23937421
Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice.
In recent years, considerable emphasis has been placed on identifying new cancer chemopreventive agents which could be useful for human populations. Silymarin, an anti-oxidant flavonoid isolated from artichoke, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. Since many antioxidants inhibit tumor promotion, and because ornithine decarboxylase (ODC) is a well known biochemical marker of tumor promotion, we assessed the effect of skin application of silymarin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced epidermal ODC activity and ODC mRNA levels in SENCAR mice. Application of silymarin at doses of 0.5-18 mg (1-37 mumol)/mouse prior to that of TPA (2.5 micrograms) treatment resulted in significant inhibition of TPA-induced epidermal ODC activity in a dose- and time-dependent manner. Northern blot analysis revealed that topical application of silymarin at the dose of 2 mg/mouse resulted in almost complete inhibition of TPA-induced epidermal ODC mRNA. In other studies, silymarin also showed significant inhibition of epidermal ODC activity induced by several other tumor promoters, including free radical-generating compounds. Our data suggest that silymarin could be a useful anti-tumor promoting agent capable of ameliorating the tumor promoting effects of a wide range of tumor promoters.
5785486
Identification of the site of photocross-linking formed in the absence of magnesium nucleotide from SH2 (Cys-697) in myosin subfragment 1 labeled with 4'-maleimidylbenzophenone.
The site of photocross-linking between Cys-697 (SH2), prelabeled with 4'-[14C]maleimidylbenzophenone, and the 50-kDa segment of myosin S1 on irradiation in the absence of nucleotide has been determined by isolation of the 20-50-kDa adduct and subsequent tryptic proteolysis. Isolation and partial sequencing of the radioactively labeled peptide indicate that the site of cross-linking is Arg-239. This result indicates that, in the absence of nucleotide, Arg-239 resides at about 1.0 nm from SH2 and, on the basis of the recent work of Sutoh and Hiratsuka (Sutoh, K. and Hiratsuka T. (1988) Biochemistry 27, 2964-2969) places Arg-239 at no more than 1.45 nm from either Lys-184 or Lys-189 of the nucleotide-binding "glycine-rich" loop prior to the binding of nucleotide.
37464296
Introduction to Special Issue on Molecular Basis for Cancer Prevention with Bioactive Food Components in Nutrition and Cancer--an International Journal.
The advance of technology and understanding of the process of cancer development suggests that the reported lesser incidence and death due to cancer in countries other than the Western and European countries might also be due to under- diagnosed and under-represented cases. Further, increases in life span as well as ignorance about the disease puts populations in South and South East Asian countries at higher risk to develop cancer. With the increasing rate of cancer incidence every year in non -Western countries, cancer is estimated to become the deadliest disease in coming decades. Conventional chemo- and radio-therapies during the past three decades have not been able to contain the disease, and also have serious side effects. Many natural agents, especially small molecules from plants are non-toxic, easily available and may have anticancer potential. Thus, screening phytochemicals as anticancer agents could be a better approach in cancer prevention and treatment. This chemoprevention approach may have translational significance for prevention and treatment of cancer. 
 
Therefore to emphasize the potential role of phytochemicals in cancer prevention and therapy, it was our privilege to host the International Symposium on Recent Advances in Cancer Research: Therapeutics to Chemoprevention, at Central University of Gujarat (CUG), Gandhinagar. The conference was co-organized by the University of Colorado Denver, USA; University of Pittsburgh, USA; University of Oklahoma, USA, during 8–9 February, 2012. Modern biological strategies, specifically the latest developments for the targeted prevention and treatment of cancer via dietary, natural and synthetic agents were discussed in detail. The symposium also emphasized the translational aspect of cancer chemoprevention strategies for various cancers. 
 
The symposium deliberations include the ideas for combinatorial chemoprevention by phytochemicals as a promising approach for cancer control and emerging trends for the use of herbal radio-modulators to sensitize the cancer cells for apoptotic cell death. Many bioactive phytochemicals such as silibinin, benzyl isothiocyanate, anthocyanidins, nexrutine, tocopherol, etc. were discussed for their in vivo efficacy in animal tumor models, associated mechanisms and translational potential. Targeting tumor microenvironment with small molecules was found promising and having translational potential for prostate and breast cancer chemoprevention. 
 
