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Chemoprevention of lung carcinogenesis is one approach to controlling the epidemic of lung cancer caused by cigarette smoking. The target for chemoprevention should be the activities of the multiple carcinogens, toxicants, co-carcinogens, tumor promoters and inflammatory compounds in cigarette smoke. There are presently many agents both synthetic and naturally occurring that prevent lung tumor development in well established animal models. It seems likely that logically constructed mixtures of these agents, developed from the ground up, will be necessary for prevention of lung carcinogenesis
Lung cancer kills more than 3000 people every day in the world and is its leading cause of cancer death. About 90% of this incredible toll is due to cigarette smoking. Clearly, we must continue our successful efforts in tobacco control which have resulted in a significant reduction in smoking prevalence in many countries. But there are still 1.3 billion smokers in the world and wealthy multinational tobacco companies continue to introduce cancer causing products designed to entice teenagers into a lifetime of nicotine addiction. While 70% of smokers attempt to quit each year, less than 5% succeed1, and the average success rates at six months post-quit, even with the most advanced smoking cessation programs, hover around 25%2.
In recent years, the rate of decrease in the prevalence of U.S. adult smoking has slowed significantly3 and remaining at about 20% from 2004 to 20074. This plateau has been observed even in some countries such as Ireland which has a significant tobacco control program (e.g., comprehensive smoke-free worksite policies, high cigarette prices and bans on tobacco advertising and promotion)5. This reduced rate of decline in smoking has been attributed to a plateau in smoking cessation success3, leading some researchers to believe that the remaining population of smokers is hardcore and are either unwilling or unable to quit6. An appreciable number of these smokers may be experiencing mental health disorders5.
The addicted smokers who fail as well as the ex-smokers who have succeeded in quitting are at high risk for lung cancer, and we must do something to help prevent this devastating disease with a 5 year survival rate of only 15%. Chemoprevention of lung carcinogenesis is one way forward. While the cardiovascular community has identified high risk individuals with biomarkers such as cholesterol and C reactive protein, and successfully treated them with preventive statins7, we in cancer research have yet to succeed in developing an effective lung carcinogenesis chemopreventive agent or strategy. The theme of this article is that a successful lung carcinogenesis chemopreventive agent will target tobacco smoke carcinogens and toxicants, the cause of lung cancer in smokers and ex-smokers, and that a successful strategy will integrate chemoprevention into the treatment portfolio of the addicted smoker as well as being available for the confirmed ex-smoker.
In chemoprevention, we aim to treat lung carcinogenesis, not lung cancer8. Lung carcinogenesis is barely in the vocabulary of the cancer research community, and certainly not in that of the lay community. The distinction is crucial. Lung cancer is the end result of lung carcinogenesis. Treatment of lung cancer is usually ineffective because a malignant tumor is discovered at a late stage. Treating lung carcinogenesis has the potential to prevent this disease.
How can we treat lung carcinogenesis? Since 90% of lung carcinogenesis is due to tobacco smoke exposure, our target must be the carcinogenic activity of tobacco smoke. In previous articles, we have presented a conceptual model for tobacco smoke-induced lung carcinogenesis9,10 (Box 1). This model indicates that, in our treatment of lung carcinogenesis, we would be wrong to focus on a single molecular pathway, because multiple pathways are altered. Others have come to similar conclusions11. We need to focus on the cause of the multiple aberrant biological pathways in lung carcinogenesis: the activities of tobacco smoke. Of course, removing tobacco smoke exposure is the ideal method for preventing lung carcinogenesis, but for reasons discussed above, this is only partially successful.
In this widely accepted model, people become addicted to nicotine in cigarette smoke, usually at a relatively young age when they experiment with cigarettes due to peer pressure and advertising. Nicotine is not a carcinogen, but each puff of each cigarette delivers a mixture of over 60 established carcinogens, along with toxicants, tumor promoters, co-carcinogens, oxidants, free radicals, and inflammatory agents. The carcinogens and their metabolites bind to DNA resulting in DNA adducts and subsequent somatic mutations. When these mutations occur in critical genes such as oncogenes and tumor suppressor genes, the result is loss of normal cellular growth control mechanisms, genomic instability, and cancer. A recent study validates this model. DNA sequencing of 623 cancer related genes revealed more than 1000 somatic mutations in 188 human lung adenocarcinomas, and 26 of these genes, including the tumor suppressor gene TP53 and the oncogene KRAS, were mutated at significantly high frequencies. Alterations were commonly observed in genes of the MAPK signaling, TP53 signaling, Wnt signaling, cell cycle and mTOR pathways144. The multiple mutations caused by tobacco smoke carcinogens are also consistent with the concept of field cancerization.
What are the activities of tobacco smoke that are critical in lung carcinogenesis? First and foremost are the lung carcinogens. Of the over 60 established carcinogens in cigarette smoke, there are at least 20 credible lung carcinogens9,10,12. These occur in both the gas phase and the particulate phase of tobacco smoke. The gas phase constituents include 1,3-butadiene, ethylene oxide, benzene, and aldehydes. The particulate phase constituents include polycyclic aromatic hydrocarbons (PAH), the best known of which is benzo[a]pyrene (BaP), and tobacco-specific nitrosamines such as the potent lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Consistent with the presence of these carcinogens, both the gas phase and the particulate phase of tobacco smoke can induce lung tumors in rodents upon exposure by inhalation13.
Second are the tumor promoters, co-carcinogens, and toxicants which have a variety of deleterious activities. Tumor promoters are not carcinogenic themselves, but enhance the activity of carcinogens when administered subsequently. The tumor promoting activities of tobacco smoke and its condensate have been clearly demonstrated by inhalation and mouse skin application studies14,15. These tumor promoters are only partially characterized, but extensive data indicate that they are found mainly in the weakly acidic fraction of tobacco smoke condensate16. Co-carcinogens are also not carcinogenic themselves, but enhance the activity of carcinogens when administered concurrently. Catechol, methyl catechols, and certain PAH are well established co-carcinogens in tobacco smoke, based on mouse skin studies15. One of the major toxicants in cigarette smoke, with a demonstrated relationship to lung carcinogenesis, is acrolein. While not strongly carcinogenic itself, acrolein is highly toxic to cilia of the lung, thus impeding clearance of tobacco smoke constituents17. Acrolein also reacts directly with DNA and protein to produce adducts with potentially important consequences18–20. Other toxicants in tobacco smoke include nitric oxide and poorly characterized free radicals, which may contribute to tumor promotion or co-carcinogenesis by causing oxidative damage.
Third are the inflammatory agents. A number of pro-inflammatory changes have been observed in smokers' lungs, and inflammation is closely associated with tumor promotion and activation of factors such as NFκB21–24. Inflammation has a role in COPD associated with smoking25, and COPD (especially emphysema) in turn is an independent risk factor for lung cancer26. The specific agents in cigarette smoke responsible for inflammation are poorly defined, but the potential roles of oxidants and reactive aldehydes such as acrolein have been discussed20,25. It is important to keep in mind that exposure to all agents in cigarette smoke is simultaneous, thus concepts such as tumor initiation and tumor promotion may be artificial, or even irrelevant.
It is apparent to us that a mixture of chemopreventive agents will be necessary to counteract these three complex activities. This mixture should be developed from the ground up, by first determining the efficacy of individual agents, and then assessing their chemopreventive activities when tested as a mixture. Wattenberg has classified chemopreventive agents into two broad groups: blocking agents which prevent the interaction of carcinogens with DNA, and suppressing agents which prevent post-carcinogen treatment downstream effects27. These definitions are still useful, and it is likely that an effective mixture would contain as a minimum an agent with each type of activity. Two crucial requirements for any chemopreventive agent or mixture are efficacy and lack of toxicity. One must demonstrate efficacy in an animal model, or preferably models, before chemopreventive agents should be seriously considered for use in people. Lack of toxicity is also critical, or clinical utility will be compromised.
