatic drugs, we investigated their effects on digoxin plasma levels and urinary digoxin excretion. In six patients with malignant lymphoma who received 0.8 mg beta-acetyldigoxin before and 24 hr after treatment with a combination of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, oncovin, and prednisone (COP), plasma digoxin concentrations were measured 0 to 8 hr after the dose and areas under the plasma concentration-time curves were calculated. In 15 patients on 0.3 mg of beta-acetyldigoxin daily, plasma glycoside concentrations and renal excretion were measured daily before and after COPP, COP, cyclophosphamide, oncovin, cytosine-arabinosine, and prednisone (COAP), or adriamycin, bleomycin, and prednisone (ABP) treatment schemes. The diminished steady-state glycoside plasma concentrations and daily renal glycoside excretion during the 24 to 168 hr after the cytostatic drug established reversible impairment of digoxin absorption. The delayed time to peak after a single dose of digoxin during cytostatic drug therapy shows that extent and rate of digoxin absorption are reduced. To maintain adequate control of digoxin therapy in patients treated with cytostatic drugs, plasma levels should be monitored.

  16. Operating Procedures of the Electrochemotherapy for Treatment of Tumor in Dogs and Cats

    Science.gov (United States)

    Tozon, Natasa; Lampreht Tratar, Ursa; Znidar, Katarina; Sersa, Gregor; Teissie, Justin; Cemazar, Maja

    2016-01-01

    Electrochemotherapy (ECT) is a local approach which is used for treating solid tumors of different histologies. Its mechanism is based on cell membrane permeabilization by means of "electroporation". To achieve the "electroporation" of the cells, electric pulses are generated by a generator and delivered to the target tissue by the use of electrodes. Electroporation is a physical method which is used to introduce molecules, like cytostatic drugs, into the cells that could not pass the cell membrane on their own. In electrochemotherapy, currently, cisplatin and bleomycin are clinically used. Electrochemotherapy antitumor effectiveness is high, for example up to 100% complete response of canine mast cell tumors smaller than 2 cm3 was achieved. Additionally, electrochemotherapy can be used for the treatment of inoperable tumors. One of the important characteristics of electrochemotherapy is that it can be effective as a one-time treatment only. However, in the case of failure or partial tumor response it can be repeated several times with equal or improved effectiveness. Electrochemotherapy is already a standard treatment for cutaneous and subcutaneous tumors of various histologies in human and veterinary oncology. Furthermore, several clinical studies exploiting electrochemotherapy for deep-seated tumors are on-going. PMID:27805594

  17. Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency.

    Science.gov (United States)

    Abdel Fattah, Elmoataz; Bhattacharya, Abhisek; Herron, Alan; Safdar, Zeenat; Eissa, N Tony

    2015-06-01

    Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia, and increased collagen content. Lung inflammation was associated with increase in several proinflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by IL-18 as a result of constitutive inflammasome activation. Following i.p. LPS injection, autophagy-deficient mice had higher levels of proinflammatory cytokines in lungs and in serum, as well as increased mortality, than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy-deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.

  18. The tolC locus affects the expression of sbmA through σE activity increase.

    Science.gov (United States)

    Corbalán, Natalia S; Adler, Conrado; de Cristóbal, Ricardo E; Pomares, María Fernanda; Delgado, Mónica A; Vincent, Paula A

    2010-10-01

    The SbmA protein is involved in the transport of MccB17-, MccJ25-, bleomycin- and proline-rich peptides into the Escherichia coli cytoplasm. sbmA gene homologues were found in a variety of bacteria. However, the physiological role of this protein still remains unknown. Previously, we found that a combination of sbmA and tolC mutations in Tn10-carrying E. coli K-12 strains results in hypersusceptibility to tetracycline. In this work, we studied sbmA expression in a tolC mutant background and observed an increased expression throughout growth. We ruled out the global transcriptional regulator RpoS and the small RNA micF as intermediates in this regulation. The tolC mutation induced the expression of other well-characterized strong σ(E) -dependent promoters in E. coli. We observed that the increase in σ(E) activity led to a greater sbmA expression, conversely eliminating σ(E) prevented expression of sbmA. We also observed that the sbmA upregulation in a tolC mutant context was abolished in an rpoE-null strain. These results suggest a σ(E) -dependent positive regulation on sbmA by the tolC mutation. We hypothesize that this mechanism might be part of a compensatory cell envelope stress response.

  19. Sulindac has strong antifibrotic effects by suppressing STAT3-related miR-21.

    Science.gov (United States)

    Zhou, Xue; Li, You-Jie; Gao, Shu-Yan; Wang, Xiao-Zhi; Wang, Ping-Yu; Yan, Yun-Fei; Xie, Shu-Yang; Lv, Chang-Jun

    2015-05-01

    Pulmonary fibrosis (PF) is a disease with an unknown cause and a poor prognosis. In this study, we aimed to explore the pathogenesis of PF and the mechanism of sulindac in attenuating bleomycin (BLM)-induced PF. The rat PF model was induced by BLM and verified through histological studies and hydroxyproline assay. The severity of BLM-induced PF in rats and other effects, such as the extent of the wet lung to bw ratios, thickening of alveolar interval or collagen deposition, was obviously ameliorated in sulindac-treated rat lungs compared with BLM-induced lungs. Sulindac also reversed the epithelial mesenchymal transition (EMT) and inhibited the PF process by restoring the levels of E-cadherin and α-smooth muscle actin (SMA) in A549 cells. Our results further demonstrated that the above effects of sulindac might be related to regulating of interferon gamma (IFN-γ) expression, which further affects signal transducers and activators of transcription 3 (STAT3) and phosphorylated STAT3 (p-STAT3) levels. Moreover, higher miR-21 levels with the decreased E-cadherin and increased α-SMA expressions were found in transforming growth factor-β1-treated A549 cells, which can be reversed by sulindac. Collectively, our results demonstrate that by decreasing IFN-γ-induced STAT3/p-STAT3 expression to down-regulate miR-21, sulindac could significantly reverse EMT in A549 cells and prevent BLM-induced PF.

  20. Ultrastructural observation on pulmonary fibrosis in E9 rats treated with compoundCarapax trionycis formula

    Institute of Scientific and Technical Information of China (English)

    Jin Ren; Li-Xuan Wang; Xue-Cheng Ji; Jia-Ying Zhou; Man-Ying Zhang

    2013-01-01

    Objective:To investigate ultrastructural changes in pulmonary tissue of a rat model of pulmonary fibrosis following treatment with compoundCarapax trionycis(C. trionycis;Biejia inChinese) formula.Methods:Sixty maleSprague-Dawley rats were randomly divided into four groups(n=15): compoundC. trionycis formula high-, middle-, and low-dose groups as well as model group. Pulmonary fibrosis was induced by bleomycin.Five rats from each group weresacrificed on day 7,14 and28 of the drug treatment, respectively.The pulmonary tissue was harvested followed by hematoxylin-eosin staining and subsequent transmission electron microscopy.TheSzapiel’s method was used to assess the degree of alveolitis and pulmonary fibrosis.Results:Compared with the model group, the compoundC. trionycis formula groups had slighter pulmonary alveolitis after the7-day treatment and also had alleviated alveolar inflammation and pulmonary fibrosis after the14-day treatment.After the28-day treatment, the compoundC. trionycis formula groups showed deposition of a small amount of fibrous tissue and lesions occupying less than21% of the whole lung area, while the model group showed focal or diffuse fibrous deposition, narrow alveolar cavity, disordered lung structure, and lesions in larger than51% of the whole lung area. Conclusions:The compoundC. trionycis formula can inhibit the proliferation of collagen fibers and resist pulmonary fibrosis.