The novel work and ideas presented at the symposium were helpful in guiding the research orientation of scientists, especially the young researchers who will be benefitted at all levels of their career development. Since chemoprevention of cancer is becoming an attractive approach for controlling cancer, we felt that the deliberations of this symposium should reach to the wider section of the researchers. Therefore, it was planned to bring out a special issue on Molecular Basis for Cancer Prevention with Bioactive Food Components in Nutrition and Cancer – An International Journal. We appreciate the researchers for contributing their novel work and ideas to this special issue. We are grateful to the Editor of Nutrition and Cancer – An International Journal, for his initiative to bring out this special issue on this relevant topic. We believe that this volume will be enlightening for the researchers working in the area of cancer chemoprevention.
35457752
Nordihydroguaiaretic acid, an inhibitor of lipoxygenase, also inhibits cytochrome P-450-mediated monooxygenase activity in rat epidermal and hepatic microsomes.
Nordihydroguaiaretic acid (NDGA), a plant lignan and phenolic antioxidant, is a known lipoxygenase inhibitor. In this study, we investigated the effect of NDGA on rat epidermal and hepatic monooxygenase activity and its interaction with rat hepatic microsomal cytochrome P-450. The addition of NDGA to epidermal microsomes prepared from control and 3-methylcholanthrene (3-MC)-pretreated rats and hepatic microsomal preparations from control, 3-MC-pretreated, and phenobarbital (PB)-pretreated rats resulted in a concentration-dependent inhibition of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (ERD) activities. The 50% inhibitory dose for NDGA ranged from 4.1 x 10(-5) to 13.1 x 10(-5) M for AHH and ERD activities in these microsomal preparations. The addition of NDGA to hepatic microsomes prepared from PB-pretreated rats resulted in spectral changes characterized by absorbance maxima at 380 nm and minima at 414 nm, typical of type I binding difference spectra. It also showed time- and concentration-dependent inhibition of the binding of carbon monoxide to dithionite or NADPH-reduced cytochrome P-450. We speculate that perhaps hydroxyl groups present in NDGA play an important role in inhibiting the monooxygenase activity and suggest that NDGA may have potential as an antimutagen and/or anticarcinogen. Furthermore, caution must be exercised in elucidating the role of lipoxygenase in metabolic pathways based solely on the criterion of inhibition by NDGA.
46117096
ras protein p21 processing enzyme farnesyltransferase in chemical carcinogen-induced murine skin tumors.
Farnesylation of ras protein p21 is crucial for the protein's membrane localization, which is essential for its cell-transforming activity, which in turn is thought to be critical for the ultimate induction of cancer. The cytosolic enzyme farnesyltransferase plays a major role in posttranslational modification of p21, but the level of farnesyltransferase activity in mammalian tumors and its relationship to the processing of cytosolic p21 that leads to tumorigenesis are unknown. We report here that farnesyltransferase activity was significantly higher in chemical carcinogen-induced benign skin papillomas in SENCAR mice than in the epidermises of control animals. The enzyme is primarily epidermal in origin, and kinetic studies with cytosol from epidermis and papillomas showed that the reaction was linear with respect to time, substrate concentration, and protein content. Skin papillomas showed significantly elevated levels of both cytosolic and membrane-bound Ha-ras p21, whereas far lesser cytosolic and almost negligible amounts of membrane-bound p21 were present in the epidermis of control mice. There was a positive correlation between increased enzyme activity in papilloma cytosol and the processing of overexpressed cytosolic Ha-ras p21 for its localization to membrane.
6837472
Apoptosis is an early event during phthalocyanine photodynamic therapy-induced ablation of chemically induced squamous papillomas in mouse skin.
Photodynamic therapy (PDT) is a promising new modality to treat malignant neoplasms including superficial skin cancers. In our search for an ideal photosensitizer for PDT, Pc 4, a silicon phthalocyanine, has shown promising results both in in vitro assays and in implanted tumors. In this study we assessed the efficacy of Pc 4 PDT in the ablation of murine skin tumors; and the evidence for apoptosis during tumor ablation was also obtained. The Pc 4 was administered through tail vein injection to SENCAR mice bearing chemically induced squamous papillomas, and 24 h later the lesions were illuminated with an argon ion-pumped dye laser tuned at 675 nm for a total light dose of 135 J/cm2. Within 72-96 h, almost complete tumor shrinkage occurred; no tumor regrowth was observed up to 90 days post-PDT. As evident by nucleosome-size DNA fragmentation, appearance of apoptotic bodies in hematoxylin and eosin staining and direct immunoperoxidase detection of digoxigenin-labeled genomic DNA in sections, apoptosis was clearly evident 6 h post-PDT at which time tumor shrinkage was less than 30%. The apoptotic bodies, as evident by the condensation of chromatin material around the periphery of the nucleus and increased vacuolization of the cytoplasm, were also observed in electron microscopic studies of the tumor tissues following Pc 4 PDT. The extent of apoptosis was greater at 15 h than at 6 and 10 h post-PDT. Taken together, our results clearly show that Pc 4 may be an effective photosensitizer for PDT of nonmelanoma skin cancer, and that apoptosis is an early event during this process.
29187320
Transferrin saturation with intravenous irons: an in vitro study.
BACKGROUND
Iron deficiency anemia in chronic kidney disease is commonly treated with one of three intravenous irons-iron dextran, iron sucrose, or iron gluconate. Substantial pharmacologic differences between drugs exist, but their ability to saturate transferrin has not been compared. Drugs that may lead to rapid transferrin saturation may lead to greater efficacy but also increased toxicity if transferring-mediated uptake of iron is the basis of this toxicity.


