In situ small-angle X-ray scattering studies during the formation of polymer/silica nanocomposite particles in aqueous solution.

This study is focused on the formation of polymer/silica nanocomposite particles prepared by the surfactant-free aqueous emulsion polymerization of 2,2,2-trifluoroethyl methacrylate (TFEMA) in the presence of 19 nm glycerol-functionalized aqueous silica nanoparticles using a cationic azo initiator at 60 °C. The TFEMA polymerization kinetics are monitored using 1H NMR spectroscopy, while postmortem TEM analysis confirms that the final nanocomposite particles possess a well-defined core-shell morphology. Time-resolved small-angle X-ray scattering (SAXS) is used in conjunction with a stirrable reaction cell to monitor the evolution of the nanocomposite particle diameter, mean silica shell thickness, mean number of silica nanoparticles within the shell, silica aggregation efficiency and packing density during the TFEMA polymerization. Nucleation occurs after 10-15 min and the nascent particles quickly become swollen with TFEMA monomer, which leads to a relatively fast rate of polymerization. Additional surface area is created as these initial particles grow and anionic silica nanoparticles adsorb at the particle surface to maintain a relatively high surface coverage and hence ensure colloidal stability. At high TFEMA conversion, a contiguous silica shell is formed and essentially no further adsorption of silica nanoparticles occurs. A population balance model is introduced into the SAXS model to account for the gradual incorporation of the silica nanoparticles within the nanocomposite particles. The final PTFEMA/silica nanocomposite particles are obtained at 96% TFEMA conversion after 140 min, have a volume-average diameter of 216 ± 9 nm and contain approximately 274 silica nanoparticles within their outer shells; a silica aggregation efficiency of 75% can be achieved for such formulations.

Non-invasive approximation of elemental composition of historic inks by LA-ICP-MS measurements of bathophenanthroline indicators.

The approximated identification of elemental composition of historic iron gall-inks is proposed based on results of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) measurements combined with a quick detection of iron (II) ions. Colorimetric response of test papers soaked with bathophenanthroline (BPhen) allows for detection of iron in the form of red-coloured complex of Fe(II) with BPhen. A co-migration of other elements (Cu, Zn, Pb, Al, K, Na, Mg) into indicators was confirmed by LA-ICP-MS measurements allowing for approximation of chemical diversity of handwritten documents in a totally non-invasive manner in respect to originals. The proposed analytical approach for in-direct studies of unique documents was tested on historic and model samples. The idea of approximation of elemental composition of the historic inks was found promising for purposes of conservation diagnosis towards estimation of corrosiveness of inks and eventual fingerprinting. It has been demonstrated that the presence of Fe as well as other elements (S, Cu and Mn) which are significant for recognition of ink corrosion can be detected in the used indicators extending the possibilities of examining valuable manuscripts in a way that is completely neutral for them.

Occurrence and detection of little cherry virus 1, little cherry virus 2, cherry green ring mottle virus, cherry necrotic rusty mottle virus, and cherry virus A in stone fruit trees in Poland.

To investigate the occurrence of little cherry virus 1 (LChV-1), little cherry virus 2 (LChV-2), cherry green ring mottle virus (CGRMV), cherry necrotic rusty mottle virus (CNRMV), and cherry virus A (CVA) in stone fruit trees in Poland, leaf samples were collected from sweet and sour cherry, peach, and apricot trees. Two sets of primers were used to increase the effectiveness of virus detection. The RT-PCR results indicated that the most frequently detected virus in all of the tested samples was CVA (60%), followed by CGRMV (13%), CNRMV (12%), LChV-1 (11%), and LChV-2 (4%). CVA and CNRMV were not detected in peaches. Mixed infections of these viruses were frequently detected. Keywords: little- cherry virus 1; little cherry virus 2; cherry green ring mottle virus; cherry necrotic rusty mottle virus; cherry virus A; RT-PCR.

Analytical, toxicological and kinetic investigation of decomposition of the drug diclofenac in waters and wastes using gamma radiation.