In keeping with the theme of inhibiting the carcinogenic and toxic activities of tobacco smoke, the ideal animal model would use tobacco smoke itself as the carcinogen. Unfortunately, this is not so simple. Rodent models for inhalation of tobacco smoke pose many difficulties13 (Box 2). In spite of the limitations, one relatively practical model using strain A/J mice has been described by Witschi and co-workers28. A/J mice develop lung tumors with age. Lung tumor multiplicity is significantly and reproducibly increased by carcinogen treatment29,30. The cigarette smoke inhalation protocol leads to a reproducible increase in lung tumor multiplicity in these mice, and in some cases, lung tumor incidence28. However, the increase in lung tumor multiplicity, from about 0.5–1 lung tumors per mouse in controls to 1.1–2.8 lung tumors per mouse in the mice treated with cigarette smoke, although significant, is relatively small. This creates severe practical problems when using this model for chemoprevention studies. A number of chemoprevention experiments using relatively small groups of animals have been reported using this smoke inhalation assay, but most of the results were statistically insignificant, with the exception of a mixture of dexamethasone and myo-inositol28. Several other mouse strains have been used in experiments of similar design, but the tumorigenic response to cigarette smoke was generally quite weak31.
Rodents are obligatory nose breathers with complex nasal structures different from those in humans, leading to different deposition patterns in rodents versus humans. Rodents will not inhale tobacco smoke voluntarily the way humans do, but rather adopt shallow breathing patterns and avoidance reactions. The exposure systems that have been used are problematic. Nose only exposure systems require extensive handling while whole body exposure systems result in deposition of particles on the pelt and oral exposure through grooming. Exposure in these systems can cause stress and lack of weight gain. Lung tumors have been induced by cigarette smoke exposure in both rats and mice, but lengthy whole body exposures are required, and the experiments used highly specialized inhalation facilities which are not widely available145,146.
By far the most commonly employed model for evaluating chemopreventive agents is the carcinogen-treated A/J mouse. The tumors induced by carcinogens have morphologic, histogenic, and molecular features similar to human lung adenocarcinoma32. The susceptibility of the A/J mouse to lung tumor development has been attributed to the pulmonary adenoma susceptibility (Pas1) gene, which is tightly linked to the Kras2 oncogene33. Four carcinogens - BaP, NNK, ethyl carbamate (urethane), and vinyl carbamate – have been extensively used for tumor induction in chemoprevention experiments (Box 3). BaP and NNK are widely viewed as important lung carcinogens in cigarette smoke. Urethane is the classic carcinogen used for lung tumor induction in A/J mice34, while vinyl carbamate is its proximate carcinogenic metabolite. Urethane has been reported as a constituent of cigarette smoke, but only sporadically, while vinyl carbamate has not been analyzed in cigarette smoke or in smokers as a metabolite. The doses of pure carcinogens used in these studies are thousands of times higher than the amounts present in cigarette smoke.
BaP: A/J mice were maintained on a semi-synthetic diet and, at age 9 weeks, were treated with 2 mg (7.9 μmol) in cottonseed oil, by gavage 56. This was repeated 4 and 7 days after the initial dose. The study was terminated 21 weeks after the last dose, giving about 13 lung tumors per mouse. A disadvantage is the induction of forestomach tumors which become large after 21 weeks and may kill the animals before the scheduled termination.
NNK: A/J mice were maintained on a semi-synthetic diet and, at 7 weeks of age, were treated with a single dose of 2 mg (10 μmol) by intraperitoneal injection. The experiment was terminated 16 weeks later, producing 8 – 12 lung tumors per mouse, and. no forestomach tumors. Use of an "open formula" diet significantly decreases tumor multiplicity147,148. The lung tumors observed at 16 weeks are all adenomas; adenocarcinoma are observed 40–50 weeks after treatment149.
Urethane: 6 week old mice were given a single i.p. injection (1 mg, about 225 μmol) per gram body weight, in saline. About 30 – 50 lung adenomas per mouse were observed 15 weeks after injection. Lung adenocarcinoma appeared 32 weeks after injection77.
Vinyl carbamate: Mice (7–8 weeks old) were injected i.p. with two doses (0.32 mg, 3.6 μmol) in saline, one week apart. The mice were sacrificed 16 weeks later and had 16 lung tumors per mouse, all of which were described as invasive carcinoma90, although in another study the carcinoma yield was apparently much lower79.
In studies with these carcinogens, statistically meaningful results can be obtained with only 15 mice per group. This approach is highly practical for examining potential chemopreventive efficacy. The chemopreventive agent can be given during carcinogen treatment, after carcinogen treatment, or throughout the experiment to decipher its potential at different stages of the carcinogenic process. These assays are relatively rapid and inexpensive. A variation on the use of single carcinogens is the use of BaP and NNK, given in multiple doses35. The object of this design is to more closely approximate the effects of cigarette smoke by using a mixture of two of its important carcinogens, and also to allow intervention with chemopreventive agents at various points during carcinogen treatment to reflect to some extent the situation in smokers who are transitioning to quitting36. This aspect has been virtually completely overlooked in previous efficacy studies. A typical design is illustrated in Figure 1. Treatment with chemopreventive agents in the diet could begin one day after the 4th carcinogen treatment (or at other intervals if desired) to approximate the transitioning smoker, or one week after the last carcinogen treatment, to mimic the situation in ex-smokers37.
While the A/J mouse is a widely used and convenient model for the induction of adenocarcinoma and investigation of the effects of chemopreventive agents, a similar model for induction of squamous cell carcinoma became available only fairly recently. Lijinsky and Reuber reported that application of N-nitroso-tris-chloroethylurea (NTCU) to the skin of Swiss mice produced various tumors including squamous cell carcinoma of the lung38. Wang et al treated 8 inbred strains of mice with NTCU by skin painting and observed that squamous cell carcinoma of the lung were produced in a strain-specific manner, with A/J, NIH Swiss and SWR/J being the most susceptible (tumor incidence 75 – 100%)39. This model should be useful for investigating chemoprevention of squamous cell carcinoma of the lung. However, it should be noted that NTCU is a synthetic carcinogen that is not present in cigarette smoke.
Treatment of F-344 rats with NNK results in the production of lung adenoma and adenocarcinoma, and this model has been used for investigating chemopreventive agents, although less frequently than the A/J mouse40. The rat studies are more expensive than the mouse experiments because 2 years are required for the development of lung tumors. The F-344 rat is far less susceptible to lung tumor induction than the A/J mouse, and there is virtually no background incidence of lung tumors. The rat model is an attractive one for confirming lung chemoprevention activity observed in mice40. In another approach, the induction and modification by chemopreventive agents of preneoplastic lesions of the lung induced by intratracheal instillation of NNK in Wistar rats has been described41. A hamster model of neuroendocrine lung carcinogenesis involving hyperoxic lung injury and treatment with NNK has also been used, as has an adenocarcinoma model initiated by NNK treatment of hamsters without hyperoxia42.
Naturally occurring and synthetic agents that prevent lung carcinogenesis in laboratory animals are summarized in Tables 1 and and2,2, and structures of individual compounds are shown in Figure 2. Our purpose here is to present an overview of current effective agents without a detailed evaluation of efficacy and potential toxicity which is beyond the scope of this review. We focus on agents that have been the subject of relatively recent investigations, mainly in this century. Previous reviews have summarized data on earlier studies40,43,44. The diversity of chemical structures in Figure 2 reflects the multiple targets that have been investigated for chemoprevention of lung carcinogenesis. This is appropriate because cigarette smoke causes multiple alterations in critical growth control pathways. Ultimately, rationally constructed mixtures of some of these agents will undoubtedly be needed for successful chemoprevention.