  1. Bioassay of Eucalyptus extracts for anticancer activity against Ehrlich ascites carcinoma (eac) cells in Swiss albino mice

    Institute of Scientific and Technical Information of China (English)

    Farhadul Islam; Hasina Khatun; Soby Ghosh; MM Ali; JA Khanam

    2012-01-01

    Objective: To evaluate the antineoplastic activity of Eucalyptus extract (EuE) against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Methods: Preliminary examination of four plant extracts (namely Eucalyptus, Costus, Azadirachta, Feronia) has been done by observing the reduction ability of number of EAC cells in previously inoculated Swiss albino mice. Among them as EuE showed maximum capability, the whole study has been conducted with EuE only. Important parameters viz. enhancement of life span, reduction of average tumor weight etc. have been studied. In addition the effects of EuE on hematological parameters in both normal and EAC inoculated mice have been measured. Effect of EuE on normal peritoneal cells has also been studied. Results: EuE reduced tumor burden remarkably. It reduced the tumor growth rate and enhanced the life span of EAC bearing mice noticeably. It reversed back the hematological parameters towards normal, reduced the trasplantability of EAC cells and enhanced the immunomodulatory effects in mice. The host toxic effect of EuE in mice is minimum and mostly reversible with time. All such data have been compared with those obtained by running parallel experiments with bleomycin at dose 0.3 mg/kg (i.p.). Conclusions: The Eucalyptus extract may be considered as a potent anticancer agent for advanced researches.

  2. Horizontal gene transfer drives adaptive colonization of apple trees by the fungal pathogen Valsa mali

    Science.gov (United States)

    Yin, Zhiyuan; Zhu, Baitao; Feng, Hao; Huang, Lili

    2016-01-01

    Horizontal gene transfer (HGT) often has strong benefits for fungi. In a study of samples from apple canker in Shaanxi Province, China, diverse microbes, along with the necrotrophic pathogen Valsa mali, were found to colonize the apple bark, thus providing ample opportunity for HGT to occur. In the present study, we identified 32 HGT events in V. mali by combining phyletic distribution-based methods with phylogenetic analyses. Most of these HGTs were from bacteria, whereas several others were from eukaryotes. Three HGTs putatively functioned in competition with actinomycetes, some of which showed a significant inhibitory effect on V. mali. Three HGTs that were probably involved in nitrogen uptake were also identified. Ten HGTs were thought to be involved in pathogenicity because they were related to known virulence factors, including cell wall-degrading enzymes and candidate effector proteins. HGT14, together with HGT32, was shown to contribute to bleomycin resistance of V. mali.These results suggest that HGT drives the adaptive evolution of V. mali. The HGTs identified here provide new clues for unveiling the adaptation mechanisms and virulence determinants of V. mali. PMID:27634406

  3. Interaction of apoptotic cells with macrophages upregulates COX-2/PGE2 and HGF expression via a positive feedback loop.

    Science.gov (United States)

    Byun, Ji Yeon; Youn, Young-So; Lee, Ye-Ji; Choi, Youn-Hee; Woo, So-Yeon; Kang, Jihee Lee

    2014-01-01

    Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  4. Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2 and HGF Expression via a Positive Feedback Loop

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    Ji Yeon Byun

    2014-01-01

    Full Text Available Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2/prostaglandin E2 (PGE2 and hepatocyte growth factor (HGF play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition.

  5. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia

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    Jaspers, N.G.; Taalman, R.D.; Baan, C.

    1988-01-01

    Fibroblast cultures from six unrelated patients having a familial type of immunodeficiency combined with microcephaly, developmental delay, and chromosomal instability were studied with respect to their response to ionizing radiation. The cells from five of them resembled those from individuals with ataxia telangiectasia (AT) in that they were two to three times more radiosensitive on the basis of clonogenic cell survival. In addition, after exposure to either X-rays or bleomycin, they showed an inhibition of DNA replication that was less pronounced than that in normal cells and characteristic of AT fibroblasts. However, the patients are clinically very different from AT patients, not showing any signs of neurocutaneous symptoms. Genetic complementation studies in fused cells, with the radioresistant DNA synthesis used as a marker, showed that the patients' cells could complement representatives of all presently known AT complementation groups. Furthermore, they were shown to constitute a genetically heterogeneous group as well. It is concluded that these patients are similar to AT patients with respect to cytological parameters. The clinical differences between these patients and AT patients are a reflection of genetic heterogeneity. The data indicate that the patients suffer from a chromosome-instability syndrome that is distinct from AT.

  6. Anti-Fibrotic Effects of Astragaloside IV in Systemic Sclerosis

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    Qing Qi

    2014-11-01

    Full Text Available Objective: To evaluate the anti-fibrotic effects of Astragaloside IV in systemic sclerosis. Methods: Treated or untreated systemic sclerosis (SSc and normal fibroblast isolated from corresponding pairs were utilized to detect expression of collagen and fibronectin by western blot, quantitative real-time RT-PCR (RT-qPCR, immunofluorescence staining and histopathological examination. SSc mouse model induced by bleomycin was used to evaluate the effects of the drug in vivo. Results: Compared to normal fibroblast (NF, the expression of collagen and fibronectin in SSc (SScF dramatically increased, and this could be reduced by Astragaloside IV (AST in a dose- or time-dependent manner at both protein and mRNA levels. Administration of Astragaloside IV consistently decreased collagen formation and partially restored the structure, as well as suppressing collagen and fibronectin expression in the skin lesions of SSc-model mice. Mechanistically, Astragaloside IV-induced fibrosis reduction may be due to deregulation of Smad 3/Fli-1, the major mediators of the fibrotic response and key molecules for TGF-β signaling. Astragaloside IV also decreased the level of p-SMAD3 and completely blocked its relocation into the nuclei. Conclusion: Astragaloside IV attenuates fibrosis by inhibiting the TGF-β-Smads3 axis in systemic sclerosis.

  7. Plants from Chernobyl zone could shed light on genome stability in radioactive environment

    Science.gov (United States)

    Shevchenko, Galina; Talalaiev, Oleksandr; Doonan, John

    2016-07-01

    For nearly 30 years, despite of chronic radiation, flora in Chernobyl zone continue to flourish, evidencing the adaptation of plants to such an environment. Keeping in mind interplanetary missions, this phenomenon is a challenge for plant space research since it highlights the possible mechanisms of genome protection and stabilization in harmful environment. Plants are sessile organisms and, contrary to animals, could not escape the external impact. Therefore, plants should evolve the robust system allowing DNA-protection against damage, which is of special interest. Our investigations show that Arabidopsis thaliana from Chernobyl zone tolerate radiomimetics and heavy metals better than control plants from non-polluted areas. Besides, its genome is less affected by such mutagens. qPCR investigations have revealed up-regulation of some genes involved in DNA damage response. In particular, expression of ATR is increased slightly and downstream expression of CycB1:1 gene is increased significantly after bleomycin treatment suggesting role of ATR-dependent pathway in genome stabilization. Several DNA repair pathways are known to exist in plants. We continue investigations on gene expression from different DNA repair pathways as well as cell cycle regulation and investigation of PCD hallmarks in order to reveal the mechanism of plant tolerance to radiation environment. Our investigations provide unique information for space researchers working on biotechnology of radiation tolerant plants.

  8. Isolated eyeball metastasis of non-seminomatous germ cell testicular tumor

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    Bojanić Nebojša

    2011-01-01

    Full Text Available Introduction. Testicular tumors most frequently metastasize to regional lymph nodes. Non-seminomatous tumor metastasis of testicle (NSGCTT to the eyeball is rare. Case report. We presented a 24-year old man, referred to the ophthalmologist due to acute pain and abrupt loss of sight in the left eye accompanied by its enlargement. Orbital and endocranial computerized tomography (CT was carried out, indicating the tumor in the left eye. His previous medical history provided the information that the right testicle was painlessly enlarged for 8 months. Ultrasonography showed a completely tumorously altered testis. Abdominal and chest CT failed to reveal any secondary deposits in visceral organs and lymph glands. Tumor markers (AFP - alpha-fetoproteins, beta hCG - human choronic gonadotropin beta were elevated. Right radical orchiactomy was performed (showed NSGCTT, followed by polychemotherapy with cisplatinum 100 mg/m2, etoposide 120 mg/m2, bleomycin 15 mg/m2 (PEB ´ 4, resulting in normalization of tumor marker values and significant regression of the left eyeball. Next, the left eye enucleation and ocular prosthesis implantation was carried out. Pathohistological evaluation indicated fibrosis and necrosis only. In a 5-year follow-up period, the patient was free of recurrence. Conclusion. Isolated hematogenous metastasis of the NSGCTT to the eye is rare. In our case, the left eye was the only metastatic localization. After chemotherapy and eye enucleation the patient was in a 4- year follow-up period free of the recurrence.