The radiolytic decomposition of the drug diclofenac (DCF), and in limited extent, also two other widely used drugs, ibuprofen and carbamazepine, was examined using liquid chromatography (LC) methods. The efficiency of DCF decomposition was examined in function of the absorbed dose of gamma radiation, and also in the presence of selected scavengers of radicals, which are commonly present in natural waters and wastes. Three different tests were employed for the monitoring of toxicity changes in the irradiated DCF solutions. The LC/mass spectrometry (MS) was used for the determination of products of DCF radiolysis. Using pulse-radiolysis method with the spectrophotometric detection, the rate constant values were determined for reactions of DCF with the main products of water radiolysis: hydroxyl radicals (1.24 ± 0.02) × 10(10) M(-1) s(-1) and hydrated electrons (3.1 ± 0.2) × 10(9) M(-1) s(-1). Their values indicate that both oxidative and reductive processes in radiolytic decomposition of DCF can take place in irradiated diluted aqueous solutions of DCF. The possibility of decomposition of all examined analytes was investigated in samples of river water and hospital waste. Compared to the previous studies, the conducted measurements in real samples were carried out at the concentration levels, which are close to those reported earlier in environmental samples. Graphical abstract ᅟ.

Equilibrative nucleoside transporter 3 depletion in ß-cells impairs mitochondrial function and promotes apoptosis: Relationship to pigmented hypertrichotic dermatosis with insulin-dependent diabetes.

Loss of function recessive mutations in the SLC29A3 gene that encodes human equilibrative nucleoside transporter 3 (ENT3) have been identified in patients with pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID). ENT3 is a member of the equilibrative nucleoside transporter (ENT) family whose primary function is mediating transport of nucleosides and nucleobases. The aims of this study were to characterise ENT3 expression in islet ß-cells and identify the effects of its depletion on ß-cell mitochondrial activity and apoptosis. RT-PCR amplification identified ENT3 expression in human and mouse islets and exocrine pancreas, and in MIN6 ß-cells. Immunohistochemistry using human and mouse pancreas sections exhibited extensive ENT3 immunostaining of ß-cells, which was confirmed by co-staining with an anti-insulin antibody. In addition, exposure of dispersed human islet cells and MIN6 ß-cells to MitoTracker and an ENT3 antibody showed co-localisation of ENT3 to ß-cell mitochondria. Consistent with this, Western blot analysis confirmed enhanced ENT3 immunoreactivity in ß-cell mitochondria-enriched fractions. Furthermore, ENT3 depletion in ß-cells increased mitochondrial DNA content and promoted an energy crisis characterised by enhanced ATP-linked respiration and proton leak. Finally, inhibition of ENT3 activity by dypridamole and depletion of ENT3 by siRNA-induced knockdown resulted in increased caspase 3/7 activities in ß-cells. These observations demonstrate that ENT3 is predominantly expressed by islet ß-cells where it co-localises with mitochondria. Depletion of ENT3 causes mitochondrial dysfunction which is associated with enhanced ß-cell apoptosis. Thus, apoptotic loss of islet ß-cells may contribute to the occurrence of autoantibody-negative insulin-dependent diabetes in individuals with non-functional ENT3 mutations.

Placental expression of eNOS, iNOS and the major protein components of caveolae in women with pre-eclampsia.

Caveolae regulate many cardiovascular functions and thus could be of interest in relation to pre-eclampsia, a pregnancy specific disorder characterised by hypertension and proteinuria. We examined placental mRNA and protein expression/localisation of the caveolae components Caveolin 1-3, Cavin 1-4 as well as eNOS/iNOS in normotensive control (n = 24) and pre-eclamptic pregnancies (n = 19). Placental mRNA expression of caveolin-1, cavin 1-3, was lower and eNOS expression was increased in pre-eclampsia (P < 0.05 for all). Additionally Caveolin-1 protein expression was also reduced in pre-eclampsia (P = 0.007); this could be an adaptive response in pre-eclampsia, possibly to attenuate the oxidative stress/inflammation.

Dark-induced senescence of barley leaves involves activation of plastid transglutaminases.