METHODS
We studied the in vitro ability of the three intravenous irons to donate iron to transferrin. Transferrin saturation was studied by direct visualization of the transferrin bands by urea polyacrylamide gel electrophoresis (PAGE), as well as a functional assay that evaluated the ability of iron to half saturate transferrin in a dose-dependent (0 to 100 microg/mL) and time-dependent (15 to 180 min) manner. Half-maximal dose (EC(50)) of iron needed to saturate transferrin was evaluated.


RESULTS
Nondextran irons were able to saturate transferrin in a dose-dependent and time-dependent manner. There was more rapid transferrin saturation with iron gluconate compared to iron sucrose. The slope of the EC(50) versus dose iron gluconate titration curve was -0.021 nmol/microg/mL (95% CI -0.025 to -0.017, P < 0.0001), for iron sucrose -0.006 nmol/microg/mL (95% CI -0.010 to -0.002, P= 0.002), and for iron dextran -0.001 nmol/microg/mL (95% CI -0.004 to 0.003, P > 0.2). The least square mean EC(50) computed for mean iron concentration was 5.95 nmol for iron gluconate (95% CI 5.82 to 6.08), 6.73 nmol for iron sucrose (95% CI 6.59 to 6.86), and 7.24 nmol for iron dextran (95% CI 7.11 to 7.38). Similar results were seen for the time-dependent transferrin saturation (drug x time interaction, F 6.0, P < 0.01). Urea PAGE analysis showed similar results as the functional assay.