Multiple studies carried out over the past three decades clearly demonstrate that isothiocyanates inhibit lung carcinogenesis in animal models45. PEITC and its metabolite PEITC-NAC have been investigated in the most detail and, among isothiocyanates, overall have the best properties consistent with chemoprevention of lung carcinogenesis36,45–48. PEITC and PEITC-NAC are particularly effective against carcinogenesis by NNK, as shown in studies in both rats and mice, but they are less effective against lung carcinogenesis by PAH, or in the post-carcinogen treatment period. Benzyl isothiocyanate (BITC) is a highly effective inhibitor of PAH carcinogenesis49. In smokers, and in those transitioning to quitting, PEITC or PEITC-NAC could potentially neutralize the lung carcinogenic effects of NNK, at least based on animal studies in which these agents inhibit the metabolic activation of NNK. PEITC is a strong inhibitor of cytochrome P450 2A13 (Ki 30 nM), the most effective catalyst of NNK metabolic activation in the human respiratory tract50. BITC has the potential to neutralize carcinogenesis by PAH. Thus, tobacco smoke carcinogens are targets of isothiocyanates, but these compounds also have some favorable downstream effects on pathways involved in apoptosis and proliferation of transformed cells51. Similar to PEITC, 8-methoxypsoralen is an inhibitor of P450 2A enzymes and an effective inhibitor of NNK induced mouse lung tumorigenesis52–54.
Wattenberg was the first to demonstrate that myo-inositol is an effective inhibitor of lung carcinogenesis by both NNK and BaP55,56. It inhibits lung carcinogenesis by a mixture of BaP plus NNK when given either during the carcinogen treatment period or afterwards, thus suggesting potential efficacy in smokers and ex-smokers57. There appear to be virtually no toxic effects associated with myo-inositol treatment, as recently confirmed in a Phase I clinical trial in which the maximum tolerated dose was 18 g per day58. Although the major mechanism(s) by which myo-inositol inhibits lung carcinogenesis are not clear, a recent study demonstrates that it inhibits activation of Akt37. Tobacco smoke carcinogens and their post-carcinogen treatment activities are targets of myo-inositol.
Many epidemiologic studies demonstrate that consumption of cruciferous vegetables is associated with lower lung cancer risk, and this effect appears to be particularly strong in people with GSTM1 and GSTT1 null genotypes, indicating a diet-gene interaction59. The unique property of cruciferous vegetables is the presence of glucosinolates which, upon consumption of the raw vegetable (or to a lesser extent, the cooked vegetable), yield isothiocyanates and indole-3-carbinol among other products60. The chemopreventive properties of isothiocyanates as noted above are consistent with these observations, but among the major products to which humans are exposed when they consume common cruciferous vegetables are indole-3-carbinol and its dimer, di-indolyl methane (DIM) which forms in the stomach due to the low pH60–62. Indole-3-carbinol and DIM are both effective inhibitors of lung carcinogenesis by BaP plus NNK, and the effects of indole-3-carbinol have been observed both in the carcinogen treatment and post-carcinogen treatment phases63–65. Indole-3-carbinol enhances the hepatic clearance of NNK, and decreases levels of some critical proteins such as hypoxia inducible factor 1α (HIF-1α) and fatty acid synthase (FAS) in mouse lung tumors66. While indole-3-carbinol appears to have multiple targets, specific inhibitors of FAS such as C75 have chemopreventive activity against mouse lung tumorigenesis67.
A large body of experimental data demonstrates that tea and its constituents inhibit lung carcinogenesis in laboratory animals68,69. Green tea, popular in Asia, contains 30–40% by weight catechins such as (−)-epigallocatechin-3-gallate (EGCG) and others, whereas black tea, more popular in Western nations, is processed in such a way as to release phenol oxidase, thus oxidizing the catechins to oligomers such as theaflavins and to polymers called thearubigins68,69. A standardized green tea polyphenol preparation called "Polyphenon E" has also been used for chemoprevention studies. In the NNK lung carcinogenesis model, and in other models, green tea, black tea, and their decaffeinated versions, as well as Polyphenon E significantly inhibited tumor development68,69. Inhibition has also been seen in models using a variety of other lung carcinogens including BaP68,69. Both black tea and Polyphenon E inhibited the progression of adenoma to adenocarcinoma in mice treated with NNK70, and Polyphenon E inhibited progression to large carcinoma in BaP-treated mice71. Multiple mechanisms have been reported for the inhibitory properties of tea and its constituents including induction of phase II enzymes, decreased oxidative damage, induction of apoptosis, inhibition of cell proliferation, and others68,69. Synergistic inhibition was observed with a combination of Polyphenon E and atorvastatin72. Another beverage which has shown chemopreventive activity against lung carcinogenesis is kava, a root extract consumed widely by South Pacific islanders. Kava inhibited lung tumorigenesis when given in the carcinogen treatment or post-carcinogen treatment phases73.
A Chinese herbal mixture called Antitumor B, also known as Zeng Sheng Ping, is comprised of six plants, and has a history of safety in clinical use. Antitumor B significantly decreased tumor multiplicity and tumor load in mice treated with BaP74. Ginseng is also a traditional medicine used in Asia. It had suppressing activity against lung tumor multiplicity in mice treated with BaP75. Pomegranate fruit extract is another plant-based agent with considerable inhibitory activity against lung tumorigenesis76.
Silibinin, a flavonone from milk thistle, is structurally related to tea polyphenols. It has been used as a dietary supplement to improve liver function and as an anti-hepatotoxic drug77. It apparently has very low toxicity. Silibinin added to the diet, at concentrations of 0.033 – 1%, of mice treated with urethane significantly decreased lung tumor incidence recorded 20 weeks later77. Silibinin treatment decreased proliferation markers and tumor microvessel density, as well as lung tumor expression of vascular endothelial growth factor, inducible nitric oxide synthase, and cyclooxygenase-2, all believed to be involved in inflammation and tumor progression77. Silibinin (0.05 – 0.1% in the diet) given prior to BaP had no effect on tumor multiplicity or tumor load78. Thus, tumor promotion and inflammation are targets of silibinin.
Dexamethasone and budesonide are glucocorticoids, which bind to and activate the cytosolic glucocorticoid receptor. Dexamethasone had been shown to inhibit the promotion stage of carcinogenesis in various models and was first applied in lung carcinogenesis studies by Wattenberg55. In further studies, it demonstrated good activity in various mouse models, and particularly in combination with myo-inositol56,79–81. This combination is the only one reported to successfully inhibit lung tumorigenesis in the tobacco smoke inhalation model described by Witschi81. Similarly, budesonide shows good activity in multiple mouse models82–85. A potentially important approach to chemoprevention uses inhaled budesonide, greatly decreasing the risk of systemic side effects, while maintaining excellent efficacy at low doses86. This approach was also successful when combined with dietary myo-inositol in mouse models86. Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase involved in tumor promotion, is also effective as a chemopreventive agent against squamous cell carcinoma when given by inhalation to hamsters87.
Oleanane and ursane triterpenoids are pentacyclic compounds derived biosynthetically from squalene. Sporn, Gribble and co-workers have targeted inflammation with diverse structural analogues which inhibit inducible nitric oxide synthase and cyclooxygenase-2, and are also phase II enzyme inducers88,89. CDDO-methyl ester as well as CDDO-ethyl amide are potent inhibitors of vinyl carbamate-induced mouse lung carcinogenesis in the post-carcinogen phase90. Rexinoids, selective ligands for the retinoid X receptors RXRα, RXRβ, and RXRγ, with anti-inflammatory activity, are also effective. Targretin and NRX194204 have shown activity in the post carcinogen phase91,92.