Transglutaminases (E.C. 2.3.2.13) catalyze the post-translational modification of proteins by establishing ε-(γ-glutamyl) lysine isopeptide bonds and by the covalent conjugation of polyamines to endo-glutamyl residues of proteins. In light of the confirmed role of transglutaminases in animal cell apoptosis and only limited information on the role of these enzymes in plant senescence, we decided to investigate the activity of chloroplast transglutaminases (ChlTGases) and the fate of chloroplast-associated polyamines in Hordeum vulgare L. 'Nagrad' leaves, where the senescence process was induced by darkness (day 0) and continued until chloroplast degradation (day 12). Using an anti-TGase antibody, we detected on a subcellular level, the ChlTGases that were associated with destacked/degraded thylakoid membranes, and beginning on day 5, were also found in the stroma. Colorimetric and radiometric assays revealed during senescence an increase in ChlTGases enzymatic activity. The MS/MS identification of plastid proteins conjugated with exogenous polyamines had shown that the ChlTGases are engaged in the post-translational modification of proteins involved in photosystem organization, stress response, and oxidation processes. We also computationally identified the cDNA of Hv-Png1-like, a barley homologue of the Arabidopsis AtPng1 gene. Its mRNA level was raised from days 3 to 10, indicating that transcriptional regulation controls the activity of barley ChlTGases. Together, the presented results deepen our knowledge of the mechanisms of the events happened in dark-induced senescence of barley leaves that might be activation of plastid transglutaminases.

Neurological symptoms associated with cerebral hyperperfusion syndrome after CEA and CAS--one centre study.

BACKGROUND: There are two equivalent in efficacy methods of the treatment of carotid artery stenosis: endarterectomy (CEA) and stenting (CAS), in which the blood flow increases in most patients by 20-40% over baseline, in some exceeding 100% and being symptomatic and leading to cerebral hyperperfusion syndrome (CHS). AIM: The aim of this study is to analyze the structure of neurological symptoms associated with CHS in patients with carotid artery revascularization. PATIENTS AND METHODS: Retrospective analysis included 1386 consecutive patients treated in the Department of General and Vascular Surgery between 2005 and 2011, with 625 of them were subjected to CEA and 761 to CAS. If neurological symptoms occurred, patients were consulted by a neurologist and ultrasonography (USG) examination and CT were performed. Neurological symptoms in patients with new onset of headache ipsilateral to the carotid revascularization were extracted from medical records and nursing documentation. RESULTS: Neurological symptoms attributed to CHS were observed in 66 (10.6%) of CEA and 61 (8.0 %) of CAS group. The frequency was similar in both groups (p = 0.43). The occurrence of epileptic attacks was similar in both study groups. The only difference was the less frequent falling of the lip in CAS group. Transient bradycardia and/or hypotension were observed in CAS (8.8% vs. 10.4% and 1.3% vs. 1.3%, respectively). No difference in stroke appearance between groups were found. CONCLUSIONS: The occurrence of neurological symptoms attributable to cerebral hyperperfusion syndrome after carotid artery revascularization in short term observation is similar regardless of the method used.

First Report of Cabbage Head Rot Caused by Fusarium avenaceum in Poland.

Cabbage (Brassica oleracea L. var. capitata L.) is an important crop in Poland. Symptoms of a disease affecting cabbage were observed in 2012 and 2013 both in mid-August during the growing season and during storage in January and February. The disease affected about 30 to 40% of crops grown on ~9,000 ha over three locations: Charsznica in south Poland and Bedlno and Skierniewice in central Poland. Circular, watery lesions ranging from 10 to 60 mm in diameter on the surface of affected cabbage heads included whitish aerial mycelium that developed orange sporodochia in the center of each lesion. After 2 to 3 weeks, infection covered each entire cabbage head. A fungal pathogen was isolated from the orange lesions and from infected internal tissue. After sterilization of the excised tissue in 70% ethanol, the sections were each rinsed twice with sterilized water, dried on sterilized filter paper, and plated onto potato dextrose agar (PDA). Isolations consistently yielded morphologically homogeneous fungal colonies with abundant aerial mycelium that ranged from yellow to brownish yellow. The fungus produced pigmentation that changed the agar medium from dark yellow to brownish-burgundy. The mean colony growth was 66 mm after 7 days at 25°C. The fungus formed macroconidia, but microconidia and chlamydospores were not observed. Macroconidia were slender, slightly falcate, usually 3- to 5-septate, 44.7 to 60.7 × 3.7 to 5.5 µm, and formed in abundant orange sporodochia. On PDA, the isolates lost the ability to form sporodochia. Morphological and cultural features were typical of those of F. avenaceum (Fries) Saccardo (2). Koch's postulates were conducted to establish pathogenicity of each of four of the isolates on cabbage heads of the cv. Jaguar F1 (Bejo Seeds, Poland). The outer leaf of each head was inoculated with an 8-mm-diameter PDA plug colonized by the appropriate isolate (four cabbage heads/isolate), and the heads stored in a growth chamber at 25°C. After 5 to 7 days, lesions similar to those observed on naturally infested cabbage were observed on all the inoculated cabbage leaves. Four cabbage heads treated similarly with water as a control treatment remained symptomless. The experiment was repeated. DNA extracted from two of the four isolates was subjected to a PCR assay with primers ITS5 and ITS4 (4) for species identification based on the ITS1 and ITS2 sequences of ribosomal DNA (rDNA). The two sequences differed by 1 bp in the ITS2 region and had 100% identity with ITS sequences of F. avenaceum Accession Nos. AY147283 and AY147285 in GenBank. The sequences were deposited in GenBank as KM189440 and KM189441. Descriptions of fusarium head rot of cabbage in the United States (1) and Canada (3) were consistent with these observations in Poland. To our knowledge, this is the first report of F. avenaceum causing head rot of cabbage in Poland and in Europe. References: (1) H. R. Dillard and A. C. Cobb. Phytopathology 96:30. 2006. (2) J. F. Leslie and B. A. Summerell. Page 132 in: The Fusarium Laboratory Manual, Blackwell Publishing, Hoboken, NJ, 2006. (3) R. D. Peters et al. HortSci. 42:737. 2007. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.