CONCLUSION
Substantial heterogeneity in direct iron transfer from iron pharmaceuticals in vitro suggests that differences may exist in safety and efficacy of these drugs in vivo. In vivo studies are needed to compare the safety and efficacy of existing nondextran parenteral irons to better define the therapeutic ratio.
26099246
Expression profiling and individualisation of treatment for ovarian cancer.
Ovarian cancer is the commonest cause of gynaecological cancer-related mortality. Patients with this disease generally undergo surgery followed by platinum-taxane chemotherapy, with additional chemotherapy at relapse. Although the prognosis for patients with advanced cancer is poor--a five-year survival of only 30-40%--there is a wide range of outcomes for individual patients. To date, clinico-pathological variables such as age, stage, grade, histology, debulking status and response to chemotherapy continue to provide the basis on which treatment decisions are made for individual patients. Immunohistochemical markers and information on p53 mutation status have been extensively evaluated in ovarian cancer, but have not yet been shown to be sufficiently informative to influence clinical decisions on a routine basis. The recent advent of expression profiling has provided a new impetus to identifying clinically useful prognostic markers. The ambition of personalised medicine through microarray-based profiling appears to be realistic, but further studies on large uniform cohorts are needed before this potential is fully realised.
205502379
Mediastinal mass in an asthmatic patient.
A 52-year-old man with a 2-year history of asthma was referred to theChestClinic becauseofworseningdyspnoea of 1-year duration. He was non-compliant with inhalers and was taking oral prednisolone as needed for control of asthma. There were no other complaints. Physical examinationshowedanobeseman(bodymass index37.8 kg/m) with cushingoid habitus. Examination of the respiratory system showed diffuse bilateral wheeze. Cardiovascular, neurological and abdominal examinations were normal. Spirometry showed moderate airway obstruction with significant bronchodilator reversibility. A chest radiograph showed a superior mediastinal widening. The possibility of upper airway obstruction secondary to the mediastinal mass was considered. Subsequently, high-resolution computed tomography (CT, Fig. 1) showed a low-attenuation unencapsulated mass in the anterior mediastinum (bold arrow), para-aortic (arrow head) and the paratracheal region (small arrow). Also seen was increased extrapleural fat (cleaved arrow head) consistent with a diagnosis of mediastinal lipomatosis. Serum cortisol at 8.00 hours was 55 nmol/L, suggesting suppression of endogenous cortisol secretion. The patient was initiated on inhaled steroids. Prednisolone 20 mg/daywas continued and slowly tapered by 2.5 mg/month. The patient was advised therapeutic lifestyle changes in the form of strict diet control and exercise. He lost 8 kg of weight over the next 6 months and is doing well on follow up. A short Synacthen test with 250 lg Synacthen was carried out at 6 months, which showed an incremental cortisol response of 330 nmol/L at 1 h. Mediastinal lipomatosis is a benign condition that can occur either secondary to obesity and exogenous Cushing’s syndrome, or as a part of symmetrical lipomatosis and is a rare cause of mediastinal mass. Its usual appearance at CT is smooth widening of the upper anterior mediastinum without tracheal deformity. Associated increase in extrapleural fat is a helpful diagnostic feature. At CT the uniform density of fat (270 to 2130 Hounsfield units) is obvious. The importanceof identifying this condition is the fact that except for the radiological opacity, it is an ‘innocent bystander’ and is generally of no pathophysiological consequence to the patient. A condition that resembles mediastinal lipomatosis, but needs to be differentiated, is multiple symmetrical lipomatosis; however, in this condition, multiple masses of benign fat compress the mediastinal structures especially trachea.
24550143
Serologic allergic bronchopulmonary aspergillosis (ABPA-S): long-term outcomes.
BACKGROUND AND AIM
ABPA is radiologically classified on the presence or absence of central bronchiectasis (CB) as ABPA-CB and serologic ABPA (ABPA-S) respectively. Few studies have described the follow-up of patients with ABPA-S. The aim of this retrospective study was to describe the outcomes of ABPA-S.


METHODS
Patients were diagnosed as ABPA-S if they met all the following criteria: asthma, immediate cutaneous hyperreactivity to Aspergillus fumigatus antigen, total IgE levels >1000 IU/mL, A. fumigatus specific IgE levels >0.35 kUA/L and normal HRCT of the chest. They were treated with glucocorticoids and followed up with history, physical examination, chest radiograph and total IgE levels every 6 weeks to 3 months. In addition, an annual spirometry and a biennial HRCT chest were performed in all patients.


RESULTS
Of the 55 patients with ABPA-S, 41 (17 men, 24 women; mean age, 38.3 years) consented for performance of repeat HRCT scans. The median duration of asthma prior to diagnosis of ABPA was six years. The duration of follow-up ranged from 24 to 77 months with the mean (SD) follow-up duration being 43.7 (10.1) months. There was improvement in FEV(1) but not the FVC values during the follow-up period (p values = 0.001 and 0.5 for FEV(1) and FVC respectively). There was no development of CB in any patient. Sixteen patients had a relapse during the follow-up period, and six patients were classified as glucocorticoid-dependent ABPA.


CONCLUSIONS
Although relapses are frequently seen, the long-term outcome of ABPA-S is good with no patient developing CB.
11594402
Intraocular Pressure-Lowering Activity of Topical Application of Aegle Marmelos Fruit Extract in Experimental Animal Models
Aim: The present study was designed to evaluate the intraocular pressure (IOP)-lowering activity of topical application of the aqueous extract of Aegle marmelos fruit in experimental animal models. Materials and Methods: New Zealand white rabbits with normal and experimentally elevated IOP using water loading and steroid-induced models were included in this study. The IOP-lowering effect of A. marmelos fruit extract in rabbits with experimentally elevated IOP was also compared with that of timolol 0.25%. Results: In rabbits with normal IOP, the A. marmelos fruit extract at a concentration of 1% showed the maximum IOP-lowering effect with 22.81% reduction from baseline IOP. The maximum IOP reduction achieved in water loading and steroid-induced models with the same concentration of A. marmelos was 27.57 and 28.41% from baseline, respectively. The efficacy was comparable to that of timolol after 45 min of water loading in the water loading model, and during the first 2 h of treatment in the steroid-induced model. Conclusion: A. marmelos fruit extract showed significant IOP-lowering activity in experimental animal models.