  9. Agrobacterium tumefaciens T-DNA Integration and Gene Targeting in Arabidopsis thaliana Non-Homologous End-Joining Mutants

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    Qi Jia

    2012-01-01

    Full Text Available In order to study the role of AtKu70 and AtKu80 in Agrobacterium-mediated transformation and gene targeting, plant lines with a T-DNA insertion in AtKu80 or AtKu70 genes were functionally characterized. Such plant lines lacked both subunits, indicating that heterodimer formation between AtKu70 and AtKu80 is needed for the stability of the proteins. Homozygous mutants were phenotypically indistinguishable from wild-type plants and were fertile. However, they were hypersensitive to the genotoxic agent bleomycin, resulting in more DSBs as quantified in comet assays. They had lower end-joining efficiency, suggesting that NHEJ is a critical pathway for DSB repair in plants. Both Atku mutants and a previously isolated Atmre11 mutant were impaired in Agrobacterium T-DNA integration via floral dip transformation, indicating that AtKu70, AtKu80, and AtMre11 play an important role in T-DNA integration in Arabidopsis. The frequency of gene targeting was not significantly increased in the Atku80 and Atku70 mutants, but it was increased at least 10-fold in the Atmre11 mutant compared with the wild type.

  10. Deletion of ku homologs increases gene targeting frequency in Streptomyces avermitilis.

    Science.gov (United States)

    Zhang, Xiaojuan; Chen, Wei; Zhang, Yang; Jiang, Libin; Chen, Zhi; Wen, Ying; Li, Jilun

    2012-06-01

    Streptomyces avermitilis is an industrially important soil bacterium known for production of avermectins, which are antiparasitic agents useful in animal health care, agriculture, and treatment of human infections. ku genes play a key role in the non-homologous end-joining pathway for repair of DNA double strand breaks. We identified homologs of eukaryotic ku70 and ku80 genes, termed ku1 and ku2, in S. avermitilis. Mutants with deletion of ku1, ku2, and both genes were constructed and their phenotypic changes were characterized. Deletion of ku genes had no apparent adverse effects on growth, spore formation, or avermectin production. The ku mutants, in comparison to wild-type strain, were slightly more sensitive to the DNA-damaging agent ethyl methanesulfonate, but not to UV exposure or to bleomycin. Gene targeting frequencies by homologous recombination were higher in the ku mutants than in wild-type strain. We conclude that ku-deleted strains will be useful hosts for efficient gene targeting and will facilitate functional analysis of genes in S. avermitilis and other industrially important bacterial strains.

  11. Long-term Disease Free and Successful Pregnancy in a Woman with Gonadal Dysgenesis and Malignant Germ Cell Tumor

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    Azamsadat Mousavi

    2012-06-01

    Full Text Available Objective: To report a case of long-term disease free and successful pregnancy after fertility sparing staging surgery with adjuvant chemotherapy in a 46,Xy gonadal dysgenetic with malignant germ cell tumor.Materials and methods: A case report from a university hospital about a 19-year-old female with 46,XY karyotype ( Swyer syndrome. The patient underwent bilateral gonadectomy and staging with uterus preservation. Six course adjuvant chemotherapy with VBP (Vinblastin, Bleomycin, Cisplatin was given. The case got pregnant through IVF- embryo donation. Disease free period and successful pregnancy is reported.Results: After treatment the patient is free of the disease after 11 years follow-up. She underwent in vitro fertilization treatment with oocyte donation and gave birth to a healthy ch.Conclusion: Improved multimodality treatment, allowance for consideration of fertility options for some women with gynecologic cancers. Since major concern in women with XY gonadal dysgenesis is ovarian malignancy, even with stage II dysgerminoma hysterectomy may not be required in some cases considering the opportunity for childbearing with the use of embryo transfer.

  12. Focused ultrasound-mediated sonochemical internalization: an alternative to light-based therapies

    Science.gov (United States)

    Gonzales, Jonathan; Nair, Rohit Kumar; Madsen, Steen J.; Krasieva, Tatiana; Hirschberg, Henry

    2016-07-01

    Activation of sonosensitizers via focused ultrasound (FUS), i.e., sonodynamic therapy has been proposed as an extension to light-activated photodynamic therapy for the treatment of brain as well as other tumors. The use of FUS, as opposed to light, allows treatment to tumor sites buried deep within tissues as well as through the intact skull. We have examined ultrasonic activation of sonosensitizers together with the anticancer agent bleomycin (BLM), i.e., sonochemical internalization (SCI). SCI is a technique that utilizes FUS for the enhanced delivery of endo-lysosomal trapped macromolecules into the cell cytoplasm in a similar manner to light-based photochemical internalization. The released agent can, therefore, exert its full biological activity, in contrast to being degraded by lysosomal hydrolases. Our results indicate that, compared to drug or FUS treatment alone, FUS activation of the sonosensitizer AlPcS2a together with BLM significantly inhibits the ability of treated glioma cells to grow as three-dimensional tumor spheroids in vitro.

  13. A case of Langerhans' cell histiocytosis following Hodgkin's disease

    Science.gov (United States)

    LI, XIN; DENG, QI; LI, YU-MING

    2016-01-01

    Langerhans' cell histiocytosis (LCH) is a group of disorders in various tissues characterized by the proliferation of Langerhans cells. It is rarely observed in adults. Langerhans cells are dendritic cells that express cluster of differentiation 1a (CD1a) and S100 protein, and contain Birbeck granules. Its etiopathogenesis remains to be elucidated. One possible etiological cause is a reactive proliferation of Langerhans cells following chemotherapy or radiotherapy for Hodgkin's disease (HD). A number of cases of LCH associated with malignant lymphoma have been reported previously. It may follow after the malignant lymphoma, or occur with it. However, fewer cases have been reported where the LCH followed after HD. In the present case report, a patient was diagnosed with HD following chemotherapy for LCH. As LCH was diagnosed, the patient was treated with a combination of various chemotherapeutic agents in two cycles of cyclophosphamide, vincristine, and prednisolone (COP), and eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). The patient went into a successful clinical remission. One year later, computed tomographic (CT) scans of the thorax and abdomen revealed augmentation of the tumor mass in the mediastinum. An excisional biopsy of the right inguinal lymph node was performed. The patient was diagnosed with nodular sclerosing Hodgkin's disease. Following four cycles of doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy, a whole-body positron emission tomographic CT scan revealed a decrease in tumor mass in the mediastinum. At present, the patient remains in treatment, and the prognosis has yet to be fully determined. PMID:27330759

  14. Electroporation adopting trains of biphasic pulses enhances in vitro and in vivo the cytotoxic effect of doxorubicin on multidrug resistant colon adenocarcinoma cells (LoVo).

    Science.gov (United States)

    Meschini, Stefania; Condello, Maria; Lista, Pasquale; Vincenzi, Bruno; Baldi, Alfonso; Citro, Gennaro; Arancia, Giuseppe; Spugnini, Enrico P

    2012-09-01

    Few articles in the literature have focused on electroporation as a strategy to reverse multidrug resistance (MDR) of tumour cells and they are mostly limited to the improved efficacy of bleomycin. We tested the application of trains of biphasic pulses to cell suspensions and to murine xenografts as a strategy to increase the uptake of doxorubicin (DOX) and to enhance its cytotoxicity against chemoresistant cells. The human colon adenocarcinoma cell line LoVo DX, expressing MDR phenotype with high levels of P-glycoprotein (P-gp), has been used. The in vitro and in vivo studies gave the following results: (i) the application of the electric pulses to the cell suspension, immediately before DOX administration, induced a significant increase of drug retention; (ii) confocal microscopy observations showed a remarkable increase of intranuclear accumulation of DOX induced by electroporation; (iii) cell survival assay revealed a decrease of cell viability in the cultures treated with the combination of electroporation and doxorubicin; (iv) scanning electron microscopy observations revealed consistent morphological changes after the combined exposure to electroporation and doxorubicin; (v) in implanted mice the combined treatment induced an evident slowdown on the tumour growth when compared to treatment with DOX alone; (vi) histopathological analysis evidenced tumour destruction and its replacement by scar tissue in the tumours treated with the combination of doxorubicin and electroporation.

  15. Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis

    Science.gov (United States)

    Sakkas, Lazaros I

    2016-01-01

    Systemic sclerosis (SSc) is a multisystem disease characterized by extensive collagen deposition in skin and internal organs, fibrointimal microvasculopathy, and activation of the immune system. T cells and B cells can promote fibrosis in SSc. Interleukin (IL)-6 is implicated in the pathogenesis of SSc. IL-6 is increased in the peripheral blood and lesional skin from patients with SSc, and induces fibroblast collagen production directly and indirectly by inducing profibrotic M2 macrophages. IL-6 also induces Th17 differentiation and promotes B cell differentiation toward Ig-producing plasma cells. IL-6 is also implicated in the pathogenesis of SSc in animal models as it is increased in mice with bleomycin-induced fibrosis, whereas neutralization of IL-6 in these mice prevents skin fibrosis. IL-6 acts on cells by binding to IL-6 receptor (IL-6R) which is transmembrane or soluble, and then recruits the signal-transducing glycoprotein 130 which is ubiquitously expressed. Tocilizumab is an anti-IL-6R humanized monoclonal antibody that blocks IL-6-mediated signaling. Tocilizumab has been approved for the treatment of moderate-to-severe rheumatoid arthritis, for polyarticular and systemic juvenile idiopathic arthritis, and for Castleman’s disease, and is well tolerated. Case reports and a Phase II, randomized trial in SSc have shown some improvement of skin tightness and delayed deterioration of lung function. A Phase III randomized trial in SSc is anticipated. PMID:27621593

  16. Comparison of Therapeutic Response of Keloids to Cryotherapy Plus Intralesional Triamcinolone Acetonide or Verapamil Hydrochloride

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    Jannati

    2015-03-01

    Full Text Available Background A keloid is dysregulated fibroproliferative scar tissue in response to skin injuries, which extends beyond the wound margin. Since it has a poor response to treatment, variable therapies are used. Current therapies of keloid include intralesional corticosteroid injection, cryotherapy and various laser therapies, silicone gel sheets (pressure therapy, interferon-α-2b, 5-fluoruracil or bleomycine administration, excision followed by low dose radiation or topical imiquimod. Objectives The aim of this study was to compare the efficacy and safety of “intralesional triamcinolone with cryotherapy” and “Intralesional verapamil with cryotherapy”. Patients and Methods Eighty patients (42 females and 38 males, aged 11 - 40 years were allocated to receive one of the four treatment methods. Group 1: Intralesional triamcinolone with cryotherapy. Group 2: Intralesional verapamil with cryotherapy. Group 3: Intralesional verapamil. Group 4: Cryotherapy. Improvement of healing was measured using modified Vancouver scar scale and centimeter scale. Results There was a real faster response in the first group; while groups 3 and 4 had the slowest responses to treatment. Rates of responsiveness seemed to have no significant difference between the groups, but side effects were significantly much frequent in the first group. Conclusions Intralesional triamcinolone acetonide with cryotherapy showed the most efficacies with more adverse effects, but intralesional verapamil with cryotherapy showed good efficacy with less adverse effects. Hence, it is a suitable alternative in the treatment of keloids.

  17. Leflunomide prevents ROS-induced systemic fibrosis in mice.

    Science.gov (United States)

    Morin, Florence; Kavian, Niloufar; Chouzenoux, Sandrine; Cerles, Olivier; Nicco, Carole; Chéreau, Christiane; Batteux, Frédéric

    2017-03-30

    Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy and immunological abnormalities. Recent insights into the polarization of macrophages in scleroderma and into the implication of STAT6 and KLF4 in this process have prompted us to investigate the effects of the inhibition of STAT6 signaling pathway by leflunomide in mice. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) or bleomycin. Mice were treated (or not) every other day, for 4 or 6 weeks, by leflunomide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 auto-antibodies. STAT6 pathway was hyperactivated and KLF4 was overexpressed in the skin and the lungs of diseased mice. Their inhibition by leflunomide prevented skin and lung fibrosis. Moreover, the hyperproliferative and pro-oxidative phenotype of skin and lung fibroblasts was reversed by leflunomide. Beneficial immunological effects of leflunomide were associated with decreased activation of CD4+ and CD8+ T cells, B cell activation, decreased auto-antibodies production and restored polarization of macrophages in the spleen. The improvement provided by leflunomide in both mouse models of SSc provides a rationale for the evaluation of this immunomodulating drug in the management of patients affected by this disease.

  18. Mutagen sensitivity as measured by induced chromatid breakage as a marker of cancer risk.

    Science.gov (United States)

    Wu, Xifeng; Zheng, Yun-Ling; Hsu, T C

    2014-01-01

    Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in the chromosomes of peripheral blood lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related maladies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by clastogenic agents, such as the γ-radiation mimetic DNA cross-linking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-nitroquinoline and the tobacco smoke constituent benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.

  19. Mutagen sensitivity has high heritability: evidence from a twin study.

    Science.gov (United States)

    Wu, Xifeng; Spitz, Margaret R; Amos, Christopher I; Lin, Jie; Shao, Lina; Gu, Jian; de Andrade, Mariza; Benowitz, Neal L; Shields, Peter G; Swan, Gary E

    2006-06-15

    Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

  20. Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.

    Science.gov (United States)

    Morry, Jingga; Ngamcherdtrakul, Worapol; Gu, Shenda; Goodyear, Shaun M; Castro, David J; Reda, Moataz M; Sangvanich, Thanapon; Yantasee, Wassana

    2015-10-01

    Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.

  1. Radiation induced skin cancer the chest wall 30 years later from breast cancer operation

    Energy Technology Data Exchange (ETDEWEB)

    Miyamoto, Kouji; Togawa, Tamotsu; Hasegawa, Takeshi; Matsunami, Hidetoshi; Ikeda, Tsuneko [Matsunami General Hospital, Kasamatsu, Gifu (Japan); Matsuo, Youichi

    1998-10-01

    This paper describes the skin cancer on the frontal chest wall induced by postoperative irradiation 30 years later from mastectomy. The patients was a 62-year-old woman, who received mastectomy of the right breast cancer (invasive ductal carcinoma, comedo type) at 31 years old, and received the postoperative radiotherapy of total 11,628 rad over 38 times. On the first medical examination in author`s hospital, the patient had an ulcer of about 10 cm diameter and was diagnosed the radiation induced skin cancer (well differentiated squamous cell carcinoma) in the biopsy. Because of the general condition of the patient was extremely bad and the skin cancer had highly developed, the excision was thought to be impossible. The radiotherapy (16 Gy) and combined local chemotherapy by OK 432 and Bleomycin were performed. In spite of the short term treatment, these therapies were effective on the reduction of the tumor size and the hemostasis, and brought the patient the improvement of QOL. The general condition of the patient improved to be stable and she recovered enough to go out from the hospital for 6 months. After 10 months, she showed anorexia and dyspnea and died after about 1 year from the admission. The present case is extremely rare, and it is required the radical therapy like the excision of chest wall at early stage. (K.H.)

  2. Adaptation of the neutral bacterial comet assay to assess antimicrobial-mediated DNA double-strand breaks in Escherichia coli

    Science.gov (United States)

    SOLANKY, DIPESH; HAYDEL, SHELLEY E.

    2012-01-01

    This study aimed to determine the mechanism of action of a natural antibacterial clay mineral mixture, designated CB, by investigating the induction of DNA double-strand breaks (DSBs) in Escherichia coli. To quantify DNA damage upon exposure to soluble antimicrobial compounds, we modified a bacterial neutral comet assay, which primarily associates the general length of an electrophoresed chromosome, or comet, with the degree of DSB-associated DNA damage. To appropriately account for antimicrobial-mediated strand fragmentation, suitable control reactions consisting of exposures to water, ethanol, kanamycin, and bleomycin were developed and optimized for the assay. Bacterial exposure to the CB clay resulted in significantly longer comet lengths, compared to water and kanamycin exposures, suggesting that the induction of DNA DSBs contributes to the killing activity of this antibacterial clay mineral mixture. The comet assay protocol described herein provides a general technique for evaluating soluble antimicrobial-derived DNA damage and for comparing DNA fragmentation between experimental and control assays. PMID:22940101

  3. Frequencies of mutagen-induced coincident mitotic recombination at unlinked loci in Saccharomyces cerevisiae

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, Kathryn M. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States); Hoffmann, George R. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)]. E-mail: ghoffmann@holycross.edu

    2007-03-01

    Frequencies of coincident genetic events were measured in strain D7 of Saccharomyces cerevisiae. This diploid strain permits the detection of mitotic gene conversion involving the trp5-12 and trp5-27 alleles, mitotic crossing-over and gene conversion leading to the expression of the ade2-40 and ade2-119 alleles as red and pink colonies, and reversion of the ilv1-92 allele. The three genes are on different chromosomes, and one might expect that coincident (simultaneous) genetic alterations at two loci would occur at frequencies predicted by those of the single alterations acting as independent events. Contrary to this expectation, we observed that ade2 recombinants induced by bleomycin, {beta}-propiolactone, and ultraviolet radiation occur more frequently among trp5 convertants than among total colonies. This excess among trp5 recombinants indicates that double recombinants are more common than expected for independent events. No similar enrichment was found among Ilv{sup +} revertants. The possibility of an artifact in which haploid yeasts that mimic mitotic recombinants are generated by a low frequency of cryptic meiosis has been excluded. Several hypotheses that can explain the elevated incidence of coincident mitotic recombination have been evaluated, but the cause remains uncertain. Most evidence suggests that the excess is ascribable to a subset of the population being in a recombination-prone state.

  4. Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Barrington, Sally F.; Somer, Edward J.; O' Doherty, Michael J. [Kings College London Division of Imaging, PET Imaging Centre at St Thomas' , London (United Kingdom); Qian, Wendi [MRC Clinical Trials Unit, London (United Kingdom); Franceschetto, Antonella; Bagni, Bruno [University of Modena and Reggio Emilia, Department of Nuclear Medicine, Modena (Italy); Brun, Eva; Almquist, Helen [Lund University Hospital, Departments of Oncology and Clinical Physiology, Lund (Sweden); Loft, Annika; Hoejgaard, Liselotte [Copenhagen University Hospital, PET and Cyclotron Unit, Rigshospitalet, Copenhagen (Denmark); Federico, Massimo [University of Modena and Reggio Emilia, Department of Haematology and Oncology, Modena (Italy); Gallamini, Andrea [Azienda Ospedaliera S. Croce e Carle, Hematology Department, Cuneo (Italy); Smith, Paul [Cancer Research UK and UCL Cancer Trials Centre, London (United Kingdom); Johnson, Peter [Cancer Research UK Clinical Centre, Southampton (United Kingdom); Radford, John [The Christie NHS Foundation Trust and the University of Manchester, Manchester (United Kingdom)

    2010-10-15

    To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting. (orig.)

  5. Do indium 111-labeled polymorphonuclear leukocytes detect neutrophil-prominent, fibrosing lung disease in rats

    Energy Technology Data Exchange (ETDEWEB)

    Williams, J.H. Jr.; Hartman, T.M.; Lichter, J.; Moser, K.M.

    1987-07-01

    The role of polymorphonuclear leukocytes (PMNs) in fibrotic lung disease remains poorly defined, but PMN prominence may predict a poor response to therapy in some patients. The bleomycin injury to rats represents a model of PMN-prominent alveolitis leading to fibrosis. We examined a method of identifying the alveolitis during its PMN-prominent phase with indium 111-labeled homologous PMNs (In-PMNs). When pairs of injured and uninjured rats were compared, greater activity was consistently found persisting in the lung images of the injured rats, both several hours (early) and a day (late) after injection of In-PMNs. Differences could likewise be identified when lung activity was normalized to activity of the injectate, the spleen, and variably the liver, as determined from organ images. These differences in gamma camera images were supported by direct measurement of activity in organs obtained by killing the animals after scanning. When groups of animals were compared, lung/spleen ratios appeared to most consistently differentiate the group of normal animals from those with alveolitis. These methods may provide a noninvasive means of identifying PMN prominence in the lung, which occurs in some fibrotic processes.

  6. Combined modality treatment for stage I-II non-Hodgkin's lymphomas: CVP versus BACOP chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Bajetta, E.; Valagussa, P.; Bonadonna, G.; Lattuada, A.; Buzzoni, R.; Rilke, F.; Banfi, A.

    1988-07-01

    This paper reports the 5-year results of a prospective randomized study beginning in 1976 on 177 evaluable patients with pathologic Stage I-IE and II-IIE non-Hodgkin's lymphomas with diffuse histology according to the Rappaport classification. Treatment consisted of either CVP or BACOP chemotherapy (3 cycles) followed by regional radiotherapy (40 to 50 Gy) and further cycles of either combination. In both arms, complete remission at the end of combined treatment was high (CVP 93%, BACOP 98%) regardless of age, stage or bulky disease. At 5 years, the comparative freedom from first progression was 62% for CVP vs 78% for BACOP (p = 0.02), respectively. Clinically relevant differences favoring BACOP chemotherapy were essentially documented in patients with large cell lymphomas (International Working Formulation), those with Stage II having more than three involved anatomical sites, bulky disease and age over 60 years. Recurrence within radiation fields was documented in only 5% of complete responders. Combined treatment was, in general, well tolerated particularly when BACOP was used. In only 2 patients given CVP post radiation cutaneous fibrosis was documented. Second solid tumors were detected in 4 patients. One patient started on CVP died because of brain stem necrosis after 45 Gy. We conclude that in Stage I-II patients with nodal and extranodal diffuse non-Hodgkin's lymphomas, particularly large cell lymphomas, combined modality approach with primary Adriamycin and bleomycin containing regimen, such as BACOP, followed by adjuvant radiotherapy offers high chances of cure with minimal toxicity.

  7. Development of a Fish Cell Biosensor System for Genotoxicity Detection Based on DNA Damage-Induced Trans-Activation of p21 Gene Expression

    Directory of Open Access Journals (Sweden)

    Huarong Guo

    2012-09-01

    Full Text Available p21CIP1/WAF1 is a p53-target gene in response to cellular DNA damage. Here we report the development of a fish cell biosensor system for high throughput genotoxicity detection of new drugs, by stably integrating two reporter plasmids of pGL3-p21-luc (human p21 promoter linked to firefly luciferase and pRL-CMV-luc (CMV promoter linked to Renilla luciferase into marine flatfish flounder gill (FG cells, referred to as p21FGLuc. Initial validation of this genotoxicity biosensor system showed that p21FGLuc cells had a wild-type p53 signaling pathway and responded positively to the challenge of both directly acting genotoxic agents (bleomycin and mitomycin C and indirectly acting genotoxic agents (cyclophosphamide with metabolic activation, but negatively to cyclophosphamide without metabolic activation and the non-genotoxic agents ethanol and D-mannitol, thus confirming a high specificity and sensitivity, fast and stable response to genotoxic agents for this easily maintained fish cell biosensor system. This system was especially useful in the genotoxicity detection of Di(2-ethylhexyl phthalate (DEHP, a rodent carcinogen, but negatively reported in most non-mammalian in vitro mutation assays, by providing a strong indication of genotoxicity for DEHP. A limitation for this biosensor system was that it might give false positive results in response to sodium butyrate and any other agents, which can trans-activate the p21 gene in a p53-independent manner.