Validation and practical implementation of a multidisciplinary cancer distress screening questionnaire.

BACKGROUND: In order to identify cancer patients with psychosocial needs during radiotherapy, a routine screening questionnaire is widely recommended in the literature. Several tools focusing mainly on psychological issues have been developed during the past decade. However, problems with their implementation into clinical routine have been repeatedly reported, due to a lack of practicability for clinicians and nurses. This study reports the compilation of a multidisciplinary screening questionnaire and an analysis of the effectiveness of its implementation into clinical routine at the Department of Radiotherapy, Medical University of Vienna. MATERIALS AND METHODS: The screening questionnaire is based on a compilation of several subscales from established and validated assessment tools. It focuses on comprehensive information with high a clinical relevance for all professions. In a pilot study, patients' acceptance was assessed qualitatively. Analysis of missing screening data in consecutively admitted patients reflects the effectiveness of implementation and representativity of the data. A validation analysis of the psychological subscales was performed using external criteria and its internal consistency was tested with Cronbachs' α. RESULTS: Qualitative patient acceptance of the screening questionnaire is good. The overall response rate in the screening procedure was 75 %. Missing patient screening data sets arose randomly-mainly due to organizational problems-and did not result in systematic errors. The psychological subscales identify highly distressed patients with a sensitivity of 89 and 78 %, and an internal consistency of 0.843 and 0.617. CONCLUSION: The multidisciplinary screening questionnaire compiled in this study has a high patient acceptance, provides reliable and representative data and identifies highly distressed patients with excellent sensitivity. Although requiring additional personnel resources, it can be implemented successfully in clinical routine with benefits for both the patient and the professional team.

Physical and psychosocial support requirements of 1,500 patients starting radiotherapy.

BACKGROUND: The need for psychosocial support in cancer patients is estimated in the literature at 14-50 %. At the Department of Radiation Oncology, Medical University of Vienna, approximately 3,000 patients are seen annually. Due to limited staff resources, highly distressed patients need to be selected for focused support. A multidisciplinary screening questionnaire covering physical, social and psychological problems and needs was successfully implemented in clinical routine. We present the results of a representative sample of 1,500 heterogeneous cancer patients before beginning radiotherapy. PATIENTS AND METHODS: The prevalence rates of physical, social and psychological problems and needs were evaluated. Independent risk factors for critical psychological distress were analyzed in a multivariate logistic regression model, in order to identify vulnerable subgroups for focused psychosocial support. RESULTS: Critical psychological distress was found in 22 % of the overall cohort, of whom only 26 % reported a need for psychological information. Clinically relevant pain was suffered by 31 %. Patients' most frequent complaints were weakness, sleeping difficulties and exhaustion. Consequently, 40 % were impaired in activities and 35 % reported a requirement for support in daily life. A need for further information was expressed by 37 % of patients. Significant risk factors for critical psychological distress included pain, functional status, support requirements and patient-reported symptoms. Differences in tumor type, metastases and sociodemographic variables had no impact on critical psychological distress. CONCLUSION: Approximately one third of all patients beginning radiotherapy have physical, social and psychological problems and should receive focused psychosocial support. Multivariate analysis reveals that patients with impaired "physical integrity" are at a significantly higher risk of experiencing critical psychological distress.