Rapamycin, a natural product isolated from Streptomyces hygroscopicus, is an inhibitor of mTOR (mammalian target of rapamycin), which is downstream from Akt and PI3K, a pathway commonly activated in lung carcinogenesis. Rapamycin decreased lung tumor load, but not tumor multiplicity, in a mouse anti-progression protocol in which BaP was the carcinogen75.
Inflammation has also been targeted by non-steroidal anti-inflammatory drugs (NSAIDS) such as sulindac. Cyclooxygenase (COX) enzymes play a key role in the synthesis of prostanoids involved in inflammation. COX-1 is constitutive while COX-2 is inducible. COX-2 is induced and becomes constitutively expressed as tumors progress. COX-2 expression is observed in human lung non-small cell lung cancer and expression of both forms has been observed in normal mouse lung and lung tumors22,93,94. Sulindac, its sulfone metabolite, and aspirin, as well as several other COX inhibitors, are effective chemopreventive agents in NNK treated mice95–99. However, the specific COX-2 inhibitor celecoxib, while reducing pulmonary inflammation, had no effect on lung tumor multiplicity in A/J mice99. Interest in COX-2 inhibitors has been affected by cardiovascular toxicity22. Lipoxygenase inhibitors, which inhibit the formation of leukotrienes involved in inflammation, have also been effective. A-79175 and MK-866 are examples which inhibit lung carcinogenesis100,101.
Human lung adenocarcinoma commonly have a mutated ras oncogene102. The ras proteins are GTPases involved in regulation of signal transduction pathways controlling proliferation and apoptosis. Ras proteins are typically farnesylated to become active, so farnesyltransferase inhibitors are natural targets for chemoprevention. Several farnesyltransferase inhibitors including R115777, FTI-276, and perillyl alcohol, have shown activity in BaP or NNK induced mouse lung tumor models103,104.
Organoselenium compounds have emerged as an interesting class of agents. 1,4-Phenylenebis(methylene)selenocyanate (XSC), a relatively non-toxic organoselenium compound, inhibits BaP plus NNK induced mouse lung tumorigenesis when given either during or after carcinogen administration, and has some favorable effects on phase I and phase II enzymes105,106. XSC reduced the expression of COX-2, NF-κB, and cyclin D1 in lung cells107. In contrast to XSC, selenium enriched yeast had no effect on NNK induced mouse lung tumorigenesis108. Another interesting class of organoselenium compounds is the selenazolidine carboxylic acids, prodrugs of selenocystine, which inhibit NNK induced lung tumorigenesis109,110.
Deguelin is an inhibitor of the PI3K/Akt pathway and decreases the expression of COX-2. It was an effective inhibitor of BaP plus NNK mouse lung tumorigenesis in both the carcinogen administration and post-carcinogen administration phases78,111. There is concern about potential toxic effects of deguelin, and structural variants are being examined112.
Inhibition of endogenous DNA hypermethylation, which can inhibit transcription of tumor suppressor genes, is another chemoprevention target. 5-Aza-2′-deoxycytidine (DAC) inhibits DNA methylation by reducing cytosine-DNA methyltransferase 1 activity. DAC inhibited NNK induced lung tumorigenesis in two different mouse models, and its effects were potentiated by the histone deacetylase inhibitor phenylbutyrate113,114.
Collectively, the data reviewed here demonstrate that effective agents exist targeting the main types of activities responsible for lung carcinogenesis: tobacco smoke carcinogens, their multiple associated and post-carcinogen proliferative activities (e.g., tumor promotion and co-carcinogenesis), and inflammation. Rationally constructed mixtures of selected agents should logically be effective in antagonizing lung carcinogenesis.
The solid efficacy and low toxicity of PEITC-NAC and myo-inositol, along with evidence that they have different targets in lung carcinogenesis, suggested that a combination of these agents might be useful for chemoprevention of lung carcinogenesis in smokers transitioning to quitting and in ex-smokers.
The first goal of this study was to test the agents alone in different temporal sequences that reflect to some extent the situation in a smoker transitioning to quitting. No smoker would begin using chemopreventive agents at the same time as initiating smoking, yet most of the experiments described in the previous section, in which agents were tested during or before the carcinogen administration phase, reflected that unlikely situation. Therefore, we tested PEITC-NAC and myo-inositol, individually and in combination, starting 24h after the 4th or 6th carcinogen administration (see Figure 1) and continued their administration until the end of the experiment, 19 weeks after the final carcinogen administration. The results were compared to those obtained when the compounds were given for the entire experiment, or only after carcinogen administration, the latter mimicking their use in ex-smokers. All treatments led to significant reductions in lung tumor multiplicity, except PEITC-NAC starting after the 6th carcinogen treatment, or given post-carcinogen. For both agents, there was a significant trend for increased reduction in lung tumor multiplicity with increased duration of treatment. Combinations of PEITC-NAC and myo-inositol were tested, using non-toxic doses at which the individual compounds significantly reduced lung tumor multiplicity. In general, the mixture of PEITC-NAC plus myo-inositol was more effective than either agent alone, and when all results were combined, the combination was significantly more effective, with the combined efficacy being roughly additive36.
These positive results set the stage for a more detailed investigation of the mixture of PEITC-NAC plus myo-inositol. Toxicity studies were carried out which established non-toxic doses of PEITC-NAC with the exception of the presence of eosinophilic granules in the bladder mucosa. The mixture of PEITC-NAC plus MI, when given from the 50% point of carcinogen administration until termination at 44 weeks, inhibited lung tumor multiplicity by 46 – 72% (depending on the dose), and by 32% when given in the post-carcinogen phase alone. All of these decreases were significant. There was also a significant reduction of up to 75% in adenocarcinoma formation by PEITC-NAC plus myo-inositol given from the 50% time point, and a significant 53% reduction when given post-carcinogen only. A photograph of typical mouse lungs from this study is shown in Figure 337. Parallel mechanistic studies demonstrated that the observed inhibition of lung tumorigenesis was attributable in part to inhibition of cell proliferation and induction of apoptosis. While NNK plus BaP treatment caused increased phosphorylation of Akt and BAD (resulting in loss of its proapoptotic function), these were inhibited by both PEITC-NAC and myo-inositol. Further, proteomic analysis demonstrated that PEITC-NAC plus myo-inositol altered levels of multiple critical proteins in lung tumors from these mice66. Collectively, these results demonstrate that the mixture of PEITC-NAC and myo-inositol is effective and can be advanced to the next stage of development.
There are presently no chemopreventive agents that have demonstrated efficacy against lung cancer in clinical trials. All trials to date have yielded negative or even damaging results, as reviewed previously22,44,115–120. While potential reasons for these negative results have been discussed extensively in previous reviews, one major explanation is a violation in some cases of rule number one: efficacy in laboratory animal models of lung carcinogenesis. In this section we summarize some current clinical trials which are based at least partially on the efficacy studies summarized in Table 1 and discussed above. These trials are described on the National Cancer Institute web site121. Trial designs for chemoprevention have also been reviewed122.
A phase II trial of PEITC is designed to determine, as the primary endpoint, whether PEITC has the same inhibitory properties on the metabolic activation of NNK in smokers as it does in rats, in a randomized, placebo controlled trial. As a secondary endpoint, the effects of GSTM1 plus GSTT1 null status on the inhibitory activity of PEITC will be determined. In an associated longer term study, the effects of PEITC on biomarkers of bronchial epithelial cell apoptosis and proliferation will be assessed. This trial finds further support from the results of two nested case control studies demonstrating a significant relationship of the NNK biomarker total NNAL to lung cancer123,124.