  8. Periostin in Skin Tissue Skin-Related Diseases

    Directory of Open Access Journals (Sweden)

    Yukie Yamaguchi

    2014-01-01

    Recently, periostin—a matricellular protein—has been highlighted for its pivotal functions in the skin. Analysis of periostin null mice has revealed that periostin contributes to collagen fibrillogenesis, collagen cross-linking, and the formation of ECM meshwork via interactions with other ECM components. Periostin expression is enhanced by mechanical stress or skin injury; this is indicative of the physiologically protective functions of periostin, which promotes wound repair by acting on keratinocytes and fibroblasts. Along with its physiological functions, periostin plays pathogenic roles in skin fibrosis and chronic allergic inflammation. In systemic sclerosis (SSc patients, periostin levels reflect the severity of skin fibrosis. Periostin null mice have shown reduced skin fibrosis in a bleomycin-induced SSc mouse model, indicating a key role of periostin in fibrosis. Moreover, in atopic dermatitis (AD, attenuated AD phenotype has been observed in periostin null mice in a house dust mite extract-induced AD mouse model. Th2 cytokine-induced periostin acts on keratinocytes to produce inflammatory cytokines that further enhance the Th2 response, thereby sustaining and amplifying chronic allergic inflammation. Thus, periostin is deeply involved in the pathogenesis of AD and other inflammation-related disorders affecting the skin. Understanding the dynamic actions of periostin would be key to dissecting pathogenesis of skin-related diseases and to developing novel therapeutic strategies.

  9. Chemotherapy combined with involved-field radiotherapy for 177 children with Hodgkin's disease treated in 1983-1987

    Energy Technology Data Exchange (ETDEWEB)

    Balwierz, W.; Armata, J.; Moryl-Bujakowska, A. (Nicolaus Copernicus Univ., Cracow (Poland). School of Medicine) (and others)

    1991-12-01

    During the period from 1983 through 1987, a total of 177 children with biopsy proven Hodgkin's disease have undergone chemotherapy combined with local irradiation. The patients were divided into low, middle, and high stage groups. MVPP chemotherapy, consisting of mechlorethamine, vinblastine, procarbazine, and prednisone, was given as the basic treatment. B-DOPA chemotherapy, consisting of bleomycin, dacarbazine, vincristine, prednisone, and adriamycin, was given to some children. Irradiation was limited to involved regions by cobalt therapy for 114 patients and by conventional radiotherapy for 56 patients. In the remaining 7 patients, radiotherapy was given to peripheral lymph nodes and cobalt therapy to mediastinal tumor and/or abdomen. Irradiation doses ranged from 30 to 40 Gy in most of the patients. One hundred and seventy five patients (98.9%) had complete remission (CR). The probability for 5-year disease-free survival and survival was 0.91 and 0.98, respectively. The most common hematological complication was leukopenia. Relapse occurred in a total of 15 patients (8.5%) within 4-48 months after establishing the first CR: it was the most frequent in the middle stage group (8 patients). Seven patients died: 4 died as a result of complications and the other 3 died during the first CR. (N.K.).

  10. Combination of ABVD and radiotherapy in early stages of Hodgkin's disease; Analysis of a series of 94 patients

    Energy Technology Data Exchange (ETDEWEB)

    Eghbali, H.; Bonichon, F.; David, B.; Roujan, J.; Audebert, A.A.; Blanc, C.M.; Zittoun, R.; Hoerni, B.; Najman, A. (Fondation Bergonie, 33 - Bordeaux (France))

    1990-06-01

    In order to reduce, if not copletely suppress, late complications of combined chemotherapy and radiotherapy in Hodgkin's disease (HD), MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) was replaced by ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Ninetyfour patients with HD clinical stages I to III with no staging laparotomy were treated by three courses of ABVD followed by radiotherapy. Irradiation was performed on extended fields in 41 cases and on involved fields in 53 others. Consolidation chemotherapy was planned in 67 cases with at least one unfavorable prognostic factor, but achieved only in 33 cases. Seventien patients relapsed within 1 to 46 months after the beginning of treatment. Ten patients died, 7 of HD and 3 of intercurrent diseases or accident. Disease-free survival rate with a median follow-up of 60 months is 80%. This study showed, on the one hand, many digestive and general side-effects after ABVD and, on the other, a satisfactory hematological tolerance. Furthermore, mediastintis or cardiovascular complications were not more frequent than with MOPP. These results point out the development and use of better tolerated regimens for initial chemotherapy in HD, without jeopardizing the good results of the treatment. (author). 36 refs.; 5 figs.; 5 tabs.

  11. Mapping gene clusters within arrayed metagenomic libraries to expand the structural diversity of biomedically relevant natural products.

    Science.gov (United States)

    Owen, Jeremy G; Reddy, Boojala Vijay B; Ternei, Melinda A; Charlop-Powers, Zachary; Calle, Paula Y; Kim, Jeffrey H; Brady, Sean F

    2013-07-16

    Complex microbial ecosystems contain large reservoirs of unexplored biosynthetic diversity. Here we provide an experimental framework and data analysis tool to facilitate the targeted discovery of natural-product biosynthetic gene clusters from the environment. Multiplex sequencing of barcoded PCR amplicons is followed by sequence similarity directed data parsing to identify sequences bearing close resemblance to biosynthetically or biomedically interesting gene clusters. Amplicons are then mapped onto arrayed metagenomic libraries to guide the recovery of targeted gene clusters. When applied to adenylation- and ketosynthase-domain amplicons derived from saturating soil DNA libraries, our analysis pipeline led to the recovery of biosynthetic clusters predicted to encode for previously uncharacterized glycopeptide- and lipopeptide-like antibiotics; thiocoraline-, azinomycin-, and bleomycin-like antitumor agents; and a rapamycin-like immunosuppressant. The utility of the approach is demonstrated by using recovered eDNA sequences to generate glycopeptide derivatives. The experiments described here constitute a systematic interrogation of a soil metagenome for gene clusters capable of encoding naturally occurring derivatives of biomedically relevant natural products. Our results show that previously undetected biosynthetic gene clusters with potential biomedical relevance are very common in the environment. This general process should permit the routine screening of environmental samples for gene clusters capable of encoding the systematic expansion of the structural diversity seen in biomedically relevant families of natural products.

  12. Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4.

    Science.gov (United States)

    Lear, Travis; McKelvey, Alison C; Rajbhandari, Shristi; Dunn, Sarah R; Coon, Tiffany A; Connelly, William; Zhao, Joe Y; Kass, Daniel J; Zhang, Yingze; Liu, Yuan; Chen, Bill B

    2016-05-30

    The E3 small ubiquitin-like modifier (SUMO) protein ligase protein inhibitor of activated STAT 4 (PIAS4) is a pivotal protein in regulating the TGFβ pathway. In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4. FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4. FIEL1 protein is highly expressed in lung tissues from patients with idiopathic pulmonary fibrosis (IPF), whereas PIAS4 protein levels are significantly reduced. FIEL1 overexpression significantly increases fibrosis in a bleomycin murine model, whereas FIEL1 knockdown attenuates fibrotic conditions. Further, we developed a first-in-class small molecule inhibitor toward FIEL1 that is highly effective in ameliorating fibrosis in mice. This study provides a basis for IPF therapeutic intervention by modulating PIAS4 protein abundance.