Adhesion, activation, and aggregation of blood platelets and biofilm formation on the surfaces of titanium alloys Ti6Al4V and Ti6Al7Nb.

Titanium alloys are still on the top list of fundamental materials intended for dental, orthopedics, neurological, and cardiovascular implantations. Recently, a special attention has been paid to vanadium-free titanium alloy, Ti6Al7Nb, that seems to represent higher biocompatibility than traditional Ti6Al4V alloy. Surprisingly, these data are not thoroughly elaborated in the literature; particularly there is a lack of comparative experiments conducted simultaneously and at the same conditions. Our study fills these shortcomings in the field of blood contact and microbiological colonization. To observe platelets adhesion and biofilm formation on the surfaces of compared titanium alloys, fluorescence microscope Olympus GX71 and scanning electron microscope HITACHI S-3000N were used. Additionally, flow cytometry analysis of platelets aggregation and activation in the whole blood after contact with sample surface, as an essential tool for biomaterial thrombocompatibility assessment, was proposed. As a result of our study it was demonstrated that polished surfaces of Ti6Al7Nb and Ti6Al4V alloys after contact with whole citrated blood and E. coli bacterial cells exhibit a considerable difference. Overall, it was established that Ti6Al4V has distinct tendency to higher thrombogenicity, more excessive bacterial biofilm formation and notable cytotoxic properties in comparison to Ti6Al7Nb. However, we suggest these studies should be extended for other types of cells and biological objects.

Radiolytic decomposition of pesticide carbendazim in waters and wastes for environmental protection.

The radiolytic degradation of widely used fungicide, carbendazim, in synthetic aqueous solutions and industrial wastewater was investigated employing γ-irradiation. The effect of the absorbed dose, initial concentration and pH of irradiated solution on the effectiveness of carbendazim decomposition were investigated. Decomposition of carbendazim in 100 µM concentration in synthetic aqueous solutions required irradiation with 600 Gy dose. The aqueous solutions of carbendazim have been irradiated in different conditions, where particular active radical species from water radiolysis predominate. The obtained data have been compared with the kinetic modeling. The reversed-phase high-performance liquid chromatography was used for the determination of carbendazim and its radiolytic decomposition products in irradiated solutions. The changes of toxicity of irradiated solutions were examined with different test organisms and human leukemia cells.

The acute effects of performing drop jumps of different intensities on concentric squat strength.

AIM: To investigate the acute effects of performing drop jumps of different intensities on subsequent squat 1 repetition maximum (1RM). METHODS: 14 participants with strength training experience completed two familiarization sessions to become accustomed with the testing procedures and 1RM-like loads. Following this, four different 1RM testing sessions were completed. In each testing session subjects performed a 5-min bicycle warm-up followed by a series of sets with increasingly heavier loads until squat 1RM was achieved. During the first of these four sessions squat 1RM was assessed without the addition of drop jumps to the 1RM warm-up routine, thus was designated the control (CTRL) condition. In the final 3 testing sessions, two drop jumps from either 30 (DJ30), 45 (DJ45), or 60 (DJ60) cm were added to the warm-up routine that preceded squat 1RM assessment. EMG activity of the vastus lateralis was also monitored during 1RM testing. RESULTS: Squat 1RM without prior plyometric activity was 128.4±36.1 kg. Following DJ30, DJ45, and DJ60 squat 1RM equaled 130.4±36.4 kg, 130.9±38.3 kg, 131.0±38.9 kg, respectively. A repeated measures ANOVA uncovered a significant main effect of warm-up condition (P=0.021). Post hoc analysis revealed that differences in the 1RM values were only significant between DJ30 and CTRL (P=0.002). No significant differences in muscle activation of the vastus lateralis were noted between the conditions. CONCLUSION: These findings indicate lower body strength in individuals familiar with resistance training can be acutely enhanced when preceded by a warm-up incorporating a low volume of low intensity drop jumps.

Radiolytic degradation of the herbicide dicamba for environmental protection.