Lam and co-workers obtained some evidence for regression of pulmonary dysplasia in subjects enrolled in a Phase I trial of myo-inositol58. This observation, together with the multiple efficacy studies described above and the established low toxicity of myo-inositol, led to a Phase II study to compare myo-inositol vs. placebo in the reversion of bronchial dysplasia in current or former smokers, as the primary endpoint. Secondary endpoints include biomarkers of proliferation, apoptosis, and angiogenesis in bronchial biopsy samples and biomarkers of inflammation in bronchial lavage and plasma samples.
A Phase II study with green tea will examine the effects of high dose green tea (four 12 oz. servings per day) or Polyphenon E (4 capsules per day) on biomarkers of oxidative damage in former smokers with COPD, as the primary endpoint. Secondary endpoints include body antioxidant status and antioxidant enzymes, and markers of apoptosis and proliferation in induced sputum. A second Phase II study of Polyphenon E will examine efficacy and safety in current or former smokers with bronchial dysplasia and increased inflammatory load as measured by C-reactive protein. Secondary endpoints in this trial include biomarkers of oxidative stress, inflammation, apoptosis, aberrant methylation, phase I and II enzyme expression, and proliferation.
A phase II trial of sulindac will examine the effects of sulindac vs. placebo on histologic grade of bronchial dysplasia determined in bronchoscopy exams in smokers or former smokers with bronchial dysplasia. Secondary endpoints include determination of the number of dysplastic lesions before and after treatment, and changes in biomarkers of the arachidonic acid pathway, as well as biomarkers of apoptosis and proliferation.
It is notable that there are no ongoing trials of mixtures of chemopreventive agents. This contrasts with a major theme of this article. The principal that mixtures can be effective in chemoprevention clinical trials has recently been established in a study of sulindac and DFMO for chemoprevention of recurrence of colon adenomas, without serious toxicity125.
The primary concern over the use of a chemopreventive agent against lung carcinogenesis is that it may give smokers a false sense of security. They may feel that smoking is "safe" or is significantly "safer," which will result in their continuing to smoke, relapsing to smoking or even initiating smoking. However, providing treatments to those individuals who continue to practice behaviors that put them at high risk for disease is not uncommon. For example, statins or anithypertensives are not withheld from patients with poor eating habits and a sedentary lifestyle because the health care providers are concerned the use of these agents might contribute to the obesity epidemic. A similar analogy can be made with chemopreventive agents for smoking.
What is clear is that safeguards need to be in place so that smokers are not misled or have the misconception that using a chemopreventive agent is the solution and makes smoking safe. A chemopreventive agent may reduce the risk of one disease, such as lung cancer, however, there are other diseases that are associated with cigarette smoking including other cancers, heart disease and lung disease126. Therefore, smoking cessation must be the primary goal for and message to the patient. Although some researchers have advocated for the use of chemopreventive agents for only those who want to quit smoking, the rate of success is low and smokers often transition in and out of quitting127 and in and out of being motivated to quit128, making it difficult to determine who should and should not receive chemopreventive treatment if the prescription criterion is based only on whether or not the smoker is ready to quit. Therefore, we believe that smokers uninterested in quitting or unable to quit should be considered for chemopreventive therapy, although this approach has been barely recognized by those interested in tobacco harm reduction strategies129. In addition to smokers, based on the mechanism of action, successful quitters or former smokers potentially can benefit from chemopreventive agents.
According to the principles that are used to guide proposed public health interventions, it is critical that the intervention reduces rather than increases morbidity and mortality on a population level, that it results in no more harm than already exists, that the risks and benefits are distributed equitably across different populations (no population benefited at the expense of another), and that the autonomous choices of individuals and communities are respected130,131. These are the criteria by which chemopreventive therapies for tobacco-related diseases should be evaluated.
In spite of the lack of success in chemoprevention of lung carcinogenesis so far, there is reason to be optimistic. The data summarized here clearly demonstrate that there are multiple agents that are effective inhibitors of lung carcinogenesis in animal models, and these agents operate by diverse mechanisms. It is likely that success will depend on judicious use of a combination of these agents because cellular damage from years of cigarette smoking is both complex and extensive. Single agents that target single pathways or carcinogens are not likely to be successful. We need to target the multiple activities of cigarette smoke: its carcinogens and toxicants and their downstream, tumor promoting, and inflammatory effects. The successful mixture will be assembled stepwise and driven by efficacy testing in one or more of the animal models described here. This chemopreventive mixture will have minimal toxicity in animal models and humans, which might be achievable by using naturally occurring compounds in doses no greater than those present in common foods such as vegetables. All smokers should be considered for chemoprevention of lung carcinogenesis but with the strong message that no chemopreventive agent makes smoking safe. In addition, chemoprevention should be given in the context of providing smoking cessation advice and assistance. Ex-smokers should also benefit from chemoprevention. Although not discussed here, genetic, molecular and phenotypic biomarkers could be used to select those subjects at highest risk for lung cancer, and treatment should be promptly delivered to such individuals. While avoidance of tobacco products is the surest way to decrease lung cancer risk, chemoprevention promises to be a useful adjunct strategy.
Stephen S. Hecht
Stephen S. Hecht, Ph.D., is Wallin Professor of Cancer Prevention and head of the Carcinogenesis and Chemoprevention Program, Masonic Comprehensive Cancer Center, University of Minnesota. Hecht laboratory research focuses on identifying individuals susceptible to the cancer causing effects of tobacco. Tobacco carcinogen biomarkers are developed for integration into a predictive algorithm to identify susceptible smokers, who can then be targeted for preventive strategies. Naturally occurring chemopreventive agents against lung carcinogenesis are identified through efficacy and toxicity testing in relevant animal models. Mixtures of these agents are tested for efficacy and parallel studies are performed to elucidate their mechanisms of action.
Fekadu Kassie
Fekadu Kassie is a member of the Carcinogenesis and Chemoprevention Program at the Masonic Comprehensive Cancer Center of the University of Minnesota, and an Assistant Professor of Oncology and Comparative Medicine in the College of Veterinary Medicine, University of Minnesota. He received his DVM degree from Addis Ababa University, Ethiopia, and MSc and Ph.D. in Toxicology from the University of Vienna, Austria. In 2004, he joined the laboratory of Stephen S. Hecht as a research associate. He assumed his current position in 2008. His research interests are cancer chemoprevention and identification of cancer biomarkers.
Dorothy Hatsukami
Dorothy Hatsukami, Ph.D. is currently Forster Family Professor in Cancer Prevention and Professor of Psychiatry at the University of Minnesota, and Director of the Tobacco Use Research Center. She is Associate Director for Cancer Prevention and Control at the University of Minnesota Masonic Comprehensive Cancer Center. She is recognized for her work in the areas of nicotine addiction and its treatment (cigarettes and smokeless tobacco) in adult and adolescent smokers. She is currently a Principal Investigator of an NIH funded Transdisciplinary Tobacco Use Research Center (TTURC) which focuses on methods to reduce tobacco toxicant exposure and toxicity.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Thanks in advance for your thoughts on this.
quite to the contrary, Agile is about continuous attention to design. The only way to be successful while embracing change is to keep the design simple and adapt it to new circumstances. A good Agile devoper never stops thinking about design issues.
The soul is dyed the color of its thoughts. Think only on those things that are in line with your principles and can bear the light of day. The content of your character is your choice. Day by day, what you do is who you become. Your integrity is your destiny - it is the light that guides your way. - Heraclitus
I think I see a difference in what is intended and what happens in practice.
In practice, when a new project is started with Scrum, many teams seem to focus on quickly delivering functionality without spending sufficient time on "just enough" design. This may partly be because the team is trying to convince the customer or the client that Scrum works, and Agile is the way to go. The only thing that the customer understand is the functionality being delivered, hence this disproportionate emphasis on quickly reaching a high velocity.