  13. Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

    Energy Technology Data Exchange (ETDEWEB)

    Rudolf, Jeffrey D. [Scripps Research Inst., Jupiter, FL (United States); Bigelow, Lance [Argonne National Lab. (ANL), Argonne, IL (United States); Chang, Changsoo [Argonne National Lab. (ANL), Argonne, IL (United States); Cuff, Marianne E. [Argonne National Lab. (ANL), Argonne, IL (United States); Lohman, Jeremy R. [Scripps Research Inst., Jupiter, FL (United States); Chang, Chin-Yuan [Scripps Research Inst., Jupiter, FL (United States); Ma, Ming [Scripps Research Inst., Jupiter, FL (United States); Yang, Dong [Scripps Research Inst., Jupiter, FL (United States); Clancy, Shonda [Argonne National Lab. (ANL), Argonne, IL (United States); Babnigg, Gyorgy [Argonne National Lab. (ANL), Argonne, IL (United States); Joachimiak, Andrzej [Argonne National Lab. (ANL), Argonne, IL (United States); Phillips, George N. [Rice Univ., Houston, TX (United States); Shen, Ben [Scripps Research Inst., Jupiter, FL (United States)

    2015-11-17

    The bleomycins (BLMs), tallysomycins (TLMs), phleomycin, and zorbamycin (ZBM) are members of the BLM family of glycopeptide-derived antitumor antibiotics. The BLM-producing Streptomyces verticillus ATCC15003 and the TLM-producing Streptoalloteichus hindustanus E465-94 ATCC31158 both possess at least two self-resistance elements, an N-acetyltransferase and a binding protein. The N-acetyltransferase provides resistance by disrupting the metal-binding domain of the antibiotic that is required for activity, while the binding protein confers resistance by sequestering the metal-bound antibiotic and preventing drug activation via molecular oxygen. We recently established that the ZBM producer, Streptomyces flavoviridis ATCC21892, lacks the N-acetyltransferase resistance gene and that the ZBM-binding protein, ZbmA, is sufficient to confer resistance in the producing strain. To investigate the resistance mechanism attributed to ZbmA, we determined the crystal structures of apo and Cu(II)-ZBM-bound ZbmA at high resolutions of 1.90 and 1.65 angstrom, respectively. A comparison and contrast with other structurally characterized members of the BLM-binding protein family revealed key differences in the protein ligand binding environment that fine-tunes the ability of ZbmA to sequester metal-bound ZBM and supports drug sequestration as the primary resistance mechanism in the producing organisms of the BLM family of antitumor antibiotics.

  14. TOXICOLOGY STUDIES OF LEWISITE AND SULFUR MUSTARD AGENTS:GENETIC TOXICITY OF LEWISITE (L) IN CHINESE HAMSTER OVARY CELLS

    Energy Technology Data Exchange (ETDEWEB)

    Jostes,R.F. Jr.; Sasser, LB; Rausch, R.J.

    1989-05-31

    The cytotoxic clastogenic and mutagenic effects of the arsenic containing vesicant, Lewisite (L) [dichloro(2-chlorovinyl) arsine], have been investigated using Chinese hamster ovary cells. One hour exposures to Lewisite were cytotoxic in uM amounts. The cell survival response yields a D37 of 0.6 uM and an extrapolation number of 2.5. The mutagenic response at the hypoxantnine-guanine phosporibosyl transferase (HGPRT) locus was sporadic and not significantly greater than control values when cells were exposed over a range of 0.125 to2.0 uM. Sister chromatid exchange (SCE) induction, a measure of chromosomal rearrangement, was weakly positive over a range of 0.25 to 1.0 uM but the values were not significantly greater than the control response. Chromosomal aberrations were induced at 0.75 and 1.0 UMin one experiment and 0.5 and 0.75 uM in another experiment. The Induced values were significantly greater than the control values. Lewisite appears to be cytotoxic and clastogenic in our investigations but SCE and mutation at the HGPRT locus are not significantly greater than control values. Lewisita toxicity was in some ways similar to radiomimetic chemicals such as bleomycin.

  15. Comparison of clastogen-induced gene expression profiles in wild-type and DNA repair-deficient Rad54/Rad54B cells

    Directory of Open Access Journals (Sweden)

    van Benthem Jan

    2010-01-01

    Full Text Available Abstract Background Previously we found that Rad54/Rad54B cells are more sensitive towards mitomycin C (MMC as compared to wild-type (WT cells. This difference in sensitivity was absent upon exposure to other clastogens like bleomycin (BLM and γ-radiation. In order to get further insight into possible underlying mechanisms, gene expression changes in WT and Rad54/Rad54B MEFs (mouse embryonic fibroblasts after exposure to the clastogens MMC and BLM were investigated. Exposures of these cells to mutagens (N-ac-AAF and ENU and vehicle were taken as controls. Results Most exposures resulted in an induction of DNA damage signaling and apoptosis genes and a reduced expression of cell division genes in cells of both genotypes. As expected, responses to N-ac-AAF were very similar in both genotypes. ENU exposure did not lead to significant gene expression changes in cells of both genotypes, presumably due to its short half-life. Gene expression responses to clastogens, however, showed a genotype-dependent effect for BLM and MMC. MMC treated Rad54/Rad54B MEFs showed no induction of p53-signaling, DNA damage response and apoptosis as seen for all the other treatments. Conclusion These data support our finding that different types of clastogens exist and that responses to these types depend on the DNA repair status of the cells.

  16. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-β Signaling Pathway.

    Science.gov (United States)

    Liu, Qingmei; Chu, Haiyan; Ma, Yanyun; Wu, Ting; Qian, Feng; Ren, Xian; Tu, Wenzhen; Zhou, Xiaodong; Jin, Li; Wu, Wenyu; Wang, Jiucun

    2016-06-09

    Pulmonary fibrosis is a progressive and fatal disorder. In our previous study, we found that the Yiqihuoxue formula (YQHX), a prescription of Traditional Chinese Medicine, had a curative effect on scleroderma, a typical fibrotic disease. The aim of this study was to determine the key ingredient mediating the therapeutic effects of YQHX and to examine its effect on pulmonary fibrosis, including its mechanism. Luciferase reporter assays showed that the most important anti-fibrotic component of the YQHX was Salviae miltiorrhiza (SM). Experiments performed using a bleomycin-instilled mouse model of pulmonary fibrosis showed that Salvianolic acid B (SAB), the major ingredient of SM, had strong anti-inflammatory and anti-fibrotic effects through its inhibition of inflammatory cell infiltration, alveolar structure disruption, and collagen deposition. Furthermore, SAB suppressed TGF-β-induced myofibroblastic differentiation of MRC-5 fibroblasts and TGF-β-mediated epithelial-to-mesenchymal transition of A549 cells by inhibiting both Smad-dependent signaling and the Smad-independent MAPK pathway. Taken together, our results suggest that SM is the key anti-fibrotic component of the YQHX and that SAB, the major ingredient of SM, alleviates experimental pulmonary fibrosis both in vivo and in vitro by inhibiting the TGF-β signaling pathway. Together, these results suggest that SAB potently inhibits pulmonary fibrosis.

  17. Astaxanthin ameliorates lung fibrosis in vivo and in vitro by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells.

    Science.gov (United States)

    Wang, Meirong; Zhang, Jinjin; Song, Xiaodong; Liu, Wenbo; Zhang, Lixia; Wang, Xiuwen; Lv, Changjun

    2013-06-01

    Astaxanthin, a member of the carotenoid family, is the only known ketocarotenoid transported into the brain by transcytosis through the blood-brain barrier. However, whether astaxanthin has antifibrotic functions is unknown. In this study, we investigated the effects of astaxanthin on transforming growth factor β1-mediated and bleomycin-induced pulmonary fibrosis in vitro and in vivo. The results showed that astaxanthin significantly improved the structure of the alveoli and alleviated collagen deposition in vivo. Compared with the control group, the astaxanthin-treated groups exhibited downregulated protein expressions of α-smooth muscle actin, vimentin, hydroxyproline, and B cell lymphoma/leukemia-2 as well as upregulated protein expressions of E-cadherin and p53 in vitro and in vivo. Astaxanthin also inhibited the proliferation of activated A549 and MRC-5 cells at median inhibitory concentrations of 40 and 30 μM, respectively. In conclusion, astaxanthin could relieve the symptoms and halt the progression of pulmonary fibrosis, partly by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells.

  18. Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer: A Danish Nationwide Cohort Study

    DEFF Research Database (Denmark)

    Kier, Maria G; Hansen, Merete K; Lauritsen, Jakob

    2016-01-01

    radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL). Main Outcomes and Measures: Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls. Results: The study...... population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We...... found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2...