The radiolytic degradation of the widely used herbicide dicamba (3,6-dichloro-2-methoxybenzoic acid), employing gamma irradiation in laboratory batch conditions and with a beam of accelerated electrons in flow-through installation, was investigated. The effects of dose magnitude, ozone or hydrogen peroxide in irradiated solution, and scavengers such as nitrate and hydrogen carbonate on the effectiveness of dicamba decomposition and the products formed were investigated. Changes in the toxicity of irradiated solutions were measured with the Microtox and Spirotox toxicity tests. The application of radiolytic degradation was also examined for decomposition of herbicides in commercial agrochemical preparations.

Antitumor activity of tributyrin in murine melanoma model.

Butyric acid has been known to inhibit growth and to induce differentiation of a variety of tumor cells. Butyrate-treated tumor cells have also been observed to undergo apoptosis. Although butyrate compounds have demonstrated antitumor activity in murine tumor models and have already been admitted to clinical trials in tumor patients, the exact mechanism of their antitumor effects has not been elucidated. The results of our study showed antitumor activity of tributyrin, a butyric acid prodrug, in murine melanoma model and are strongly suggestive that antiangiogenic effects could participate in antitumor effects of butyrate compounds in vivo.

Butyric acid enhances in vivo expression of hTNF-alpha in transduced melanoma cell line.

Butyric acid (NaBut) and its derivatives are well-known agents eliciting tumor cell differentiation and apoptosis. In experimental models, NaBut is also used to enhance the efficacy of viral vectors. With the use of B78 murine melanoma cells transduced with the retroviral vector containing human tumor necrosis factor alpha (hTNF-alpha) gene, we investigated the ability of NaBut to increase the cytokine expression. We observed an increase in hTNF-alpha expression in vitro after incubation with NaBut. We also describe that the NaBut pro-drug tributyrin is able to increase hTNF-alpha expression in transduced B78 cells in a tumor vaccination model in mice. This observation strongly suggests a novel potential role for NaBut and its derivatives in tumor therapy. It could be used not only as a therapeutic directly acting on tumor cells but, in parallel, as a genetic vaccine "enhancer".

Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice.

The ubiquitin-proteasome pathway is becoming an attractive target in cancer therapy. The inhibitors of proteasomes have recently been shown to induce apoptosis of tumor cells in vitro and to exert significant antitumor effects in murine tumor models in vivo. Proteasome inhibitors, also prevent NF-kappa B activation. Since this transcription factor is responsible for counteracting apoptosis induced by numerous agents, and proteasome inhibitors have already proved efficacious in increasing the proapoptotic activity of TNF in vitro, we decided to evaluate the antitumor effects of the combined PSI and TNF treatment against a murine C-26 carcinoma. Both agents separately exerted moderate antitumor efficacy. However, their combination proved to exert dramatic antitumor activity with retardation of tumor growth and prolongation of mice survival time. Moreover, 50% of the mice were completely cured by this drug combination. Unexpectedly, there was no potentiation of the cytostatic/cytotoxic effects of these drugs in in vitro assays which argues against the direct influence on C-26 cells. Similarly, the influence of these drugs on tumor induced angiogenesis does not seem to explain the observed antitumor effects. Further studies are necessary to explain the striking antitumor effects of the PSI and TNF combination.

Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice.

Lovastatin, a drug commonly used in the clinic to treat hypercholesterolemia, has previously been reported to exert antitumor effects in rodent tumor models and to strengthen the antitumor effects of immune response modifiers (tumor necrosis factor alpha and IFN-gamma) or chemotherapeutic drugs (cisplatin). In the present report, we show in three murine tumor cell lines (Colon-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) that lovastatin can also effectively potentiate the cytostatic/cytotoxic activity of doxorubicin. In three tumor models (Co-ion-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (15 mg/kg for 10 days) and doxorubicin (3 x 2.5 mg/kg; cumulative dose, 7.5 mg/kg) as compared with either agent acting alone. Lovastatin treatment also resulted in a significant reduction of troponin T release by cardiomyocytes in doxorubicin-treated mice. This observation is particularly interesting because lovastatin is known to reduce doxorubicin-induced cardiac injury.

Potentiation of the anti-tumour effects of Photofrin-based photodynamic therapy by localized treatment with G-CSF.

Photofrin-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing.