Dong M.,University of Tübingen |
Philippi C.,Saarland University |
Loretz B.,Saarland University |
Nafee N.,Saarland University |
And 7 more authors.
International Journal of Pharmaceutics | Year: 2011
Nanoparticles delivery of oligonucleotides represents a potential approach for cancer treatment. However, most of the experiments were based on established cancer cell lines and may not reflect the original solid tumor in vivo. Both, tumor microenvironment and tumor cell biological properties in the tumor can influence the delivery efficiency of oligonucleotides. Therefore, it is important to understand the effect of nanoparticles delivery of oligonucleotides on tumor response in intact tissue architecture of individual tumors. We used freshly isolated human tumor tissue slices and primary lung cancer cells from non-small cell lung cancer patients to evaluate this nanocarrier system. Chitosan-coated poly(lactide-co-glycolide) (PLGA) nanoparticles were used to form oligonucleotide-nanoparticle-complexes (nanoplexes) with antisense 2′-O-methyl-RNA (OMR) that can inhibit telomerase activity by binding to the RNA component of telomerase. OMR cellular uptake was strongly enhanced by nanoplexes mediated delivery in both, primary cells and tissue slices. More than 80% of primary cancer cells and 50% of cells in tissue slices showed OMR uptake. Telomerase activity was inhibited by approximately 45% in primary cancer cells and about 40% in tissue slices. Nanoplexes could penetrate into tumor tissue without influencing tissue architecture and the delivered OMR was able to inhibit telomerase activity with relatively low cytotoxicity. © 2011 Elsevier B.V. All rights reserved.
Wertz M.S.,University of California at San Francisco |
Kyriss T.,Schillerhoehe Hospital |
Paranjape S.,University of California at San Francisco |
Glantz S.A.,University of California at San Francisco
PLoS Medicine | Year: 2011
Background: In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations. Methods and Findings: We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as "Project MIX." Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect. Conclusion: The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes. © 2011 Wertz et al.
Tan C.E.,University of California at San Francisco |
Kyriss T.,Schillerhoehe Hospital |
Glantz S.A.,University of California at San Francisco
PLoS Medicine | Year: 2013
Background:Spurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco "harm reduction," leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine how the tobacco industry organized to try to influence the IOM committee that prepared the report.Methods and Findings:We analyzed previously secret tobacco industry documents in the University of California, San Francisco Legacy Tobacco Documents Library, and IOM public access files. (A limitation of this method includes the fact that the tobacco companies have withheld some possibly relevant documents.) Tobacco companies considered the IOM report to have high-stakes regulatory implications. They developed and implemented strategies with consulting and legal firms to access the IOM proceedings. When the IOM study staff invited the companies to provide information on exposure and disease markers, clinical trial design for safety and efficacy, and implications for initiation and cessation, tobacco company lawyers, consultants, and in-house regulatory staff shaped presentations from company scientists. Although the available evidence does not permit drawing cause-and-effect conclusions, and the IOM may have come to the same conclusions without the influence of the tobacco industry, the companies were pleased with the final report, particularly the recommendations for a tiered claims system (with separate tiers for exposure and risk, which they believed would ease the process of qualifying for a claim) and license to sell products comparable to existing conventional cigarettes ("substantial equivalence") without prior regulatory approval. Some principles from the IOM report, including elements of the substantial equivalence recommendation, appear in the 2009 Family Smoking Prevention and Tobacco Control Act.Conclusions:Tobacco companies strategically interacted with the IOM to win several favored scientific and regulatory recommendations.Please see later in the article for the Editors' Summary. © 2013 Tan et al.
Ehmann R.,Ambulante Pneumologie |
Boedeker E.,Schillerhoehe Hospital |
Friedrich U.,TeamCanin |
Sagert J.,TeamCanin |
And 3 more authors.
European Respiratory Journal | Year: 2012
Patient prognosis in lung cancer largely depends on early diagnosis. The exhaled breath of patients may represent the ideal specimen for future lung cancer screening. However, the clinical applicability of current diagnostic sensor technologies based on signal pattern analysis remains incalculable due to their inability to identify a clear target. To test the robustness of the presence of a so far unknown volatile organic compound in the breath of patients with lung cancer, sniffer dogs were applied. Exhalation samples of 220 volunteers (healthy individuals, confirmed lung cancer or chronic obstructive pulmonary disease (COPD)) were presented to sniffer dogs following a rigid scientific protocol. Patient history, drug administration and clinicopathological data were analysed to identify potential bias or confounders. Lung cancer was identified with an overall sensitivity of 71% and a specificity of 93%. Lung cancer detection was independent fromCOPD and the presence of tobacco smoke and food odours. Logistic regression identified two drugs as potential confounders. It must be assumed that a robust and specific volatile organic compound (or pattern) is present in the breath of patients with lung cancer. Additional research efforts are required to overcome the current technical limitations of electronic sensor technologies to engineer a clinically applicable screening tool. Copyright©ERS 2012.