I am really interested in hearing what Jeff and Tim have found in their practice too...
The future is here. It's just not evenly distributed yet. - William Gibson
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Ranch Hand
As usual, Ilja is dead on.
Your question is extremely important. I view the impact of very short iterations as potentially devastating--they can exacerbate and highlight whatever challenges you may have.
In agile, the customer is allowed to change focus as their needs and the needs of the marketplace change. This allows them to steer software so that it remains competitive. But that kind of change can create havoc on a code base, as developers try to shoe-horn in the new features week after week, particularly in trying to meet fast and continually-coming iteration deadlines.
It's concerns like this that Tim and I try to touch on throughout the cards. We don't think you'll be successful if you don't do what Ilja says, and continually pay attention to design. We cover practices such as TDD, pair programming, continual refactoring, and simple design, all of which are about trying to ensure the design is as clean as possible for the current set of features in the system. (We also relate these practices back to the underlying concern of design--it's possible to do things like TDD and pairing and not understand how they impact design quality.)
Scrum doesn't officially talk about these technical practices. The sensible Scrum proponents will say that you absolutely have to consider good software "engineering" practices in order to sustain system quality (and the ability to keep delivering at a consistent rate) over time.
One more way to look at this, and then it's time to hit the dentist. In our view, to be successful in agile, you must consider design at all times. We do enough design up front to provide a roadmap, but not low-level detail that we know will change as we learn and as things change. During every iteration/scrum planning session, we discuss design, sometimes explicitly and sometimes implicitly. We break stories into tasks, which requires some design considerations. As we code, we first write tests, which drives decoupled and cohesive designs (mostly because such a design is easier to test). Since we have TDD-created tests, we are afforded opportunities every few minutes to examine the small amount of changes we just made to the design. We refactor the code, looking at every possible design element we are aware of (including Kent Beck's four Simple Design rules, which are covered in the deck, and including other design heuristics and principles such as SOLID). Since we have the tests that tell us immediately if we messed up, if we just created deficiencies in the design, we fix it, instead of fearing making a change.
Books: Pragmatic Unit Testing in Java, Agile Java, Modern C++ Programming with TDD, Essential Java Style, Agile in a Flash. Contributor, Clean Code.
The enemy, as given, is the idea of adding features by slapping them on the outside of the system, perhaps with a flag and a few conditional statements. This is a very "junior maintenance programmer" way of working a system. Agile expects constant attention to design, and enables it, and expects that practitioners will not be doing slap-dash work. \
I can also recommend the Software Craftsmen groups for teaching clean practices, and Robert Martin's book Clean Code (to which Jeff and I were contributors).
He writes code. He likes it.
Here is a specific example, on which I was called by a "Certified Scrum Master". I noticed in a group of classes that some code was doing type-specific functionality in an if/else kind of structure, and observed that it was an opportunity to use the Template Method pattern to allow the subclasses to "do their thing". The overall structure was defined at the superclass level, and each subclass had the ability to perform one or more steps in the algorithm according to their type. It was, to me, a classic case of using a Design Pattern to clean up an obviously bad structure in the first place, and to provide a good basis for future changes...and I think of Design Patterns as kind of "tactical" design tools, as opposed to "strategic" design decisions. I estimated that it would take about an hour to code and maybe half that to test. Anyway, the Scrum Master made it very clear that we should not do anything that was not specifically called for as part of a deliverable, and that the definition of the deliverable was to be viewed as that of functionality, not (as he put it) "nice to haves".
So where does the concept of design changes that DON'T specifically change functionality fall in the agile spectrum? More than one person has told me that the "Certified Scrum Master" was just plain wrong in his judgment on this issue, but honestly I see his position as being right in line with the overall philosophy of agile. My position was simple: the original code was just bad, by almost anyone's measure. And yet it worked, if in a really nasty and hard-coded way. Again, my exposure and experience is quite limited, so please help me understand when and where non-functional design changes fits in Scrum or XP iterations.
Thanks all!
Tom Fulton wrote:
Here is a specific example, on which I was called by a "Certified Scrum Master". I noticed in a group of classes that some code was doing type-specific functionality in an if/else kind of structure, and observed that it was an opportunity to use the Template Method pattern to allow the subclasses to "do their thing". The overall structure was defined at the superclass level, and each subclass had the ability to perform one or more steps in the algorithm according to their type. It was, to me, a classic case of using a Design Pattern to clean up an obviously bad structure in the first place, and to provide a good basis for future changes...and I think of Design Patterns as kind of "tactical" design tools, as opposed to "strategic" design decisions. I estimated that it would take about an hour to code and maybe half that to test. Anyway, the Scrum Master made it very clear that we should not do anything that was not specifically called for as part of a deliverable, and that the definition of the deliverable was to be viewed as that of functionality, not (as he put it) "nice to haves".
I would have likely disagreed with your CSM given only what I see in this paragraph. In general, I think that getting code under control (wrapped in tests) and refactored is part of the red-green-refactor cycle, and that a pair partner who cares wouldn't have allowed changes to be added in a shallow way. I would expect the pairs who touched the code to have cleaned it up.
However, the value of a coach is partly that they are embedded in the culture and context of the team and can guide a team differently based on its immediate "team growth" needs. I am a little surprised that your CSM was presiding over your coding practices at that level, but I don't know where you are in your journey at this time.
Jeff and I have an article coming out this month in Pragmatic Bookshelf which will cover software volatility, which is a factor you should consider. Joshua Kerievsky talks about design that doesn't have to be great and generally he is referring to non-volatile modules having tolerable design flaws (not sloppy or untested code). If the volatility of your code is very low, you might be able to ignore the design debt until someone opens it up to modify it next time. If it is a high-volatility file, then I suggest you bring it back up. More on this is available in my agileotter blog posts on heatmap and explaining refactoring, and these might give you new ideas, at least until the next Pragmatic Bookshelf issue.
Tim Ottinger
He writes code. He likes it.
To me, good code is both functional and well-designed. And just as correctly functioning code requires overhead (implementation and thorough testing), design requires overhead. When you say "design debt", are you implying that all functionality incurs a debt (required overhead) that must be addressed by regular design changes or at least study? If so, I agree entirely, and am happy to hear that agile supports the principle.
Thanks again!
Tom Fulton wrote:Thanks for your reply, Tim. I have to ask what you mean by "design debt", however. The seems to be used in the sense of "the need to redesign/refactor", but how does the design debt become incurred? Or am I misunderstanding the term?
Technical Debt is technical work not yet done, and design debt is the same for design. The design of the code is not all that it should be, and you know it has to be changed eventually. This is like a loan, where someone has chosen to pay later for the opportunity to release something sub-optimal today. It is expected that it might cost more later (like interest) and that eventually the debt must be repaid. For instance, if more functionality is heaped on the class you mentioned without refactoring, it will become harder to clean up the design. Eventually, the code might become riddled with flags and conditionals to the point that any change is likely to result in breakage and unwanted side-effects. It will become expensive, indeed. Here is what we say on the blog about it: http://agileinaflash.blogspot.com/2009/02/technical-debt.html
But maybe it won't become difficult. Maybe this code will not be touched for years, meaning that there is no real pressure on cleanup. One time-honored approach is to mark it, and the next person who picks it up changes it. If nobody touches it, then it's probably okay as-is. This is why I mention volatility as a factor. If this file is constantly changing, then cleaning it now makes a lot more sense and is defensible. If it's in a backwater of the app, it might not make as much sense now. I would point you to the volatility article, but it's not published yet. As we mentioned in our card (http://agileinaflash.blogspot.com/2010/01/refactoring-inhibitors.html) technical debt can be so bad as to effectively prevent the refactoring "cure."
Please don't misunderstand me. The idea is not to "first burn the toast and then scrape it" -- that is wasteful of energy and time. Code should be written well all the time, hence the 'refactor' step in Red/Green/Refactor. The question is what you do when the code has already been written with a design defect that is not a functional defect. What is the basis? I would think that an hour or two is negligible and a good risk, because it's not a big investment and it is a reasonable bit of insurance. Your CSM may feel that a lot of time has been spent in reworking old code and that it has not shown its benefits yet in fluid delivery, or may feel that this code is not worth the time right now. You have to ask the reasons.
One final note: "Technical debt" was never intended to mean shoddy workmanship. It was intended to refer to releasing software speculatively to see what is really needed by customers. It would be like taking a loan now and then paying it off when you know enough to do so. Here is a video on the debt metaphor: http://www.youtube.com/watch?v=pqeJFYwnkjE
He writes code. He likes it.
Ranch Hand
This is a great topic to bring up. I don't frequently introduce quotes in order to project authority, but the 12 agile principles (hey--we have a card for that!) are pretty clear:
"Continuous attention to technical excellence and good design enhances agility."
"Agile processes promote sustainable development. The sponsors, developers, and users should be able to maintain a constant pace indefinitely."
Our experience: You can't keep a sustained, reasonable pace of development if you allow the design to progressively degrade. The interesting thing about "sprinting" is that it requires ridiculous expenditures of energy. If you run such a sprint, then immediately run another as fast as possible, and continue to do that, you'll simply collapse and die. I have many tales from personal experience (both watching the sick little race and being in it) that back this up--for example, systems that had to be discarded after 12-18 months total development because they could no longer accommodate changes easily or safely. Or a government entity that called after two months of doing TDD without refactoring, saying, "we have a code disaster on our hands."
In your case, I could also take the side of the CSM. Technically, you shouldn't be changing the system without some sort of story to drive that change. You will be spending a significant amount of time on something the customer cannot see or understand easily; going down that path will begin to eat away at the trust relationship between them and you. If your if/else logic is stable, and you have no need to add new logic into its midst, then the best bet is to leave it alone until a change in that area is required.
Don't ask for separate stories / tasks around refactoring--it just creates bad blood and also generates risk that may be deemed unacceptable. Better, try to find a way to incorporate it into an upcoming, relevant story. Address the fix incrementally if you cannot do it without using up inordinate amounts of time.
One of the reasons we like TDD is that the refactoring step provides us the ability to incrementally address design deficiencies. The lesson to take back is to never pass up the opportunity to take a look at the design impact and correct it if necessary. An if-else structure should have suggested the opportunity for introducing some form of polymorphism from the very first "else." Trivial and premature as it might have seemed at the time (to whoever was building it), it's almost never too soon to begin fixing the problem.
If you build clean-up into a simple, regular cycle like this, no one should ever notice or complain. I've tried to advance my "incrementalist thinking" over the years, and have found that taking yet smaller steps (i.e. in this case addressing impacts to design even sooner) is in most cases a better choice.
Books: Pragmatic Unit Testing in Java, Agile Java, Modern C++ Programming with TDD, Essential Java Style, Agile in a Flash. Contributor, Clean Code.
Ranch Hand
Turns out Tim and I wrote these last two messages at around the same time, so I didn't see his before replying. (And it looks like it took me 8 minutes longer to compose my message. Drat.)
Books: Pragmatic Unit Testing in Java, Agile Java, Modern C++ Programming with TDD, Essential Java Style, Agile in a Flash. Contributor, Clean Code.
He writes code. He likes it.
Incidentally, a couple of days ago Martin Fowler posted a nice entry that I think has much relevance for this topic - http://martinfowler.com/bliki/TradableQualityHypothesis.html.
The future is here. It's just not evenly distributed yet. - William Gibson
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subset: commoncrawl


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This press release was submitted by Right Now Marketing Group, LLC


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Tehnologii noi de exploatare a lemnului și necesitatea realizării parteneriatelor pentru exploatarea sustenabilă a lemnului
In the last period, the Romanian profile market is the subject of introducing new modern-concept timber harvesting machines. This represents a partial technological progress due the fact that despite their introducing in forest operations, the design, organizing and harvesting control activities are still empirically or not at all realized. This is a consequence of a lack of knowledge (available data) in such tasks on national level. In this context, the paper presents the new technologies in timber harvesting (available on the Romanian market) as well as the need (problems to be solved in the closer future) for a sustainable development in timber harvesting using these technologies.
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Volume (Year): 127 (2012)
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EAST ST. LOUIS – There were factors suggesting the Alton Redbirds' 65-62 Southwestern Conference boys basketball victory Friday night over the East St. Louis Flyers earned 'great win' status.
Alton coach Eric Smith brought it down a level.
"It was good," Smith said. "I think a lot of people kind of take the rivalry between us and East St. Louis and get pretty excited about it. They're good. If I'm not mistaken, I don't think they lost a game in the conference, all levels, last year."
The loss halted East Side's 19-game winning streak in the SWC. The Redbirds handed the Flyers their first league defeat since East Side fell Feb. 7, 2014 at Edwardsville. East Side last season became the first team to sweep the league at 14-0 since Edwardsville in 2005-06.
Alton, runner-up to the Flyers with a 12-2 SWC record last season, improves to 3-1 and 1-0 in the conference. East Side is 1-3 and 0-1 in the SWC.
The Flyers led by as many as 14 points (32-18) in the first half before settling for a 32-22 halftime lead. Kenny Roberson, a 6-foot-2 senior, went off in the second quarter for five 3-pointers without a miss and 17 of his 19 first-half points.
Alton opened the third quarter in a box-and-one defense to shadow Roberson and the move paid big dividends.
"It was something new so the guys got away from what we wanted to run," said Flyers first-year coach Phillip Gillbert, a former standout at East Side before a college career at Bradley. "We got stagnant with that. That shouldn't negate us from doing what we want to do. We've just got to regroup and concentrate on getting better."
With Roberson effectively taken out of the Flyers offense, the Redbirds rallied. Alton wiped out East Side's 36-23 lead with a 34-11 run over a 10-minute stretch.
"We've just been trying to beat it into our kids' heads that if we play unselfish and we play hard, we'll be fine," Smith said. "The first half, we struggled with that a little bit. Our kids, to their credit, they played together and that's when we went on our run."
Maurice Edwards scored 19 points, Kevin Caldwell had 16 and Marcus Latham finished with 14 for the Redbirds. Alton made 13 of 18 shots, including 6 of 7 3-pointers, in the second half.
Back-to-back treys from Caldwell, the second off a nice baseline drive and kick out from Kenneth Burnett, sparked the Redbirds' third-quarter surge. Latham added a 3-pointer and drove the lane before finding Edwards on the arc for a buzzer-beating 3 to draw the Redbirds even at 43-43 after three quarters.
Alton made its first seven shots in the fourth quarter, including five points from Tre Smith in the opening minute, and the Flyers had no answer. After making 6 of 10 3-pointers in the second quarter, East Side misfired on its first nine in the second half with Roberson getting nothing from the arc. The Flyers made three 3-pointers in the final minute to trime into an Alton lead that had grown as large as 11 points (62-51).
The victory was Alton's first at East Side since Feb. 8, 2011. The Flyers had won eight of the last nine matchups with the Redbirds.
"We've got to pick up the intensity, we've got to sustain runs, play the whole four quarters," Gilbert said. "You've got to play the whole four quarters. Our guys kind of got down on themselves late. They've got to fight and be resilient and play their game."