  19. Ruptured Granulosa Cell Tumor of the Ovary as a Cause of Acute Abdomen in Postmenopausal Woman

    Directory of Open Access Journals (Sweden)

    Tufan Oge

    2012-01-01

    Full Text Available Acute abdomen with hemoperitoneum is a very rare entity in postmenopausal women due to gynecologic conditions. A 54-year-old, postmenopausal woman was brought to emergency department with severe abdominal pain. Physical examination revealed acute abdomen findings with 15 cm pelvic mass on the right adnexal region. Immediate exploratory laparotomy was performed. During laparotomy 1000 cc of bloodstained fluid, ruptured and actively bleeding large mass arising from right ovary was observed. Right salpingo-oopherectomy was performed in emergency conditions, and pathology report revealed an adult type of granulosa cell tumor. After this result, staging surgery was performed and patient was diagnosed as granulosa cell tumor stage 1 c. Cisplatin, etoposide, and bleomycin chemotherapy was given. Clinicians should be aware of granulosa cell tumors which may occur at any age and prone to rupture. Frozen section will be helpful in order to avoid incomplete surgeries especially in postmenopausal women presented with intra-abdominal bleeding.

  20. Radiation therapy for early stage unfavorable Hodgkin lymphoma: is dose reduction feasible?

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    Laskar, Siddhartha; Kumar, Deepak P; Khanna, Nehal; Menon, Hari; Sengar, Manju; Arora, Brijesh; Gujral, Sumeet; Shet, Tanuja; Sridhar, Epari; Rangarajan, Venkatesh; Muckaden, Mary Ann; Nair, Reena; Banavali, Shripad

    2014-10-01

    One hundred and fifty-one patients aged between 3 and 70 years with early stage unfavorable Hodgkin lymphoma were included. Patients received 4-6 cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and involved field radiation therapy (IFRT). The most common histology was mixed cellularity (43%). The majority had stage IIAX disease. IFRT doses were 25.2 Gy/14 fractions and 34.2 Gy/19 fractions for adults with a complete response (CR) and partial response (PR), respectively, while the doses were 19.8 Gy/11 fractions and 30.6 Gy/17 fractions, respectively, for children. After 60 months (median), the 10-year progression-free survival (PFS) and overall survival (OS) were 88.4% and 93.2%, respectively. On univariate analysis, prognostic factors with significant impact on PFS were age ≥ 18 years, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) histology, extranodal disease and response to treatment. Extranodal disease had a significant impact on OS. On multivariate analysis, NLPHL histology (p = 0.001) and response at 3 months (p = 0.000) had a significant impact on PFS. There were no in-field relapses in patients with bulky disease receiving RT doses > 25.2 Gy. Chemotherapy related acute pulmonary toxicity was documented in 21.4% and 4.8% of patients after six and four cycles of ABVD chemotherapy (p = 0.041). Four cycles of ABVD and reduced dose IFRT resulted in optimal outcomes.

  1. Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.

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    Bryant, Andrew J; Carrick, Ryan P; McConaha, Melinda E; Jones, Brittany R; Shay, Sheila D; Moore, Christy S; Blackwell, Thomas R; Gladson, Santhi; Penner, Niki L; Burman, Ankita; Tanjore, Harikrishna; Hemnes, Anna R; Karwandyar, Ayub K; Polosukhin, Vasiliy V; Talati, Megha A; Dong, Hui-Jia; Gleaves, Linda A; Carrier, Erica J; Gaskill, Christa; Scott, Edward W; Majka, Susan M; Fessel, Joshua P; Haase, Volker H; West, James D; Blackwell, Timothy S; Lawson, William E

    2016-02-01

    Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

  2. Employing libraries of zinc finger artificial transcription factors to screen for homologous recombination mutants in Arabidopsis.

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    Lindhout, Beatrice I; Pinas, Johan E; Hooykaas, Paul J J; van der Zaal, Bert J

    2006-11-01

    A library of genes for zinc finger artificial transcription factors (ZF-ATF) was generated by fusion of DNA sequences encoding three-finger Cys(2)His(2) ZF domains to the VP16 activation domain under the control of the promoter of the ribosomal protein gene RPS5A from Arabidopsis thaliana. After introduction of this library into an Arabidopsis homologous recombination (HR) indicator line, we selected primary transformants exhibiting multiple somatic recombination events. After PCR-mediated rescue of ZF sequences, reconstituted ZF-ATFs were re-introduced in the target line. In this manner, a ZF-ATF was identified that led to a 200-1000-fold increase in somatic HR (replicated in an independent second target line). A mutant plant line expressing the HR-inducing ZF-ATF exhibited increased resistance to the DNA-damaging agent bleomycin and was more sensitive to methyl methanesulfonate (MMS), a combination of traits not described previously. Our results demonstrate that the use of ZF-ATF pools is highly rewarding when screening for novel dominant phenotypes in Arabidopsis.

  3. Identification of the DNA repair defects in a case of Dubowitz syndrome.

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    Jingyin Yue

    Full Text Available Dubowitz Syndrome is an autosomal recessive disorder with a unique set of clinical features including microcephaly and susceptibility to tumor formation. Although more than 140 cases of Dubowitz syndrome have been reported since 1965, the genetic defects of this disease has not been identified. In this study, we systematically analyzed the DNA damage response and repair capability of fibroblasts established from a Dubowitz Syndrome patient. Dubowitz syndrome fibroblasts are hypersensitive to ionizing radiation, bleomycin, and doxorubicin. However, they have relatively normal sensitivities to mitomycin-C, cisplatin, and camptothecin. Dubowitz syndrome fibroblasts also have normal DNA damage signaling and cell cycle checkpoint activations after DNA damage. These data implicate a defect in repair of DNA double strand break (DSB likely due to defective non-homologous end joining (NHEJ. We further sequenced several genes involved in NHEJ, and identified a pair of novel compound mutations in the DNA Ligase IV gene. Furthermore, expression of wild type DNA ligase IV completely complement the DNA repair defects in Dubowitz syndrome fibroblasts, suggesting that the DNA ligase IV mutation is solely responsible for the DNA repair defects. These data suggests that at least subset of Dubowitz syndrome can be attributed to DNA ligase IV mutations.

  4. DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

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    Guo Li

    2015-01-01

    Full Text Available Background. Paraquat (PQ poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered. Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated. Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

  5. Management of keloids and hypertrophic scars: current and emerging options

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    Gauglitz GG

    2013-04-01

    Full Text Available Gerd G GauglitzDepartment of Dermatology and Allergy, Ludwig-Maximilian University, Munich, GermanyAbstract: In the context of growing aesthetic awareness, a rising number of patients feel disappointed with their scars and are frequently seeking help for functional and aesthetic improvement. However, excessive scarring following surgery or trauma remains difficult to improve despite a plethora of advocated treatment strategies as frequently observed in daily clinical routine. It is thus still preferable to prevent scarring by minimizing risk factors as much as possible. Hence, it remains crucial for the physician to be aware of basic knowledge of healing mechanisms and skin anatomy, as well as an appreciation of suture material and wound closure techniques to minimize the risk of postoperative scarring. Next to existing, well known prophylactic and therapeutic strategies for the improvement of excessive scarring, this article discusses emerging techniques such as intralesional cryotherapy, intralesional 5-fluorouracil, interferon, and bleomycin. Some of them have been successfully tested in well-designed trials and already have extended or may extend the current spectrum of excessive scar treatment in the near future. Innovative options such as imiquimod 5% cream, photodynamic therapy, or botulinum toxin A may also be of certain importance; however, the data currently available is too contradictory for definite recommendations.Keywords: intralesional cryotherapy, lasers, triamcinolone acetonide, TGF-β

  6. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury.

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    Haak, Andrew J; Tsou, Pei-Suen; Amin, Mohammad A; Ruth, Jeffrey H; Campbell, Phillip; Fox, David A; Khanna, Dinesh; Larsen, Scott D; Neubig, Richard R

    2014-06-01

    Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)-and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)-and transforming growth factor β (TGFβ)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.

  7. Erlotinib Induced Fatal Interstitial Lung Disease in a Patient with Metastatic Non-Small Cell Lung Cancer: Case Repor