Kyriss T.,Schillerhoehe Hospital |
Schneider N.K.,German Cancer Research Center
Tobacco Control | Year: 2013
Background Tobacco-specific nitrosamines (TSNAs) are a group of carcinogens, which originate from nicotine and other tobacco alkaloids during fermentation and burning of tobacco. Between 1990 and 2010, the tobacco industry-funded extensive academic research on TSNAs in Germany. The objective was to gain better knowledge of how industry aims and strategies correlate with contents of publications by German toxicologists accepting tobacco industry funding by focusing on one prominent such toxicologist. Methods and findings The authors analysed previously secret tobacco industry documents that were disclosed following a series of litigation cases in the USA and compared them with peer-reviewed published results of tobacco industry-funded toxicologists. The tobacco industry, in particular Philip Morris, developed sophisticated strategies to downplay TSNA's carcinogenic potential. Over 2 decades, German toxicologist Elmar Richter, faculty member of the renowned Ludwig-Maximilians-University, Munich, received substantial financial support from the tobacco industry. Numerous publications show that his research findings supported the aims of the tobacco industry. In his commissioned work, he suggested that TSNA burden can be explained by misclassification of smokers or assay background levels caused by TSNA-like molecules from food. Other publications cast doubt on the relevance of animal testing for TSNAs to humans claiming a detoxifying effect of nicotine on the metabolism of TSNAs or suggesting that adducts of TSNAs are unsuitable as biomarkers of exposure to tobacco smoke. Conclusions Economic interests of the tobacco industry have strongly influenced the research activity of Richter and his group. The publications of his working group about carcinogenic effects of TSNAs published between 1992 and 2009 should therefore not be regarded as independent. Scientists and policy makers should consider the long-standing and intensive inter-relation between certain toxicologists and the tobacco industry when assessing the research results and consider ignoring them.
Bures M.,Hannover Medical School |
Zardo P.,Otto Von Guericke University of Magdeburg |
Langer F.,Hannover Medical School |
Zhang R.,University Hospital of Tuebingen |
Zhang R.,Schillerhoehe Hospital
Journal of Cardiothoracic Surgery | Year: 2016
Background: Albumin-glutaraldehyde glue has gained widespread acceptance for treatment of alveolar air leaks (AAL) in thoracic surgery. As liquid run-off during application is detrimental to its sealing efficacy, we developed a modified technique and assessed it in vitro. Methods: Caudal lobes of freshly excised swine lungs (n = 20) were intubated and ventilated. A standardized focal superficial parenchymal defect (40 × 25 mm) was created on the inflated lung. AAL was assessed under exposure to increasing inspired tidal volume (TVi). Lung lobes were randomly selected and subjected to either a standard sealing suggested by the manufacturer (control group) or a modified technique relying on placement of a square silicone frame around the lesion site (study group). AAL was subsequently assessed until burst failure occurred and the occuring lesions length was recorded on the inflated lung to evaluate elasticity of underlying tissue. Results: Superficial parenchymal defects resulted in AAL increasing with ascending TVi. AAL prior to sealant application was comparable in both groups. An application error occurred once in our control group. At TVi = 400, 500, 600 and 700 ml, the albumin-glutaraldehyde glue achieved complete sealing in 10, 10, 9 and 8 lungs respectively in our study group, as opposed to 9, 7, 6 and 4 lobes in the control group. The required mean burst pressure was significantly higher in our study group (41.0 ± 1.0 vs. 37.5 ± 4.2 cmH2O, p = 0.0195), but there was no difference in expansion of covered defect between both groups (1.0 ± 0.4 vs. 1.5 ± 1.7 mm, p = 0.3772). Conclusions: Our tests suggest that frame-assisted sealant application might prevent glue run-off and thus improves its sealing efficacy. We encourage further investigation of this technique in well-designed, controlled clinical trials. © 2016 The Author(s).
Hampel M.,University of Stuttgart |
Dally I.,University of Stuttgart |
Walles T.,Fraunhofer Institute for Interfacial Engineering and Biotechnology |
Walles T.,Schillerhoehe Hospital |
And 4 more authors.