Greg Shashack may be reached at 618-798-1486 or on Twitter @gregshashack


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text: Goofy question here.... Thinking of clearing out the tennis locker again and moving a few redundant frames on the big site. (I know, I'll regret it and whine about it later:?) Where do all you sellers get racquet shipping boxes? I do not have access to a local pro shop to ask for freebees......so where does one go to acquire such an odd shaped box? I don't want to pay a lot for boxes and have to pass the cost on to a buyer....so looking for cheap here. Suggestions? (buying more racquets on da bay and saving the boxes isn't going to work this time)


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- Website: http://www.enyukeji.com
Published date: September 7, 2012 -
- Business Description: Wuhan Entai Technology Co., Ltd. is a research and development, production, marketing fine chemicals, pharmaceutical intermediates, organic intermediates, biochemical reagents of high tech company, own about 400 kinds of products can provide some more than a thousand kinds of products. The company Wuhan University, Wuhan Engineering University, backed by technical force and production of technical development and the company are all employees with a bachelor degree or above, its own R & D center, pilot base and production base, the company staffed by senior engineers or engineers with the title of senior technical staff and technicians, laboratory workers, and so formed a good echelon. The company has a relatively comprehensive analysis of its own equipment, such as high performance liquid chromatography, high performance gas chromatography.
Company's products are organic and pharmaceutical intermediates, fine intermediates, electroplating intermediates, asphalt modification agent for several major series, including electroplating intermediates and asphalt modifier to provide large volume industrial products, the other for small volume and pilot test the amount of product. Another company also commissioned to undertake custom synthesis and technical development.
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Steven Davis' sojourn on Los Angeles' skid row last year was brief but unusually fruitful. Davis, a 32-year-old schizophrenic, was dumped in front of the New Image Shelter last year by College Hospital in Costa Mesa, not long after being diagnosed as dangerously delusional and paranoid. He made his way eventually to California Hospital Medical Center, which tracked down his relatives in the area. The medical center then found a place for him in a "board and care" facility equipped to support the mentally ill. Davis' experience prompted a yearlong investigation by the city attorney's office, which culminated Wednesday in a court order that should deter hospitals from tossing others like him onto the streets. Just as important, the order could help hospitals manage the challenges that homeless patients with mental illnesses present.
The investigation uncovered evidence that vans dispatched by the College Hospital chain left as many as 150 mentally ill patients on skid row in the last two years. That kind of routine dumping has abated in the wake of crackdowns by the city attorney's office and the City Council. Yet there is widespread agreement that, when it comes to patients such as Davis, the safety net is badly ripped. In particular, there's no procedure for conveying mentally ill patients who are homeless, or whose families can't care for them, from the hospitals that provide emergency help to the residential facilities that supply the day-to-day support. The situation is exacerbated by the shortage of board-and-care beds.
As a result, hospitals in Los Angeles County often discharge such patients to the Salvation Army shelter in Bell, where they can get help for a few days before being released to fend for themselves.
It's unreasonable to expect hospitals to manage the long-term care of the mentally ill patients who land in their emergency rooms. Federal regulations require medical facilities to come up with a plan for follow-up care, but they don't order hospitals to make sure their discharged patients actually receive it. That's no excuse for dumping patients on the sidewalk in skid row. In addition to prohibiting College Hospital from dropping off homeless psychiatric patients in downtown Los Angeles, the court order gives the hospital's owners and the city attorney a year to come up with a protocol for discharging such patients that will "take advantage of all available public and private resources" for housing and services. The point is to provide "a continuum of care" by plugging the hospitals into a well-coordinated network of state mental-health services, supportive housing facilities and other sources of outpatient care. Such a system is overdue for hospitals and patients alike.


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Longest Night On December 22 Will Experience to PH! How and Why?
December 22, 2016 will mark another complete annual circuit of the Earth around the sun and the Philippine Atmospheric, Geophysical and Astronomical Services Administration (PAGASA) announced that the Philippines will be experiencing the longest night on this date. Furthermore, the sun will be at the farthest point south of the equator at exactly 6:44am.
This phenomenon is called the Winter's Solstice where nights are longer especially in areas that are far from the equator.
PAGASA specified that Basco, Batanes will have 13 hours and five minutes while Manila will have 12 hours and 46 minutes of night time. Cebu City will have a night which will last for 12 hours and 28 minutes and General Santos City night will last 12 hours and 14 minutes.


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An Interview with Mayor Eric Garcetti's Chief of Staff Ana Guerrero
In a city like Los Angeles, the nation's second most populous metropolitan, there are not enough hours in a day for one person, agency or city department to get all that needs to be done completed.
This city requires top talent to help it run smoothly. Enter Ana Guerrero, Mayor Eric Garcetti's choice to run his office as Chief of Staff.
Born in Guanajuato, Mexico, Guerrero's pathway to city hall was anything but a bee-line.
As a community organizer with the Sonoma County Faith Based Community Organizing Project, Guerrero honed her skills as a public servant while at the same time becoming familiar with job creation and affordable housing matters.
These attributes would later serve her as she made the move to Los Angeles in the mid-1990's to lead the United Neighborhoods Organizations (UNO) efforts helping immigrant populations become naturalized and politically active.
This drive to help underrepresented communities eventually led her to work with then Councilman Garcetti.
Today, Guerrero serves as the number two person in the City of Angels establishing a reputation for coalition-building amongst city departments, outside groups, including community based organizations, the private sector and city council offices.
"The Mayor's office is here to help provide the residents of Los Angeles with a livable, prosperous and safe community," said Guerrero. "My duties include working with the Mayor building consensus on issues important to the City, its residents and the business community."
One area in which Guerrero is helping to drive business growth and job creation forward is by eliminating the gross receipts tax and reducing the business tax. "We need to provide access to opportunity," added Guerrero. "This includes modernizing our city and embracing technology to connect and engage Angelinos."
Guerrero continues to aid the Mayor in his push to have city government do more, which includes bringing in new dynamic talent to City Hall, cultivating the next generation of leaders that accurately reflects and represents the City's diverse populations.


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The Lawrence Arts Center's Free State Festival is a week-long celebration of film, music, art, and ideas in the heart of Lawrence's Cultural District. Started as a small independent film festival in 2011 by the Lawrence Arts Center's Director of Film and New Media, Marlo Angell, the Free State Festival has become an interdisciplinary festival featuring an international slate of more than 10 feature films, 40 short films, outdoor concerts, stage performances, digital media installations, and provocative panel discussions. Last year's festival attracted approximately 12,000 audience members, and featured sold-out film screenings, lively discussions, and packed outdoor performances. Funded in part by a National Endowment for the Arts creative placemaking grant, the Free State Festival highlights diverse art and artists with the long-term goal of enhancing the socioeconomic wellbeing of the region and providing opportunities for artists of all disciplines and backgrounds.
The Free State Festival headquarters are located at the Lawrence Arts Center. The Free State Festival is an integral part of the Lawrence Arts Center's mission to enrich and invigorate the community by offering the best in contemporary exhibitions, performance, and visual and performing arts education. The Lawrence Arts Center hosts many of the festival's film screenings, discussions, installations, receptions, and performances in its beautiful 300 seat theatre, unique gallery spaces, intimate black box theater, and outdoor environs. Partnering organizations in Lawrence's .78 square-mile Cultural Arts District infuse the Festival with vibrancy, community spirit, and local color, and provide venue space for networking happy hours, outdoor projections, family activities, and supplementary music and film events.
Free State Festival Director and Ideas Programming email@example.com
Free State Festival Artistic Director of Film and email@example.com
Free State Festival Artistic Director of Art and email@example.com
Free State Festival Graphic Designer and Web email@example.com
Free State Festival Development Director and Logistics email@example.com