European Journal of Cardio-thoracic Surgery | Year: 2010
Objective: In the treatment of advanced stages of lung cancer, increasingly more multimodality approaches applying radiotherapy and/or chemotherapy in a neo-adjuvant setting are being introduced. The impact of induction therapy, especially radiotherapy, on bronchial tissue viability has not been investigated so far. Methods: In 2008, we determined the tissue viability of bronchial segments obtained during surgery in 45 consecutive patients, including patients after neo-adjuvant radiochemotherapy (RCTX). Bronchial tissue viability was analysed by histology, life-dead assay and cell proliferation in tissue-specific culture media. Biomedical findings were compared with the clinical course of the patients. Results: Tissue samples of 44 patients were included into this study. Fourteen patients (32%) had undergone neo-adjuvant RCTX. Histology and life-dead assay of the bronchial segments did not show significant differences. While patient age, sex, tumour entity and site of resection had no influence on cell proliferation in vitro, previous RCTX resulted in a 46% decrease of bronchial tissue viability (P = 0.01). However, this effect was not reflected by the clinical course of the operated patients. Conclusions: Neo-adjuvant RCTX reduces bronchial tissue viability substantially. However, this impairment does not necessarily translate into an increased rate of postoperative bronchial insufficiencies. Standard histological work-up is not sensitive enough to characterise changes in bronchial tissue viability following RCTX. © 2009 European Association for Cardio-Thoracic Surgery.
Boedeker E.,Schillerhoehe Hospital |
Friedel G.,Schillerhoehe Hospital |
Walles T.,Schillerhoehe Hospital
Interactive Cardiovascular and Thoracic Surgery | Year: 2012
Lung cancer (LC) continues to represent a heavy burden for health care systems worldwide. Epidemiological studies predict that its role will increase in the near future. While patient prognosis is strongly associated with tumour stage and early detection of disease, no screening test exists so far. It has been suggested that electronic sensor devices, commonly referred to as 'electronic noses', may be applicable to identify cancer-specific volatile organic compounds in the breath of patients and therefore may represent promising screening technologies. However, three decades of research did not bring forward a clinically applicable device. Here, we propose a new research approach by involving specially trained sniffer dogs into research strategies by making use of their ability to identify LC in the breath sample of patients. © The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
PubMed | Schillerhoehe Hospital
Type: | Journal: Thoracic surgical science | Year: 2011
Pulmonary aspergillosis is a devastating complication in immunocompromised patients. Timing of surgery is controversial and depends on the patients general condition.From 2000 to 2007, 16 patients (mean age 47 years, range 20-64) underwent surgery for pulmonary aspergillosis. All patients were receiving immunosuppressive drugs due to chemotherapy of hematological malignancies, ten with additional bone marrow or stem cell transplantation. Perioperatively, aspergillosis was treated with antifungal agents. If granulocyte numbers in the peripheral blood was below 1.0x10(9)/l, granulocyte stimulating factor and granulocyte transfusions were administered perioperatively.Four patients underwent lobectomy and wedge resections of the same lung, one patient bilobectomy, two patients lobectomy, eight patients wedge resections of one lung, and one patient wedge resections of both lungs. All patients survived surgery without major complications. Five patients were bone marrow or stem cell transplanted 1, 2, 3, 7 and 10 months after surgery. Three of them died due to recurrence of the underlying malignancy. All other patients are alive and free of fungal disease.Timing of surgery in the context of antifungal therapy and adequate numbers of granulocytes and platelets in the peripheral blood appear essential for successful surgical therapy and avoidance of major complications.
PubMed | Schillerhoehe Hospital
Type: Journal Article | Journal: Tobacco control | Year: 2013
Tobacco-specific nitrosamines (TSNAs) are a group of carcinogens, which originate from nicotine and other tobacco alkaloids during fermentation and burning of tobacco. Between 1990 and 2010, the tobacco industry-funded extensive academic research on TSNAs in Germany. The objective was to gain better knowledge of how industry aims and strategies correlate with contents of publications by German toxicologists accepting tobacco industry funding by focusing on one prominent such toxicologist.The authors analysed previously secret tobacco industry documents that were disclosed following a series of litigation cases in the USA and compared them with peer-reviewed published results of tobacco industry-funded toxicologists. The tobacco industry, in particular Philip Morris, developed sophisticated strategies to downplay TSNAs carcinogenic potential. Over 2 decades, German toxicologist Elmar Richter, faculty member of the renowned Ludwig-Maximilians-University, Munich, received substantial financial support from the tobacco industry. Numerous publications show that his research findings supported the aims of the tobacco industry. In his commissioned work, he suggested that TSNA burden can be explained by misclassification of smokers or assay background levels caused by TSNA-like molecules from food. Other publications cast doubt on the relevance of animal testing for TSNAs to humans claiming a detoxifying effect of nicotine on the metabolism of TSNAs or suggesting that adducts of TSNAs are unsuitable as biomarkers of exposure to tobacco smoke.Economic interests of the tobacco industry have strongly influenced the research activity of Richter and his group. The publications of his working group about carcinogenic effects of TSNAs published between 1992 and 2009 should therefore not be regarded as independent. Scientists and policy makers should consider the long-standing and intensive inter-relation between certain toxicologists and the tobacco industry when assessing the research results and consider ignoring them.